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1
Casteilla, Louis, Béatrice Cousin, and Mamen Carmona. "PPARs and Adipose Cell Plasticity." PPAR Research 2007 (2007): 1–7. http://dx.doi.org/10.1155/2007/68202.
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Due to the importance of fat tissues in both energy balance and in the associated disorders arising when such balance is not maintained, adipocyte differentiation has been extensively investigated in order to control and inhibit the enlargement of white adipose tissue. The ability of a cell to undergo adipocyte differentiation is one particular feature of all mesenchymal cells. Up until now, the peroxysome proliferator-activated receptor (PPAR) subtypes appear to be the keys and essential players capable of inducing and controlling adipocyte differentiation. In addition, it is now accepted that adipose cells present a broad plasticity that allows them to differentiate towards various mesodermal phenotypes. The role of PPARs in such plasticity is reviewed here, although no definite conclusion can yet be drawn. Many questions thus remain open concerning the definition of preadipocytes and the relative importance of PPARs in comparison to other master factors involved in the other mesodermal phenotypes.
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Olson, Lorin E., and Philippe Soriano. "PDGFRβ Signaling Regulates Mural Cell Plasticity and Inhibits Fat Development." Developmental Cell 20, no. 6 (June 2011): 815–26. http://dx.doi.org/10.1016/j.devcel.2011.04.019.
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Bielczyk-Maczynska, Ewa. "White Adipocyte Plasticity in Physiology and Disease." Cells 8, no. 12 (November 25, 2019): 1507. http://dx.doi.org/10.3390/cells8121507.
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Cellular plasticity is a transformation of a terminally differentiated cell into another cell type, which has been long known to occur in disease and regeneration. However, white adipocytes (fat cells) have only recently been observed to undergo different types of cellular plasticity. Adipocyte transdifferentiation into myofibroblasts and cancer-associated fibroblasts occurs in fibrosis and cancer, respectively. On the other hand, reversible adipocyte dedifferentiation into adipocyte progenitor cells (preadipocytes) has been demonstrated in mammary gland and in dermal adipose tissue. Here we discuss the research on adipocyte plasticity, including the experimental approaches that allowed to detect and study it, the current state of the knowledge, major research questions which remain to be addressed, and the advances required to stimulate adipocyte plasticity research. In the future, the knowledge of the molecular mechanisms of adipocyte plasticity can be utilized both to prevent adipocyte plasticity in disease and to stimulate it for use in regenerative medicine.
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MOULIN, Karine, Nathalie TRUEL, Mireille ANDRÉ, Emmanuelle ARNAULD, Maryse NIBBELINK, Béatrice COUSIN, Christian DANI, Luc PÉNICAUD, and Louis CASTEILLA. "Emergence during development of the white-adipocyte cell phenotype is independent of the brown-adipocyte cell phenotype." Biochemical Journal 356, no. 2 (May 24, 2001): 659–64. http://dx.doi.org/10.1042/bj3560659.
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In mammals, two types of adipose tissue are present, brown and white. They develop sequentially, as brown fat occurs during late gestation whereas white fat grows mainly after birth. However, both tissues have been shown to have great plasticity. Thus an apparent transformation of brown fat into white fat takes place during post-natal development. This observation raises questions about a possible conversion of brown into white adipocytes during development, although indirect data argue against this hypothesis. To investigate such questions in vivo, we generated two types of transgenic line. The first carried a transgene expressing Cre recombinase specifically in brown adipocytes under the control of the rat UCP1 promoter. The second corresponded to an inactive lacZ gene under the control of the human cytomegalovirus promoter. This dormant gene is inducible by Cre because it contains a Stop sequence between two loxP sequences, separating the promoter from the coding sequence. Adipose tissues of progeny derived by crossing independent lines established from both constructs were investigated. LacZ mRNA corresponding to the activated reporter gene was easily detected in brown fat and not typically in white fat, even by reverse transcriptase PCR experiments. These data represent the first direct experimental proof that, during normal development, most white adipocytes do not derive from brown adipocytes.
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Linehan, Victoria, Lisa Z. Fang, Matthew P. Parsons, and Michiru Hirasawa. "High-fat diet induces time-dependent synaptic plasticity of the lateral hypothalamus." Molecular Metabolism 36 (June 2020): 100977. http://dx.doi.org/10.1016/j.molmet.2020.100977.
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Herzog, Erica L., Li Chai, and Diane S. Krause. "Plasticity of marrow-derived stem cells." Blood 102, no. 10 (November 15, 2003): 3483–93. http://dx.doi.org/10.1182/blood-2003-05-1664.
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AbstractBone marrow (BM) contains hematopoietic stem cells (HSCs), which differentiate into every type of mature blood cell; endothelial cell progenitors; and marrow stromal cells, also called mesenchymal stem cells (MSCs), which can differentiate into mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent findings indicate that adult BM also contains cells that can differentiate into additional mature, nonhematopoietic cells of multiple tissues including epithelial cells of the liver, kidney, lung, skin, gastrointestinal (GI) tract, and myocytes of heart and skeletal muscle. Experimental results obtained in vitro and in vivo are the subject of this review. The emphasis is on how these experiments were performed and under what conditions differentiation from bone marrow to epithelial and neural cells occurs. Questions arise regarding whether tissue injury is necessary for this differentiation and the mechanisms by which it occurs. We also consider which bone marrow subpopulations are capable of this differentiation. Only after we have a better understanding of the mechanisms involved and of the cells required for this differentiation will we be able to fully harness adult stem cell plasticity for clinical purposes. (Blood. 2003; 102:3483-3493)
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De Fano, Michelatonio, Desirèe Bartolini, Cristina Tortoioli, Cristiana Vermigli, Massimo Malara, Francesco Galli, and Giuseppe Murdolo. "Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities." International Journal of Molecular Sciences 23, no. 10 (May 14, 2022): 5511. http://dx.doi.org/10.3390/ijms23105511.
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Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications.
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Rabhi, Nabil, and Stephen R. Farmer. "Unraveling the complexity of thermogenic remodeling of white fat reveals potential antiobesity therapies." Genes & Development 35, no. 21-22 (November 1, 2021): 1395–97. http://dx.doi.org/10.1101/gad.349053.121.
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Adipose tissue is a complex organ consisting of a mixture of mature adipocytes and stromal vascular cells. It displays a remarkable ability to adapt to environmental and dietary cues by changing its morphology and metabolic capacity. This plasticity is demonstrated by the emergence of interspersed thermogenic beige adipocytes within white depots in response to catecholamines secretion. Coordinated cellular interaction between different cell types within the tissue and a fine-tuned transcriptional program synergistically take place to promote beige remodeling. However, both cell–cell interactions and molecular mechanisms governing beige adipocyte appearance and maintenance are poorly understood. In this and the previous issue of Genes & Development, Shao and colleagues (pp. 1461–1474) and Shan and colleagues (pp. 1333–1338) advance our understanding of these issues and, in doing so, highlight potential therapeutic strategies to combat obesity-associated diseases.
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Petan, Toni, Eva Jarc, and Maida Jusović. "Lipid Droplets in Cancer: Guardians of Fat in a Stressful World." Molecules 23, no. 8 (August 3, 2018): 1941. http://dx.doi.org/10.3390/molecules23081941.
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Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress.
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Baragetti, Andrea, and Giuseppe Danilo Norata. "The High Fat Diet Impacts the Plasticity between Fresh and Aged Neutrophils." Journal of Cellular Immunology 5, no. 5 (2023): 168–73. http://dx.doi.org/10.33696/immunology.5.182.
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Metabolic alterations induced by unhealthy lifestyles, including obesity and insulin resistance are often associated with increased innate immune response and chronic inflammation. Cholesterol has been identified as a key metabolite driving the activation of the inflammasome and the “epigenetic memory” in long-term living hematopoietic stem cells. In addition to these mechanisms, the physiological aging of short-living neutrophils is a relevant modifier of their immune competency, as while they egress from medullary niches as “fresh”, fully competent, cells, they turn into “aged”, disarmed cells, when they extravasate into peripheral tissues to fight against pathogens or they reach the spleen for disposal. We recently observed that cardio-metabolic alterations induced by a lipid enriched unhealthy diet critically accelerate this process. Indeed, the chronic feeding with a high fat diet (HFD) results in the increase of aged neutrophils in the circulation and their accumulation in liver. This profile is associated with a deteriorated insulin response and obesity. The HFD primes aged, but not fresh neutrophils, to infiltrate in the liver and promotes inflammation coupled to altered cell immune architecture in visceral adipose tissue. Preventing the aging of neutrophils via selective ablation of CXCR2, reduces the development of obesity and improves the sensitivity to insulin. In humans, plasma levels of CXCL1, one of the cytokines binding CXCR2 and promoting neutrophil aging, are directly associated with abdominal adiposity and fatty liver independently of other risk factors. Together these findings point to a direct role of aged neutrophils in the development of metabolic disorders.
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Natale, Francesca, Matteo Spinelli, Saviana Antonella Barbati, Lucia Leone, Salvatore Fusco, and Claudio Grassi. "High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms." Cells 11, no. 17 (August 27, 2022): 2661. http://dx.doi.org/10.3390/cells11172661.
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Early-life metabolic stress has been demonstrated to affect brain development, persistently influence brain plasticity and to exert multigenerational effects on cognitive functions. However, the impact of an ancestor’s diet on the adult neurogenesis of their descendants has not yet been investigated. Here, we studied the effects of maternal high fat diet (HFD) on hippocampal adult neurogenesis and the proliferation of neural stem and progenitor cells (NSPCs) derived from the hippocampus of both the second and the third generations of progeny (F2HFD and F3HFD). Maternal HFD caused a multigenerational depletion of neurogenic niche in F2HFD and F3HFD mice. Moreover, NSPCs derived from HFD descendants showed altered expression of genes regulating stem cell proliferation and neurodifferentiation (i.e., Hes1, NeuroD1, Bdnf). Finally, ancestor HFD-related hyper-activation of both STAT3 and STAT5 induced enhancement of their binding on the regulatory sequences of Gfap gene and an epigenetic switch from permissive to repressive chromatin on the promoter of the NeuroD1 gene. Collectively, our data indicate that maternal HFD multigenerationally affects hippocampal adult neurogenesis via an epigenetic derangement of pro-neurogenic gene expression in NSPCs.
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Bräunig, P., W. G. Glanzner, V. B. Rissi, and P. B. D. Gonçalves. "The differentiation potential of adipose tissue-derived mesenchymal stem cells into cell lineage related to male germ cells." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 70, no. 1 (January 2018): 160–68. http://dx.doi.org/10.1590/1678-4162-9132.
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ABSTRACT The adipose tissue is a reliable source of Mesenchymal stem cells (MSCs) showing a higher plasticity and transdifferentiation potential into multilineage cells. In the present study, adipose tissue-derived mesenchymal stem cells (AT-MSCs) were isolated from mice omentum and epididymis fat depots. The AT-MSCs were initially compared based on stem cell surface markers and on the mesodermal trilineage differentiation potential. Additionally, AT-MSCs, from both sources, were cultured with differentiation media containing retinoic acid (RA) and/or testicular cell-conditioned medium (TCC). The AT-MSCs expressed mesenchymal surface markers and differentiated into adipogenic, chondrogenic and osteogenic lineages. Only omentum-derived AT-MSCs expressed one important gene marker related to male germ cell lineages, after the differentiation treatment with RA. These findings reaffirm the importance of adipose tissue as a source of multipotent stromal-stem cells, as well as, MSCs source regarding differentiation purpose.
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Shuo, Wang, Haicong Li, Nishijo Muneko, Nishino Yoshikazu, Nobuo Kato, Yuji Kasamaki, Tadashi Ueda, and Tsugiyasu Kanda. "Combination effects of a fatty diet and exercise on the depressive state and cardioprotection in apolipoprotein E knockout mice with a change in RCAN1 expression." Journal of International Medical Research 48, no. 11 (November 2020): 030006052096401. http://dx.doi.org/10.1177/0300060520964016.
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Objective Regulator of calcineurin 1 (RCAN1) controls plasticity of the nervous system and depressive conditions by regulating brain-derived neurotropic factor (BDNF) and plays a crucial role in neural and cardiac pathways. The apolipoprotein E gene ( ApoE) is a robust risk factor for progression of Alzheimer’s disease. A fatty diet is considered detrimental for metabolic disorders, such as obesity and cardiovascular diseases. Methods We examined the neuronal and cardiac protective roles of RCAN1 in ApoE−/− mice that were fed a high- or low-fat diet with and without voluntary movement for 3 months. Organ weights, laboratory data, histology, RNA expression, and behavior were examined. Results A high-fat diet with exercise improved depressive function, as examined by the forced swimming test, and RCAN1 mRNA expression was induced in the hippocampus. A low-fat diet with exercise resulted in a reduced body weight, higher heart weight/body weight ratio, and lower circulating triglyceride levels compared with a low-fat diet without exercise. RCAN1 mRNA expression was increased in cardiomyocytes in ApoE−/− mice. Conclusions The combination of a high-fat diet and exercise might reduce depressive function, whereas a low-fat diet with exercise leads to cardioprotection. Induction of RCAN1 expression might affect neuroplasticity and cardiac function.
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Rosell, Meritxell, Myrsini Kaforou, Andrea Frontini, Anthony Okolo, Yi-Wah Chan, Evanthia Nikolopoulou, Steven Millership, et al. "Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice." American Journal of Physiology-Endocrinology and Metabolism 306, no. 8 (April 15, 2014): E945—E964. http://dx.doi.org/10.1152/ajpendo.00473.2013.
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Brown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. We explored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by cold exposure. By comparing cold-induced genes in white fat to those enriched in brown compared with white fat, at thermoneutrality we defined a “brite” transcription signature. We identified the genes, pathways, and promoter regulatory motifs associated with “browning,” as these represent novel targets for understanding this process. For example, neuregulin 4 was more highly expressed in brown adipose tissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neurite outgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in response to cold. A cell culture system that allows us to reproduce the differential properties of the discrete adipose depots was developed to study depot-specific differences at an in vitro level. The key transcriptional events underpinning white adipose tissue to brown transition are important, as they represent an attractive proposition to overcome the detrimental effects associated with metabolic disorders, including obesity and type 2 diabetes.
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Rusli, Fenni, Mark V. Boekschoten, Vincenzo Borelli, Chen Sun, Carolien Lute, Aswin L. Menke, Joost van den Heuvel, et al. "Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age." Aging Cell 17, no. 2 (December 21, 2017): e12696. http://dx.doi.org/10.1111/acel.12696.
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Shatova, Olga P., Anastasia A. Zabolotneva, Mikhail B. Potievskiy, Aleksandr V. Shestopalov, and Sergei A. Roumiantsev. "Milestones in Molecular Mechanisms of Adipogenesis and Adipose Tissue Plasticity." International Journal of Biomedicine 11, no. 3 (September 9, 2021): 323–32. http://dx.doi.org/10.21103/article11(3)_ra3.
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This review focuses on the problem of adipogenesis mechanisms and the biological role of adipose tissue (AT) in the human body. Over the past decades, various types of adipocytes have been identified and characterized—white, brown, beige, yellow, and pink. An important feature of AT is a high plasticity and the ability to transdifferentiate and de-differentiate into another cell type. In this case, the pathway of transformation mostly depends on adipocytes’ cellular and metabolic microenvironment. The mechanisms of adipogenesis and the ways of its regulation remain not fully understood. The principal role in the terminal differentiation of preadipocytes is assigned to PPARγ and receptors activated by bone morphogenetic proteins, insulin, and cortisol. However, in chronic inflammation, adipogenesis is suppressed and old adipocytes increase the production of proinflammatory cytokines, which leads to the death of inflamed cells and hypertrophy of neighboring adipocytes. Thus, disruption of adipogenesis, premature aging of white adipocytes, perturbations in the metabolic and cellular microenvironment of preadipocytes, and early apoptosis of fat cells cause the development of insulin resistance and metabolically unhealthy obesity.
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Tchkonia, Tamara, Yourka D. Tchoukalova, Nino Giorgadze, Tamar Pirtskhalava, Iordanes Karagiannides, R. Armour Forse, Ada Koo, et al. "Abundance of two human preadipocyte subtypes with distinct capacities for replication, adipogenesis, and apoptosis varies among fat depots." American Journal of Physiology-Endocrinology and Metabolism 288, no. 1 (January 2005): E267—E277. http://dx.doi.org/10.1152/ajpendo.00265.2004.
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Fat depots vary in function and size. The preadipocytes that fat cells develop from exhibit distinct regional characteristics that persist in culture. Human abdominal subcutaneous cultured preadipocytes undergo more extensive lipid accumulation, higher adipogenic transcription factor expression, and less TNF-α-induced apoptosis than omental preadipocytes. We found higher replicative potential in subcutaneous and mesenteric than in omental preadipocytes. In studies of colonies arising from single preadipocytes, two preadipocyte subtypes were found, one capable of more extensive replication, differentiation, and adipogenic transcription factor expression and less apoptosis in response to TNF-α than the other. The former was more abundant in subcutaneous and mesenteric than in omental preadipocyte populations, potentially contributing to regional variation in replication, differentiation, and apoptosis. Both subtypes were found in strains derived from single human preadipocytes stably expressing telomerase, confirming that both subtypes are of preadipocyte lineage. After subcloning of cells of either subtype, both subtypes were found, indicating that switching can occur between subtypes. Thus proportions of preadipocyte subtypes with distinct cell-dynamic properties vary among depots, potentially permitting tissue plasticity through subtype selection during development. Furthermore, mesenteric preadipocyte cell-dynamic characteristics are distinct from omental cells, indicating that visceral fat depots are not functionally uniform.
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Spinelli, Matteo, Francesca Natale, Marco Rinaudo, Lucia Leone, Daniele Mezzogori, Salvatore Fusco, and Claudio Grassi. "Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 8994. http://dx.doi.org/10.3390/ijms21238994.
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Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity-related genes and the activation of cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)-derived exosomes (exo-NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo-NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD-related memory impairment and provide evidence of the potential therapeutic effect of exo-NSC against metabolic disease-related cognitive decline.
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Giordano, Antonio, Arianna Smorlesi, Andrea Frontini, Giorgio Barbatelli, and Saverio Cinti. "MECHANISMS IN ENDOCRINOLOGY: White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ." European Journal of Endocrinology 170, no. 5 (May 2014): R159—R171. http://dx.doi.org/10.1530/eje-13-0945.
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In mammals, adipocytes are lipid-laden cells making up the parenchyma of the multi-depot adipose organ. White adipocytes store lipids for release as free fatty acids during fasting periods; brown adipocytes burn glucose and lipids to maintain thermal homeostasis. A third type of adipocyte, the pink adipocyte, has recently been characterised in mouse subcutaneous fat depots during pregnancy and lactation. Pink adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Emerging evidence suggests that they derive from the transdifferentiation of subcutaneous white adipocytes. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity. Cold exposure induces an increase in the ‘brown’ component of the organ to meet the increased thermal demand; in states of positive energy balance, the ‘white’ component expands to store excess nutrients; finally, the ‘pink’ component develops in subcutaneous depots during pregnancy to ensure litter feeding. At the cell level, plasticity is provided not only by stem cell proliferation and differentiation but also, distinctively, by direct transdifferentiation of fully differentiated adipocytes by the stimuli that induce genetic expression reprogramming and through it a change in phenotype and, consequently function. A greater understanding of adipocyte transdifferentiation mechanisms would have the potential to shed light on their biology as well as inspire novel therapeutic strategies against metabolic syndrome (browning) and breast cancer (pinking).
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Yu, I.-Chen Ivorine, Hallel C. Paraiso, Ping-Chang Kuo, Barbara A. Scofield, Fen-Lei Chang, and Jui-Hung Yen. "Single-cell transcriptome analysis reveals CNS innate immune landscape plasticity in diet-induced obesity and type 2 diabetes." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 111.11. http://dx.doi.org/10.4049/jimmunol.206.supp.111.11.
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Abstract Midlife obesity and type 2 diabetes are strong risk factors for late-life cognitive impairment and dementia. Previous studies show that obesity is associated with a heightened state of neuroinflammation, indicating that systemic factors profoundly influence brain innate immunity. Here, we reported that the diversity and plasticity of brain myeloid cells are reshaped in middle-aged mice fed with a high-fat diet (HFD). Using single-cell RNA sequencing, we revealed the heterogeneity of brain-resident myeloid cells, including microglia (MG, Tmem119/P2ry12/Hexb) and border-associated macrophages (BAMs, Mrc1/Ms4a7/Pf4). MG from HFD-fed mice exhibited changes of genes involved in oxidative phosphorylation and lipoprotein metabolism, suggesting a modulated cellular metabolism in MG responding to HFD. A subset of MG displayed induced disease-associated MG (DAM) gene signature during HFD feeding. We found that Apoe was predominantly expressed in BAM clusters and up-regulated in HFD-fed MG clusters. Several distinct subsets of BAMs enriched in MHC-II (H2-Eb1, H2-Aa, and Cd74), or leukocyte adhesion and migration (Clec4n, Ccl7, Vcam1) genes, displayed the increased cell proportion in HFD-fed mice. In addition, HFD feeding led to the IL-10 downregulation in MHC-II-expressing BAMs. These data suggested that pro-inflammatory BAMs might incorporate T cell immunity to potentiate cerebrovascular inflammation during chronic HFD consumption. Overall, our results highlighted the heterogeneity and plasticity of the brain myeloid cells in middle-aged obesity. The identified BAM subsets provide insights into crosstalk between CNS innate immune cells and T cells to feature neuroinflammation in obesity-associated cognitive decline.
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Cousin, B., S. Cinti, M. Morroni, S. Raimbault, D. Ricquier, L. Penicaud, and L. Casteilla. "Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization." Journal of Cell Science 103, no. 4 (December 1, 1992): 931–42. http://dx.doi.org/10.1242/jcs.103.4.931.
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Brown adipocytes are thermogenic cells which play an important role in energy balance. Their thermogenic activity is due to the presence of a mitochondrial uncoupling protein (UCP). Until recently, it was admitted that in rodents brown adipocytes were mainly located in classical brown adipose tissue (BAT). In the present study, we have investigated the presence of UCP protein or mRNA in white adipose tissue (WAT) of rats. Using polymerase chain reaction or Northern blot hybridization, UCP mRNA was detected in mesenteric, epidydimal, retroperitoneal, inguinal and particularly in periovarian adipose depots. The uncoupling protein was detected by Western blotting in mitochondria from periovarian adipose tissue. When rats were submitted to cold or to treatment with a beta-adrenoceptor agonist, UCP expression was increased in this tissue as in typical brown fat. Moreover, the expression was decreased in obese fa/fa rats compared to lean controls. Morphological studies showed that periovarian adipose tissue of rats kept at 24 degrees C contained cells with numerous typical BAT mitochondria with or without multilocular lipid droplets. Immunocytochemistry confirmed that multilocular cells expressed mitochondrial UCP. Furthermore, the number of brown adipocytes and the density of mitochondrial cristae increased in parallel with exposure to cold. These results demonstrate that adipocytes expressing UCP are present in adipose deposits considered as white fat. They suggest the existence of a continuum in rodents between BAT and WAT, and a great plasticity between adipose tissue phenotypes. The physiological importance of brown adipocytes in WAT and the regulation of UCP expression remain open questions.
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Lee, Carlin, Meng Yao Liu, C. Benjamin Ma, Xuhui Liu, and Brian Feeley. "Inducible endogenous stem cells within human rotator cuff muscle to promote muscle regeneration after rotator cuff repair." Orthopaedic Journal of Sports Medicine 8, no. 7_suppl6 (July 1, 2020): 2325967120S0033. http://dx.doi.org/10.1177/2325967120s00332.
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Objectives: Rotator cuff (RC) tears are the most common upper extremity injury, with over two million Americans seeking medical attention annually. Secondary muscle degradation following RC tears, including atrophy and fatty infiltration (FI), are critical factors that directly determine the clinical outcome of patients with this injury In mouse studies, the importance of fibro/adipogenic (FAP) cells in the development of FI after RC tears has been shown, determining that these cells are the predominant cell line responsible for the development of FI. FAP cells have garnered considerable interest in mediating both positive and negative effects on muscle cells. In regenerative conditions, FAPs stimulate satellite cell (SC) growth and differentiation, but in degenerative states, these cells differentiate into fat and fibrotic tissue. Additionally, FAPs have the ability to express factors consistent with beige fat, which may have important regenerative potential. In this study, we harvested samples from supraspinatus muscle in patients undergoing RC repair to determine for 1) the presence of FAP cells; 2) the presence of satellite cells; and 3) the ability of FAPs to differentiate into fat and/or fibrotic tissue. We hypothesized that both FAPs and SC would increase, and FAPs would display considerable cell plasticity and have the ability to differentiate into beige fat, adipocytes, and fibroblasts. Methods: The study was approved by the institutional IRB. At the time of surgery, a 3mm × 3 mm Supraspinatus (SS) and Deltoid (DL) biopsy was collected during surgery from 20 different clinical cases (Average age was 65 years, with 15 men and 5 women). Half of the biopsy was used for histology and half for Flow cytometry. For the vitro analysis, FAPs were isolated from human specimens using BD Aria II with PI live and Dead staining, and further isolated using CD31-, CD45-, CD184-, CD29-. CD56-, CD34+, CD140a + markers. SCs were sorted with PI live and dead staining, and further isolated using CD31-, CD45-, CD184+, CD29-, CD56+, CD34-, CD140a + markers. FAPs were cultured in 24 wells cell culture plates in standard media (F10+20%FBS+1% Antibiotics), Fibrogenic media (10ng/ml TGFβ-1) and Adipogenic media (stempro kit) for 2 weeks. For the Amibegron treatment group, FAPs were cultured in adipogenic media for 2 weeks first and switch to Adipogenic media with 10uM Amibegron (Sigma). FAPs were fixed with 4% PFA and stained with collagen I for quantify fibrosis index and perilipin A for Adipogenic index. The Paired ANOVA was used for statistical comparisons between groups, with p<0.05. Data are presented as mean +/- standard deviation. Results: A total of 20 patients were included in the study with different tear sizes. While SC number did not increase when comparing tear sizes, FAP cell number increased with increasing tear sizes. Patients with RC tears all had significantly more FAPs (7.8+/-2% vs 1.3 +/- .4%, p<0.05) compared to patients with partial tears. When divided by tear size, patients with medium and large tears had more FAPs compared to partial and small tears, a difference that was statistically significant. Histological analysis demonstrated that muscle architecture was preserved, but those with full thickness tears had more fat and fibrosis, with increased FAPs (Stained Red, Figure 2). FAPs from patients with full thickness tears had increased ability to differentiate into adipocytes and fibroblasts compared to partial tears (Figure 3), and had increased expression of UCP-1 (P<0.05). FAPs that were isolated from full thickness tears demonstrated increased expression of several promyogenic factors including IGF-1 and follistatin. Conclusions: Patients with full thickness RC tears have increased FAPs compared to control muscle and partial tears. FAPs from full thickness tears increase with tear size and have more differentiation potential compared. This data confirms that these cells are likely the cellular source for FI in humans, but that they also may serve a regenerative potential as they show differentiation plasticity and expression markers consistent with a beige fat phenotype. The fact that FAPS are able to differentiate and express pro-myogenic factors such as IGF-1 and follistatin suggest that they may serve as an endogenous stem cell source for improving muscle quality after RC repair.
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Song, Tongxing, and Shihuan Kuang. "Adipocyte dedifferentiation in health and diseases." Clinical Science 133, no. 20 (October 2019): 2107–19. http://dx.doi.org/10.1042/cs20190128.
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Abstract Adipose tissues collectively as an endocrine organ and energy storage are crucial for systemic metabolic homeostasis. The major cell type in the adipose tissue, the adipocytes or fat cells, are remarkably plastic and can increase or decrease their size and number to adapt to changes in systemic or local metabolism. Changes in adipocyte size occur through hypertrophy or atrophy, and changes in cell numbers mainly involve de novo generation of new cells or death of existing cells. Recently, dedifferentiation, whereby a mature adipocyte is reverted to an undifferentiated progenitor-like status, has been reported as a mechanism underlying adipocyte plasticity. Dedifferentiation of mature adipocytes has been observed under both physiological and pathological conditions. This review covers several aspects of adipocyte dedifferentiation, its relevance to adipose tissue function, molecular pathways that drive dedifferentiation, and the potential of therapeutic targeting adipocyte dedifferentiation in human health and metabolic diseases.
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Shi, Yunpeng, Chengrui Nan, Zhongjie Yan, Liqiang Liu, Jingjing Zhou, Zongmao Zhao, and Depei Li. "Synaptic Plasticity of Human Umbilical Cord Mesenchymal Stem Cell Differentiating into Neuron-like Cells In Vitro Induced by Edaravone." Stem Cells International 2018 (October 28, 2018): 1–11. http://dx.doi.org/10.1155/2018/5304279.
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Objective. The human umbilical cord mesenchymal stem cells (hUMSCs) are characterized with the potential ability to differentiate to several types of cells. Edaravone has been demonstrated to prevent the hUMSCs from the oxidative damage, especially its ability in antioxidative stress. We hypothesized that Edaravone induces the hUMSCs into the neuron-like cells. Methods. The hUMSCs were obtained from the human umbilical cord tissue. The differentiation of hUMSCs was induced by Edaravone with three different doses: 0.65 mg/ml, 1.31 mg/ml, and 2.62 mg/ml. Flow cytometry was used to detect the cell markers. Protein and mRNA levels of nestin, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) were detected by Western blot and RT-PCR. The expression of synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95) was detected by Real-Time PCR. Results. As long as the prolongation of the culture, the hUMSCs displayed with the long strips or long fusiform to fat and then characterized with the radial helix growth. By using flow cytometry, the cultured hUMSCs at the 3rd, 5th, and 10th passages were expressed with CD73, CD90, and CD105 but not CD11b, CD19, CD34, CD45, and HLA-DR. Most of the hUMSCs cultured with Edaravone exhibited typical nerve-immediately characters including the cell body contraction, increased refraction, and protruding one or more elongated protrusions, which were not found in the control group without addition of Edaravone. NSE, nestin, and GFAP were positive in these neuron-like cells. Edaravone dose-dependently increased expression levels of NSE, nestin, and GFAP. After replacement of maintenance fluid, neuron-like cells continued to be cultured for five days. These neuron-like cells were positive for SYN, PSD95, and GAP43. Conclusion. Edaravone can dose-dependently induce hUMSCs to differentiate into neuron-like cells that expressed the neuronal markers including NSE, nestin, and GFAP and synaptic makers such as SYN, PSD95, and GAP43.
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Romo-Araiza, Alejandra, Rocío I. Picazo-Aguilar, Ernesto Griego, Luis A. Márquez, Emilio J. Galván, Yolanda Cruz, Ana María Fernández-Presas, et al. "Symbiotic Supplementation (E. faecium and Agave Inulin) Improves Spatial Memory and Increases Plasticity in the Hippocampus of Obese Rats: A Proof-of-Concept Study." Cell Transplantation 32 (January 2023): 096368972311773. http://dx.doi.org/10.1177/09636897231177357.
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Obesity has been linked to cognitive impairment through systemic low-grade inflammation. High fat and sugar diets (HFSDs) also induce systemic inflammation, either by induced Toll-like receptor 4 response, or by causing dysbiosis. This study aimed to evaluate the effect of symbiotics supplementation on spatial and working memory, butyrate concentration, neurogenesis, and electrophysiological recovery of HFSD-fed rats. In a first experiment, Sprague-Dawley male rats were given HFSD for 10 weeks, after which they were randomized into 2 groups ( n = 10 per group): water (control), or Enterococcus faecium + inulin (symbiotic) administration, for 5 weeks. In the fifth week, spatial and working memory was analyzed through the Morris Water Maze (MWM) and Eight-Arm Radial Maze (RAM) tests, respectively, with 1 week apart between tests. At the end of the study, butyrate levels from feces and neurogenesis at hippocampus were determined. In a second experiment with similar characteristics, the hippocampus was extracted to perform electrophysiological studies. Symbiotic-supplemented rats showed a significantly better memory, butyrate concentrations, and neurogenesis. This group also presented an increased firing frequency in hippocampal neurons [and a larger N-methyl-d-aspartate (NMDA)/α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) current ratio] suggesting an increase in NMDA receptors, which in turn is associated with an enhancement in long-term potentiation and synaptic plasticity. Therefore, our results suggest that symbiotics could restore obesity-related memory impairment and promote synaptic plasticity.
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Comstock, Sarah M., Lynley D. Pound, Jacalyn M. Bishop, Diana L. Takahashi, Ashley M. Kostrba, M. Susan Smith, and Kevin L. Grove. "High-fat diet consumption during pregnancy and the early post-natal period leads to decreased α cell plasticity in the nonhuman primate." Molecular Metabolism 2, no. 1 (February 2013): 10–22. http://dx.doi.org/10.1016/j.molmet.2012.11.001.
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Deugnier, Marie-Ange, Marisa M. Faraldo, Bassam Janji, Patricia Rousselle, Jean Paul Thiery, and Marina A. Glukhova. "EGF controls the in vivo developmental potential of a mammary epithelial cell line possessing progenitor properties." Journal of Cell Biology 159, no. 3 (November 11, 2002): 453–63. http://dx.doi.org/10.1083/jcb.200207138.
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The bilayered mammary epithelium comprises a luminal layer of secretory cells and a basal layer of myoepithelial cells. Numerous data suggest the existence of self-renewing, pluripotent mammary stem cells; however, their molecular characteristics and differentiation pathways are largely unknown. BC44 mammary epithelial cells in culture, display phenotypic characteristics of basal epithelium, i.e., express basal cytokeratins 5 and 14 and P-cadherin, but no smooth muscle markers. In vivo, after injection into the cleared mammary fat pad, these cells gave rise to bilayered, hollow, alveolus-like structures comprising basal cells expressing cytokeratin 5 and luminal cells positive for cytokeratin 8 and secreting β-casein in a polarized manner into the lumen. The persistent stimulation of EGF receptor signaling pathway in BC44 cells in culture resulted in the loss of the in vivo morphogenetic potential and led to the induction of active MMP2, thereby triggering cell scattering and motility on laminin 5. These data (a) suggest that BC44 cells are capable of asymmetric division for self-renewal and the generation of a differentiated progeny restricted to the luminal lineage; (b) clarify the function of EGF in the control of the BC44 cell phenotypic plasticity; and (c) suggest a role for this phenomenon in the mammary gland development.
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Wang, Qiong (Annabel). "AGING-RELATED ADIPOSE REMODELING AND DYSFUNCTION." Innovation in Aging 6, Supplement_1 (November 1, 2022): 320. http://dx.doi.org/10.1093/geroni/igac059.1262.
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Abstract Aging is associated with insulin resistance, cardiovascular dysfunction, and many other chronic metabolic disorders, significantly shortening healthspan and lifespan. Fat (adipose) tissue, as the major site for energy storage, maintains whole-body energy homeostasis and insulin sensitivity. Adipose tissue has extraordinary plasticity, and it was not until recently that fat tissue remodeling during aging is considered to play an essential role in aging-associated metabolic disorders. Benefiting from recent technology advances, especially the single-cell technology and comprehensive genetic mouse models, we are beginning to unmask how adipose tissue remodels during aging cellularly and molecularly. This symposium features internationally-renowned aging research scientists whose work focuses on how aging remodels adipose tissues and how adipose tissue is vital for healthy aging and longevity. We will hear from Philipp Scherer from The University of Texas Southwestern Medical Center, who will present his research on the impact of adipocyte-derived factors on Healthspan and Lifespan; Hei Sook SUL from the University of California Berkeley will discuss “Aging dependent changes in adipose precursors”; Annabel Wang from the City of Hope will introduce her recent discovery of a new type of adipocyte progenitor cell that promotes aging-related visceral adiposity; and lastly, Gina Wade from the University of Wisconsin-Madison who will talk about “Regulation of aging energy expenditure by plasma lipid signaling”. Attendees will learn about the latest breakthroughs in adipose tissue aging, and the role of adipose tissue in maintaining and restoring metabolic health in aged individuals.
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Theobalt, Natalie, Isabel Hofmann, Sonja Fiedler, Simone Renner, Georg Dhom, Annette Feuchtinger, Axel Walch, et al. "Unbiased analysis of obesity related, fat depot specific changes of adipocyte volumes and numbers using light sheet fluorescence microscopy." PLOS ONE 16, no. 3 (March 16, 2021): e0248594. http://dx.doi.org/10.1371/journal.pone.0248594.
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In translational obesity research, objective assessment of adipocyte sizes and numbers is essential to characterize histomorphological alterations linked to obesity, and to evaluate the efficacies of experimental medicinal or dietetic interventions. Design-based quantitative stereological techniques based on the analysis of 2D-histological sections provide unbiased estimates of relevant 3D-parameters of adipocyte morphology, but often involve complex and time-consuming tissue processing and analysis steps. Here we report the application of direct 3D light sheet fluorescence microscopy (LSFM) for effective and accurate analysis of adipocyte volumes and numbers in optically cleared adipose tissue samples from a porcine model of diet-induced obesity (DIO). Subcutaneous and visceral adipose tissue samples from DIO-minipigs and lean controls were systematically randomly sampled, optically cleared with 3DISCO (3-dimensional imaging of solvent cleared organs), stained with eosin, and subjected to LSFM for detection of adipocyte cell membrane autofluorescence. Individual adipocytes were unbiasedly sampled in digital 3D reconstructions of the adipose tissue samples, and their individual cell volumes were directly measured by automated digital image analysis. Adipocyte numbers and mean volumes obtained by LSFM analysis did not significantly differ from the corresponding values obtained by unbiased quantitative stereological analysis techniques performed on the same samples, thus proving the applicability of LSFM for efficient analysis of relevant morphological adipocyte parameters. The results of the present study demonstrate an adipose tissue depot specific plasticity of adipocyte growth responses to nutrient oversupply. This was characterized by an exclusively hypertrophic growth of visceral adipocytes, whereas adipocytes in subcutaneous fat tissue depots also displayed a marked (hyperplastic) increase in cell number. LSFM allows for accurate and efficient determination of relevant quantitative morphological adipocyte parameters. The applied stereological methods and LSFM protocols are described in detail and can serve as a guideline for unbiased quantitative morphological analyses of adipocytes in other studies and species.
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Natale, Francesca, Lucia Leone, Marco Rinaudo, Raimondo Sollazzo, Saviana Antonella Barbati, Francesco La Greca, Matteo Spinelli, Salvatore Fusco, and Claudio Grassi. "Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche." Stem Cells 40, no. 3 (January 21, 2022): 318–31. http://dx.doi.org/10.1093/stmcls/sxab026.
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Abstract Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non-communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on insulin receptor substrate-1 (IRS-1)/ Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS-1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high-fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.
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Chamas, Lamis, Isabelle Seugnet, Roseline Poirier, Marie-Stéphanie Clerget-Froidevaux, and Valérie Enderlin. "A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation." International Journal of Molecular Sciences 23, no. 19 (October 8, 2022): 11938. http://dx.doi.org/10.3390/ijms231911938.
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Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.
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Lupien, Leslie E., Katarzyna Bloch, Jonas Dehairs, Nicole A. Traphagen, William W. Feng, Wilson L. Davis, Thea Dennis, et al. "Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells." Journal of Lipid Research 61, no. 2 (December 5, 2019): 205–18. http://dx.doi.org/10.1194/jlr.ra119000327.
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We previously described the expression of CD36 and LPL by breast cancer (BC) cells and tissues and the growth-promoting effect of VLDL observed only in the presence of LPL. We now report a model in which LPL is bound to a heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to internalize VLDLs via receptor-mediated endocytosis. We also demonstrate that gene-expression programs for lipid synthesis versus uptake respond robustly to triglyceride-rich lipoprotein availability. The literature emphasizes de novo FA synthesis and exogenous free FA uptake using CD36 as paramount mechanisms for lipid acquisition by cancer cells. We find that the uptake of intact lipoproteins is also an important mechanism for lipid acquisition and that the relative reliance on lipid synthesis versus uptake varies among BC cell lines and in response to VLDL availability. This metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that the inhibition of FA synthesis may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology..
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Qu, Guanlin, Yan Li, Lu Chen, Qin Chen, Duohong Zou, Chi Yang, and Qing Zhou. "Comparison of Osteogenic Differentiation Potential of Human Dental-Derived Stem Cells Isolated from Dental Pulp, Periodontal Ligament, Dental Follicle, and Alveolar Bone." Stem Cells International 2021 (April 7, 2021): 1–12. http://dx.doi.org/10.1155/2021/6631905.
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Background. Mesenchymal stem cells (MSCs) have become promising candidates for regeneration medicine due to their multidifferentiation potential and immunomodulatory ability. Compared with classic MSCs derived from the bone marrow and fat, dental-derived MSCs show high plasticity, accessibility, and applicability. Therefore, they are considered alternative sources for regeneration medicine. Methods. Four types of MSCs were isolated from the dental pulp, periodontal ligament, dental follicle, and alveolar bone of the same donor, and there were five different individuals. We analyzed their morphology, immunophenotype, proliferation rate, apoptosis, trilineage differentiation potential, and the gene expression during osteogenic differentiation. Results. Our research demonstrated that DPSCs, PDLSCs, DFPCs and ABMMSCs exhibited similar morphology and immunophenotype. DFPCs showed a higher rate of proliferation and apoptosis. When cultured in the trilineage differentiation medium, all types of MSCs presented the differentiation potential of osteogenesis, adipogenesis, and chondrogenesis. Through staining and genetic analysis during osteogenic induction, ABMMSCs and PDLSCs showed the highest osteogenic ability, followed by DPSCs, and DFPCs were the lowest. Conclusions. Overall, our results indicated that different dental-derived stem cells possessed different biological characteristics. For bone tissue engineering, ABMMSCs and PDLSCs can be used as optimal candidates of seed cells.
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O’Hara, Stephanie E., Kelly M. Gembus, and Lisa M. Nicholas. "Understanding the Long-Lasting Effects of Fetal Nutrient Restriction versus Exposure to an Obesogenic Diet on Islet-Cell Mass and Function." Metabolites 11, no. 8 (August 4, 2021): 514. http://dx.doi.org/10.3390/metabo11080514.
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Early life represents a window of phenotypic plasticity. Thus, exposure of the developing fetus to a compromised nutritional environment can have long term consequences for their health. Indeed, undernutrition or maternal intake of an obesogenic diet during pregnancy leads to a heightened risk of type 2 diabetes (T2D) and obesity in her offspring in adult life. Given that abnormalities in beta-cell function are crucial in delineating the risk of T2D, studies have investigated the impact of these exposures on islet morphology and beta-cell function in the offspring in a bid to understand why they are more at risk of T2D. Interestingly, despite the contrasting maternal metabolic phenotype and, therefore, intrauterine environment associated with undernutrition versus high-fat feeding, there are a number of similarities in the genes/biological pathways that are disrupted in offspring islets leading to changes in function. Looking to the future, it will be important to define the exact mechanisms involved in mediating changes in the gene expression landscape in islet cells to determine whether the road to T2D development is the same or different in those exposed to different ends of the nutritional spectrum.
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Hemnes, Anna R., Joshua P. Fessel, Xinping Chen, Shijun Zhu, Niki L. Fortune, Christopher Jetter, Michael Freeman, John H. Newman, James D. West, and Megha H. Talati. "BMPR2 dysfunction impairs insulin signaling and glucose homeostasis in cardiomyocytes." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 2 (February 1, 2020): L429—L441. http://dx.doi.org/10.1152/ajplung.00555.2018.
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Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating AktSer473 via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.
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Conese, Massimo, Luigi Annacontini, Annalucia Carbone, Elisa Beccia, Liberato Roberto Cecchino, Domenico Parisi, Sante Di Gioia, et al. "The Role of Adipose-Derived Stem Cells, Dermal Regenerative Templates, and Platelet-Rich Plasma in Tissue Engineering-Based Treatments of Chronic Skin Wounds." Stem Cells International 2020 (January 9, 2020): 1–17. http://dx.doi.org/10.1155/2020/7056261.
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The continuous improvements in the field of both regenerative medicine and tissue engineering have allowed the design of new and more efficacious strategies for the treatment of chronic or hard-to-heal skin wounds, which represent heavy burden, from a medical and economic point of view. These novel approaches are based on the usage of three key methodologies: stem cells, growth factors, and biomimetic scaffolds. These days, the adipose tissue can be considered the main source of multipotent mesenchymal stem cells, especially adipose-derived stem cells (ASCs). ASCs are easily accessible from various fat depots and show an intrinsic plasticity in giving rise to cell types involved in wound healing and angiogenesis. ASCs can be found in fat grafts, historically used in the treatment of chronic wounds, and have been evaluated as such in both animal models and human trials, to exploit their capability of accelerating wound closure and inducing a correct remodeling of the newly formed fibrovascular tissue. Since survival and fitness of ASCs need to be improved, they are now employed in conjunction with advanced wound dressings, together with dermal regenerative templates and platelet-rich plasma (as a source of growth and healing factors). In this work, we provide an overview of the current knowledge on the topic, based on existing studies and on our own experience.
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Takchi, Andrew, and Tufia C. Haddad. "Effect of DUAL pharmacological blockade of AURKA and PD-L1 pathways on plasticity and metastasis for triple negative breast cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e13100-e13100. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e13100.
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e13100 Background: Aurora-A mitotic kinase (AURKA) plays a pivotal role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype (Cancer Stem Cells) characterized by high self-renewal capacity and intrinsic drug resistance. Cancer Stem Cells (CSCs) also shows high PD-L1 expression that plays a critical role in inducing tumor immune escape through CD8+ T-cells exhaustion. For these reasons, molecular characterization of oncogenic pathways that promote stemness and intra-tumoral PD-L1 expression is essential to evaluate whether novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis may impact cancer progression. Methods: (1) TNBC Models: MDA-MB 231 and variant MDA-MB 231/LM cells, and unique TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting assay. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x106 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were randomized into four groups (5 mice per group) and treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. Control groups were treated with saline solution placebo. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Combination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Remarkably, combination of atezolizumab and alisertib also induced a significant reduction of ALDHHigh CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to impair cancer cell plasticity, immune evasion capacity and halt the progression of metastatic TNBCs that currently has limited effective therapeutic options.
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Ruzhytska, O. V., A. R. Kucher, V. Yu Vovk, Yu V. Vovk, A. V. Paliy, L. V. Kovpak, and I. M. Uglyar. "Clinical and Sonographic Analysis of Biometric Indicators of Cheek Thickness and Cheek Fat Body in Patients with Different Face Types." Ukraïnsʹkij žurnal medicini, bìologìï ta sportu 6, no. 6 (December 25, 2021): 177–82. http://dx.doi.org/10.26693/jmbs06.06.177.
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The purpose of the study was to conduct a scientific and practical analysis of clinical sonographic results of examination of patients with different face types in the process of planning the reconstruction of facial soft tissues with the involvement of buccal fat pad. Materials and methods. The study was conducted on 28 patients of different age groups (from 20 to 45 years old) with defects and deformities of the tissues of the dental system. Instrumental sonographic analysis of the thickness of the buccal fat body was performed using an ultrasound scanner GE Logiq E (USA), transducer frequency 7.5-12 MHz. The types of buccal fat pad of correct (oval) or irregular (“hourglass”) shapes were determined, as well as its localization in relation to the median axial location of the crown of the first upper molars and the average value of the buccal fat pad thickness with an accuracy of 0.01 mm. Results and discussion. The results of a clinical study of the average value of the thickness of the cheek of patients with mesofacial type of face allowed to establish that on the left its value is 8.94±0.89 mm, on the right side – 9.05±0.82 mm. In patients with brachyfacial type of face on the left the value of the thickness of the cheek is 12.33±1.63 mm, and on the right side – 12.44±1.54 mm. In patients with dolichofacial type of face on the left, the index of the thickness of the cheek reaches the value of 7.53±0.61 mm, on the right side – 8.58±1.093 mm. Statistical significance was determined in comparison with data from the group of patients with mesofacial facial type. The obtained statistical results show mediocre values of buccal fat pad thickness in patients with mesofacial type of face, which are 1.117 times larger than in dolichofacials and 0.73 times smaller than in brachyfacials, which should be taken into account when conducting sonographic studies. Differences in the quantitative values of buccal fat pad thickness, which are established by clinical and sonographic studies conducted in patients with different types of faces is recommended to take into account when choosing surgical approaches during surgical closure of tissue defects of the alveolar processes of the jaws with autologous buccal fat pad. Conclusion. Buccal fat pad has morphological advantages associated with its saturation with cell complexes that have significant degree of vascularization, pliable texture, plasticity and direct participation in the implementation of the basic functions of the maxillofacial area
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Perruchot, Marie-Hélène, Louis Lefaucheur, Corinne Barreau, Louis Casteilla, and Isabelle Louveau. "Age-related changes in the features of porcine adult stem cells isolated from adipose tissue and skeletal muscle." American Journal of Physiology-Cell Physiology 305, no. 7 (October 1, 2013): C728—C738. http://dx.doi.org/10.1152/ajpcell.00151.2013.
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A better understanding of the control of body fat distribution and muscle development is of the upmost importance for both human and animal physiology. This requires a better knowledge of the features and physiology of adult stem cells in adipose tissue and skeletal muscle. Thus the objective of the current study was to determine the type and proportion of these cells in growing and adult pigs. The different cell subsets of stromal vascular cells isolated from these tissues were characterized by flow cytometry using cell surface markers (CD11b, CD14, CD31, CD34, CD45, CD56, and CD90). Adipose and muscle cells were predominantly positive for the CD34, CD56, and CD90 markers. The proportion of positive cells changed with age especially in intermuscular adipose tissue and skeletal muscle where the percentage of CD90+ cells markedly increased in adult animals. Further analysis using coimmunostaining indicates that eight populations with proportions ranging from 12 to 30% were identified in at least one tissue at 7 days of age, i.e., CD90+/CD34+, CD90+/CD34−, CD90+/CD56+, CD90+/CD56−, CD90−/CD56+, CD56+/CD34+, CD56+/CD34−, and CD56−/CD34+. Adipose tissues appeared to be a less heterogeneous tissue than skeletal muscle with two main populations (CD90+/CD34− and CD90+/CD56−) compared with five or more in muscle during the studied period. In culture, cells from adipose tissue and muscle differentiated into mature adipocytes in adipogenic medium. In myogenic conditions, only cells from muscle could form mature myofibers. Further studies are now needed to better understand the plasticity of those cell populations throughout life.
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Gong, Pengfei, Danielle Bailbé, Lola Bianchi, Gaëlle Pommier, Junjun Liu, Stefania Tolu, Maria G. Stathopoulou, Bernard Portha, Valérie Grandjean, and Jamileh Movassat. "Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner." Biomolecules 11, no. 5 (May 18, 2021): 751. http://dx.doi.org/10.3390/biom11050751.
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The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.
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Vettor, Roberto, Gabriella Milan, Chiara Franzin, Marta Sanna, Paolo De Coppi, Rosario Rizzuto, and Giovanni Federspil. "The origin of intermuscular adipose tissue and its pathophysiological implications." American Journal of Physiology-Endocrinology and Metabolism 297, no. 5 (November 2009): E987—E998. http://dx.doi.org/10.1152/ajpendo.00229.2009.
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The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.
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Greenhill, Claire. "Plasticity of fat cells." Nature Reviews Endocrinology 14, no. 9 (July 2, 2018): 504. http://dx.doi.org/10.1038/s41574-018-0053-x.
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Cavaliere, Gina, Angela Catapano, Giovanna Trinchese, Fabiano Cimmino, Eduardo Penna, Amelia Pizzella, Claudia Cristiano, Adriano Lama, Marianna Crispino, and Maria Pina Mollica. "Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity." Antioxidants 12, no. 1 (December 20, 2022): 4. http://dx.doi.org/10.3390/antiox12010004.
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Neurodegenerative diseases (NDDs) are characterized by cognitive impairment and behavioural abnormalities. The incidence of NDDs in recent years has increased globally and the pathological mechanism is not fully understood. To date, plentiful evidence has showed that metabolic alterations associated with obesity and related issues such as neuroinflammation, oxidative stress and mitochondrial dysfunction may represent an important risk factor, linking obesity and NDDs. Numerous studies have indicated a correlation between diet and brain activities. In this context, a key role is played by mitochondria located in the synaptic fraction; indeed, it has been shown that high-fat diets cause their dysfunction, affecting synaptic plasticity. In this scenario, the use of natural molecules that improve brain mitochondrial function represents an important therapeutic approach to treat NDDs. Recently, it was demonstrated that butyrate, a short-chain fatty acid is capable of counteracting obesity in an animal model, modulating mitochondrial function. The aim of this study has been to evaluate the effects of butyrate on neuroinflammatory state, oxidative stress and mitochondrial dysfunction in the brain cortex and in the synaptic fraction of a mouse model of diet-induced obesity. Our data have shown that butyrate partially reverts neuroinflammation and oxidative stress in the brain cortex and synaptic area, improving mitochondrial function and efficiency.
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Hügle, Thomas, Jeroen Geurts, Corina Nüesch, Magdalena Müller-Gerbl, and Victor Valderrabano. "Aging and Osteoarthritis: An Inevitable Encounter?" Journal of Aging Research 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/950192.
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Osteoarthritis (OA) is a major health burden of our time. Age is the most prominent risk factor for the development and progression of OA. The mechanistic influence of aging on OA has different facets. On a molecular level, matrix proteins such as collagen or proteoglycans are modified, which alters cartilage function. Collagen cross-linking within the bone results in impaired plasticity and increased stiffness. Synovial or fat tissue, menisci but also ligaments and muscles play an important role in the pathogenesis of OA. In the elderly, sarcopenia or other causes of muscle atrophy are frequently encountered, leading to a decreased stability of the joint. Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking.
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Gentile, Pietro, and Simone Garcovich. "Systematic Review: Adipose-Derived Mesenchymal Stem Cells, Platelet-Rich Plasma and Biomaterials as New Regenerative Strategies in Chronic Skin Wounds and Soft Tissue Defects." International Journal of Molecular Sciences 22, no. 4 (February 3, 2021): 1538. http://dx.doi.org/10.3390/ijms22041538.
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The number of clinical trials evaluating adipose-derived mesenchymal stem cells (AD-MSCs), platelet-rich plasma (PRP), and biomaterials efficacy in regenerative plastic surgery has exponentially increased during the last ten years. AD-MSCs are easily accessible from various fat depots and show intrinsic plasticity in giving rise to cell types involved in wound healing and angiogenesis. AD-MSCs have been used in the treatment of soft tissue defects and chronic wounds, employed in conjunction with a fat grafting technique or with dermal substitute scaffolds and platelet-rich plasma. In this systematic review, an overview of the current knowledge on this topic has been provided, based on existing studies and the authors’ experience. A multistep search of the PubMed, MEDLINE, Embase, PreMEDLINE, Ebase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus database, and Cochrane databases has been performed to identify papers on AD-MSCs, PRP, and biomaterials used in soft tissue defects and chronic wounds. Of the 2136 articles initially identified, 422 articles focusing on regenerative strategies in wound healing were selected and, consequently, only 278 articles apparently related to AD-MSC, PRP, and biomaterials were initially assessed for eligibility. Of these, 85 articles were excluded as pre-clinical, experimental, and in vitro studies. For the above-mentioned reasons, 193 articles were selected; of this amount, 121 letters, expert opinions, commentary, and editorials were removed. The remaining 72 articles, strictly regarding the use of AD-MSCs, PRP, and biomaterials in chronic skin wounds and soft tissue defects, were analyzed. The studies included had to match predetermined criteria according to the patients, intervention, comparator, outcomes, and study design (PICOS) approach. The information analyzed highlights the safety and efficacy of AD-MSCs, PRP, and biomaterials on soft tissue defects and chronic wounds, without major side effects.
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Bauer-Rowe, Khristian, Alexia Kim, Benjamin Pham, Michelle Griffin, Jeffrey Norton, Jeong Hyun, and Michael Longaker. "CREEPING FAT-DERIVED FIBROBLASTS PARTICIPATE IN INTESTINAL FIBROSIS IN A NOVEL MOUSE MODEL OF INTESTINAL STRICTURES." Inflammatory Bowel Diseases 30, Supplement_1 (January 25, 2024): S58. http://dx.doi.org/10.1093/ibd/izae020.118.
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Abstract INTRODUCTION An intestinal stricture is a common morbidity in Crohn's disease, but its pathogenesis is poorly understood. CF forms adjacent to strictures and is associated with stricture recurrence, but whether it promotes stricture formation is unclear. Adipocytes display remarkable plasticity, and adipocyte-derived fibroblasts (ADFs) play important roles in tissue wound healing and fibrosis. Here, we show that CF ADFs may promote intestinal stricture formation. METHODS We developed a novel mouse model of CF and intestinal fibrosis by creating anti-mesenteric colotomies. We then created colotomies in Adipoq-Cre; mTmG mice and harvested the mice at post-operative day (POD) 14. This system exclusively labels adipocytes and their derivatives GFP+, whereas all other cells are TdTomato+ (Figure 1A-B). We immunostained sham and colotomy bowel for mature adipocyte marker PLIN1. We quantified GFP+ lineage-negative ADFs (CD45-CD31-Terr119-EPCAM-ECadherin-) isolated from either sham or colotomy bowel at POD 14. We then isolated ADFs (GFP+) and non-ADFs (nADFs) (TdTomato+) by flow cytometry and performed single-cell RNA-seq (scRNA-seq) (Figure 1F). RESULTS The creation of a colotomy is sufficient to induce localized mesenteric adipose tissue (MAT) expansion around the colotomy site, consistent with CF formation (Figure 1C). We observed the presence of GFP+ cells with a fibroblast morphology that lost the expression of adipocyte markers and acquired the expression of fibroblast markers. (Figure 1D). Furthermore, we observed that GFP+ ADFs expanded in colotomy bowel compared to sham (Figure 1E). scRNA-seq of ADFs and nADFs revealed 5 major fibroblast clusters, including a Clu+ pro-fibrotic population and a Pi16+ progenitor population, which were enriched in bowel GFP+ ADFs (Figure 1G-H). Finally, quantification of gene expression revealed that GFP+ ADFs lacked mature adipocyte markers, expressed fibroblast markers, and were enriched for various ECM proteins. CONCLUSIONS An anti-mesenteric model of intestinal strictures and CF in combination with immunostaining and scRNA-seq revealed that ADFs from CF infiltrate the bowel wall and expand at the site of fibrosis. ADFs exhibit fibroblast heterogeneity and are enriched for pro-fibrotic and stromal progenitor populations. Finally, ADFs produce collagen and fibronectin, suggesting that they may be pro-fibrotic. Altogether, these data highly suggest that CF contains pro-fibrotic stromal cells that infiltrate the stricture site to promote fibrosis.
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Rowlands, David S., Andre R. Nelson, Frederic Raymond, Sylviane Metairon, Robert Mansourian, Jim Clarke, Trent Stellingwerff, and Stuart M. Phillips. "Protein-leucine ingestion activates a regenerative inflammo-myogenic transcriptome in skeletal muscle following intense endurance exercise." Physiological Genomics 48, no. 1 (January 2016): 21–32. http://dx.doi.org/10.1152/physiolgenomics.00068.2015.
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Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested 70/15/180/30 g protein-leucine-carbohydrate-fat (15LEU), 23/5/180/30 g (5LEU), or 0/0/274/30 g (CON) beverages during the first 90 min of a 240 min recovery period. Vastus lateralis muscle samples (30 and 240 min postexercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by protein-leucine in a dose-dependent manner affecting the inflammatory response and muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with gene-set functions involving cell-cycle arrest (Z-score 2.0–2.7, P < 0.01), leukocyte maturation (1.7, P = 0.007), cell viability (2.4, P = 0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development program correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL-1I-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0–2.6, <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF- β, SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (−1.8–2.4, P < 0.01), increased apoptosis of myeloid and muscle cells (2.2–3.0, P < 0.002), and cell metabolism (2.0–2.4, P < 0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity.
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Samoilova, Yu G., D. V. Podchinenova, M. V. Matveeva, O. A. Oleynik, D. A. Kudlay, and M. A. Kovarenko. "PROSPECTS FOR THE USE OF LIPIDOMIC ANALYSIS IN THE DIAGNOSIS OF METABOLIC DISORDERS." Pediatria. Journal named after G.N. Speransky 102, no. 5 (October 13, 2023): 174–80. http://dx.doi.org/10.24110/0031-403x-2023-102-5-174-180.
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Lipid metabolism disorders play an important role in the development of a number of diseases associated with obesity. However, not all obese people have the traditional abnormal clinical plasma lipid levels, which is especially common in children and adolescents. Given this controversial relationship it is necessary to clarify the new lipid biomarkers in obesity. From this point of view, of particular interest is lipidomics, which allows identifying the diversity of different types of lipids presented in a cell, tissue, biological fluid or in the entire body using tandem mass spectrometry. The human lipidomic profile reflects lipid metabolism, including the early phase of pathophysiological changes associated with the formation of the obesity phenotype. Studying the connection between the lipidome and metabolic plasticity can provide new insight into the biological mechanisms of the development of obesity and its complications, the relationship between fat and carbohydrate metabolism in the development of insulin resistance, disruption of the functioning of intestinal incretins (cholecystokinin, glucagon-like peptide 1 and 2 etc.). From a public health perspective, a thorough understanding of the pathophysiological changes that lead to obesity at the earliest stage will have far-reaching promise for slowing the enormous global incidence of obesity and type 2 diabetes mellitus. This bibliographical review was conducted using the PubMed, Google Scholar and Cyberleninka databases through 2013-2023 sources.
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Grossi, Alberto, Laura Pierdomenico, Laura Bonsi, Cosetta Marchionni, Francesco Alviano, Valentina Fossati, Ennio Becchetti, et al. "Differentiation and Immunoregulatory Activity of Dental Pulp-Derived Mesenchymal Cells." Blood 104, no. 11 (November 16, 2004): 4245. http://dx.doi.org/10.1182/blood.v104.11.4245.4245.
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Abstract INTRODUCTION. Mesenchymal Stem Cells (MSC) have the ability to renew and differentiate into various lineages of mesenchymal tissue such as bone, cartilage, fat, muscle, etc. Moreover they are not immunogenic and display immunoregulatory activity in preclinical animal models. The aim of this study was to investigate whether dental pulp MSC (DPMSC) were able to differentiate toward osteogenesis, chondrogenesis and adipogenesis and express the characteristic immunomodulatory activity of MSC derived from known sources such as bone marrow. METHODS and RESULTS. We isolated MSC from dental pulp and bone marrow samples obtained from fully informed healthy donors. Flow cytometric analysis showed that either DPMSC or bone marrow MSC (BMMSC) expressed the membrane antigens SH2, SH3, SH4, CD29 and CD166, while CD 14, CD 34 and CD 45 were negative. Cell differentiation was evaluated after PDMSC and BMMSC were cultured in appropriate conditions. To evaluate adipogenesis after 2–3 weeks of culture the cells, containing neutral lipids in fat vacuoles, were fixed in 10% formalin and stained with fresh oil red-O solution. To demonstrate osteogenic differentiation, the cultures were fixed and subjected to alkaline phosphatase and von Kossa staining. For chondrogenic differentiation pellets were formalin fixed, embedded in paraffin, examined morphologically and immunostained for Type II collagen. We observed that either PDMSC and BMMSC were able to express clear osteogenic and chondrogenic differentiation as demonstrated by von Kossa staining and Type II collagen immunostaining respectively, but a lower number of adipocytes was obtained, according to morphology and red-oil staining, in DPMSC cultures. For proliferation assay cells were incubated overnight, then [methyl-3H] Thymidine was added (Time 0) and radioactivity followed for up to 15 days. DPMSC and BMMSc presented a very different behaviour in that DPMSC radioactivity had a steep increase from day 3 to 8, then decreasing at day 15, although still above the baseline value. On the contrary BMMSC radioactivity did not change significantly over the time of observation. Modulation of T Lymphocyte proliferation was studied by coculturing PHA stimulated T cells in the presence of MSC. Compared to cultures of T cells alone, the uptake of [methyl-3H] Thymidine was inhibited by 75%±3%(BMMSC)or 91%±4% (DPMSC). CONCLUSIONS: Dental pulp is a source of cells expressing the typical phenotype of MSC. Compared to BMMSC, DPMSC present a higher rate of proliferating cells (S-phase), and lower differentiation capabilities toward adipogenesis. These results suggest that BMMSC and DPMSCs are present at diverse differentiation stages, possibly not evidenced by phenotypic characteristics, and their plasticity in different experimental conditions should be further investigated. DPMSC are able to suppress stimulated T lymphocyte proliferation, as described for BMMSC. Therefore they are good candidates when modulation of T cell activity is required, as shown recently by Le Blanc (2003) in the treatment of GVHD in allogeneic transplantation setting.
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Hawley, John A., Louise M. Burke, Stuart M. Phillips, and Lawrence L. Spriet. "Nutritional modulation of training-induced skeletal muscle adaptations." Journal of Applied Physiology 110, no. 3 (March 2011): 834–45. http://dx.doi.org/10.1152/japplphysiol.00949.2010.
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Skeletal muscle displays remarkable plasticity, enabling substantial adaptive modifications in its metabolic potential and functional characteristics in response to external stimuli such as mechanical loading and nutrient availability. Contraction-induced adaptations are determined largely by the mode of exercise and the volume, intensity, and frequency of the training stimulus. However, evidence is accumulating that nutrient availability serves as a potent modulator of many acute responses and chronic adaptations to both endurance and resistance exercise. Changes in macronutrient intake rapidly alter the concentration of blood-borne substrates and hormones, causing marked perturbations in the storage profile of skeletal muscle and other insulin-sensitive tissues. In turn, muscle energy status exerts profound effects on resting fuel metabolism and patterns of fuel utilization during exercise as well as acute regulatory processes underlying gene expression and cell signaling. As such, these nutrient-exercise interactions have the potential to activate or inhibit many biochemical pathways with putative roles in training adaptation. This review provides a contemporary perspective of our understanding of the molecular and cellular events that take place in skeletal muscle in response to both endurance and resistance exercise commenced after acute and/or chronic alterations in nutrient availability (carbohydrate, fat, protein, and several antioxidants). Emphasis is on the results of human studies and how nutrient provision (or lack thereof) interacts with specific contractile stimulus to modulate many of the acute responses to exercise, thereby potentially promoting or inhibiting subsequent training adaptation.