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1
Wattrus, Samuel J., and Leonard I. Zon. "Stem cell safe harbor: the hematopoietic stem cell niche in zebrafish." Blood Advances 2, no. 21 (November 13, 2018): 3063–69. http://dx.doi.org/10.1182/bloodadvances.2018021725.
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Abstract Each stem cell resides in a highly specialized anatomic location known as the niche that protects and regulates stem cell function. The importance of the niche in hematopoiesis has long been appreciated in transplantation, but without methods to observe activity in vivo, the components and mechanisms of the hematopoietic niche have remained incompletely understood. Zebrafish have emerged over the past few decades as an answer to this. Use of zebrafish to study the hematopoietic niche has enabled discovery of novel cell–cell interactions, as well as chemical and genetic regulators of hematopoietic stem cells. Mastery of niche components may improve therapeutic efforts to direct differentiation of hematopoietic stem cells from pluripotent cells, sustain stem cells in culture, or improve stem cell transplant.
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Ribeiro-Filho, Antonio Carlos, Débora Levy, Jorge Luis Maria Ruiz, Marluce da Cunha Mantovani, and Sérgio Paulo Bydlowski. "Traditional and Advanced Cell Cultures in Hematopoietic Stem Cell Studies." Cells 8, no. 12 (December 12, 2019): 1628. http://dx.doi.org/10.3390/cells8121628.
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Hematopoiesis is the main function of bone marrow. Human hematopoietic stem and progenitor cells reside in the bone marrow microenvironment, making it a hotspot for the development of hematopoietic diseases. Numerous alterations that correspond to disease progression have been identified in the bone marrow stem cell niche. Complex interactions between the bone marrow microenvironment and hematopoietic stem cells determine the balance between the proliferation, differentiation and homeostasis of the stem cell compartment. Changes in this tightly regulated network can provoke malignant transformation. However, our understanding of human hematopoiesis and the associated niche biology remains limited due to accessibility to human material and the limits of in vitro culture models. Traditional culture systems for human hematopoietic studies lack microenvironment niches, spatial marrow gradients, and dense cellularity, rendering them incapable of effectively translating marrow physiology ex vivo. This review will discuss the importance of 2D and 3D culture as a physiologically relevant system for understanding normal and abnormal hematopoiesis.
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Kandarakov, Oleg, Alexander Belyavsky, and Ekaterina Semenova. "Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells." International Journal of Molecular Sciences 23, no. 8 (April 18, 2022): 4462. http://dx.doi.org/10.3390/ijms23084462.
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The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro.
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Goldman, Devorah C., Alexis S. Bailey, Dana L. Pfaffle, Azzah Al Masri, Jan L. Christian, and William H. Fleming. "BMP4 regulates the hematopoietic stem cell niche." Blood 114, no. 20 (November 12, 2009): 4393–401. http://dx.doi.org/10.1182/blood-2009-02-206433.
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Abstract Bone morphogenetic protein 4 (BMP4) is required for mesoderm commitment to the hematopoietic lineage during early embryogenesis. However, deletion of BMP4 is early embryonically lethal and its functional role in definitive hematopoiesis is unknown. Consequently, we used a BMP4 hypomorph to investigate the role of BMP4 in regulating hematopoietic stem cell (HSC) function and maintaining steady-state hematopoiesis in the adult. Reporter gene expression shows that Bmp4 is expressed in cells associated with the hematopoietic microenvironment including osteoblasts, endothelial cells, and megakaryocytes. Although resting hematopoiesis is normal in a BMP4-deficient background, the number of c-Kit+, Sca-1+, Lineage− cells is significantly reduced. Serial transplantation studies reveal that BMP4-deficient recipients have a microenvironmental defect that reduces the repopulating activity of wild-type HSCs. This defect is even more pronounced in a parabiosis model that demonstrates a profound reduction in wild-type hematopoietic cells within the bone marrow of BMP4-deficient recipients. Furthermore, wild-type HSCs that successfully engraft into the BMP4-deficient bone marrow show a marked decrease in functional stem cell activity when tested in a competitive repopulation assay. Taken together, these findings indicate BMP4 is a critical component of the hematopoietic microenvironment that regulates both HSC number and function.
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Park, Dongsu. "The hematopoietic stem cell niche." Frontiers in Bioscience 17, no. 1 (2012): 30. http://dx.doi.org/10.2741/3913.
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Frenette, Paul S., Simón Méndez-Ferrer, Daniel Lucas-Alcaraz, Michela Batista, Sergio Lira, Tatyana V. Michurina, and Grigori N. Enikolopov. "The Hematopoietic Stem Cell Niche." Blood 114, no. 22 (November 20, 2009): SCI—49—SCI—49. http://dx.doi.org/10.1182/blood.v114.22.sci-49.sci-49.
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Abstract Abstract SCI-49 The concept of stem cell niche, proposed by Schofield 30 years ago, refers to the ability of the microenvironment to regulate stem cell fate. The niche provides critical signals allowing hematopoietic stem cells (HSC) to survive, and if so, whether to remain in or to leave the niche (mobilization), or whether to remain quiescent or divide. Some of these signals originate locally from the niche cell(s) but others are coming from afar. For example, we have found that signals from the sympathetic nervous system (SNS) promote the release of HSCs from the bone marrow (BM) niche. Under steady-state conditions, HSC egress in blood is orchestrated in a circadian manner where the fluctuations of circulating HSCs/progenitors are matched with antiphase oscillations in the expression of Cxcl12 mRNA in the BM microenvironment. These oscillations are entrained in the brain by the molecular clock through the local delivery of norepinephrine by SNS nerve terminals in the BM, and transmitted specifically by the β3 adrenergic receptor (Adrβ3) expressed on CXCL12-producing stromal cells, thereby leading to the cyclical degradation of the Sp1 transcription factor. In humans, the circadian release of HSC is inverted compared to rodents and may influence the stem cell yield even when mobilization is enforced by granulocyte colony-stimulating factor (G-CSF), suggesting the potential benefit to harvest HSCs in the clinic at the optimal circadian time. Given the coupling of nervous signals with the stem cell niche, we would expect that the stromal cell forming the niche would be intimately associated with nerve fibers. We have recently found using transgenic mice expressing the green fluorescent protein (GFP) under the Nestin promoter elements (Nes-Gfp), that GFP+ cells (referred to as Nestin+) form a HSC niche in the marrow. Nestin+ cells comprise a relatively small subset (0.08 ± 0.01%) of total BM nucleated cells that is anatomically and functionally associated with the vast majority of CD150+ CD48- Lin- HSCs near blood vessels and SNS fibers of the BM. Nestin+ niche cells express high levels of core genes regulating HSC retention (Cxcl12, Kit ligand, Vcam-1, Angiopoietin-1), and these genes are downregulated by mobilization induced by G-CSF or administration of Adrβ3 agonists. We have identified putative Nestin+ niche cells as bona fide mesenchymal stem cells (MSCs) since they can be propagated as single clonal spheres capable of self-renewal, dramatic in vivo expansion, and multipotency to form osteoblasts, adipocytes, and chondocytes. These data argue for a unique bone marrow niche formed by the pairing of the two rare stem cells, mesenchymal and hematopoietic, that exist in the marrow. Co-authors: Simón Méndez-Ferrer, Ph.D., Daniel Lucas, Ph.D., Michela Batista, Ph.D., Sergio A. Lira, M.D., Mount Sinai School of Medicine, New York, NY; Tatyana V. Michurina, Ph.D., Grigori N. Enikolopov Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY Disclosures Frenette: Glycomimetic: Research Funding.
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Boulais, Philip E., and Paul S. Frenette. "Making sense of hematopoietic stem cell niches." Blood 125, no. 17 (April 23, 2015): 2621–29. http://dx.doi.org/10.1182/blood-2014-09-570192.
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Abstract The hematopoietic stem cell (HSC) niche commonly refers to the pairing of hematopoietic and mesenchymal cell populations that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the developmental stage that allows proliferating HSCs to expand before they reach the bone marrow where they adopt a quiescent phenotype that protects their integrity and functions. Recent studies have sought to clarify the complexity behind the HSC niche by assessing the contributions of specific cell populations to HSC maintenance. In particular, perivascular microenvironments in the bone marrow confer distinct vascular niches that regulate HSC quiescence and the supply of lineage-committed progenitors. Here, we review recent data on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches.
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Fielding, Claire, and Simón Méndez-Ferrer. "Neuronal regulation of bone marrow stem cell niches." F1000Research 9 (June 16, 2020): 614. http://dx.doi.org/10.12688/f1000research.22554.1.
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The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.
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Chan, Charles, Ching-Cheng Chen, Daniel L. Kraft, Cynthia Luppen, Jae-Beom Kim, Anthony DeBoer, Kevin Wei Wei, and Irving L. Weissman. "Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population." Blood 112, no. 11 (November 16, 2008): 3574. http://dx.doi.org/10.1182/blood.v112.11.3574.3574.
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Abstract Introduction: Identification and understanding of the cells and processes that can generate, sustain and influence the HSC niche and hematopoiesis are critical for the development of a more comprehensive knowledge of normal hematopoiesis, stem cell homing, trafficking, differentiation and hematopoietic pathology. Growth and renewal in many tissues are initiated by stem cells, supported by the microenvironment (niche) in which they reside. While recent work has begun to describe functional interactions between stem cells and their niches, little is known about the formation of stem cell niches. Methods & Results: We established a functional, in vivo assay (via implantation of cells under the renal capsule) to isolate the determinants of hematopoietic stem cell (HSC) niche formation and activity. Using this novel assay, we show that a population of progenitor cells (CD45−Tie2-aV+CD105+Thy1.1−; CD105+Thy1−) sorted from 15.5 dpc fetal limbs and transplanted under the adult mouse renal capsule recruit host-derived vasculatures in a VEGF dependent manner, produce donor-derived ectopic bones through endochondral ossification, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45−Tie2-aV+CD105+Thy1a+ (CD105+Thy1+) progenitors form bone that does not contain a marrow cavity. While analyzing these and other sorted populations, we did not observe any instances where niche was present without bone, suggesting that skeletal progenitors are necessary for initiating an HSC niche but osteoblasts alone cannot initiate and support niche activity. Suppression of factors important for HSC maintenance, such as steel factor (SLF), in progenitor populations prior to transplant did not alter their ability to initiate and support an HSC niche. On the other hand, suppression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation. Furthermore, CD105+Thy1− progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification form only bone without marrow in our assay. Conclusions: In addition to identifying the limb-derived skeletal progenitor capable of endochondral ossification involved and the basic mechanisms of HSC niche initiation, our study provides a functional framework by which future studies on HSC-niche interactions at the cellular level can be carried out.
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Esmaeli-Azad, Babak, Anand S. Srivastava, Cybele Frederico, Geraldo Martinez, Satoshi Yasukawa, and Ewa Carrier. "Artificial Hematopoietic Stem Cell Niche Sustains Growth and Differentiation of Human ES-Derived Early Hematopoietic Progenitors." Blood 110, no. 11 (November 16, 2007): 1415. http://dx.doi.org/10.1182/blood.v110.11.1415.1415.
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Abstract Using a novel Microplate Biomaterial Microarray (MBM™) technology, we have created an artificial hematopoietic stem cell niche that can sustain growth and differentiation of human embryonic stem cells-derived (hES) early hematopoietic progenitors. This hydrogel based ex-vivo niche allows uploading of human embryonal stem cells, human mesenchymal stem cells (MSC), genes (bcl-2 preventing apoptosis and HoxB4 enhancing hematopoiesis) and extracellular matrices to support growth and differentiation of human ES cells. These experiments were done using NIH-approved hES cell lines H1 and H9. Serum-free, feeder-free culture conditions were established and early hematopoietic progenitors grown using SCF, TPO, VEGF and IL-3 with high efficiency. At day 3–5 dual CD34+/CD31+ progenitors were identified, while on day 7–8 CD34+ hematopoietic progenitors were isolated, which formed typical hematopoietic colonies. These progenitors expressed genes related to early hematopoiesis, such as TAL1/SCL, FLT1, GATA2, GATA1, EPOR and TPOR. The early dual endothelio-hematopoietic progenitor (hemangioblast) expressed PECAM-1 and CD34 and showed typical blast-like morphology. Based on mathematical simulations, various micro-niches were designed to establish optimal differentiation conditions for this progenitor using IL-3, IL-6, TPO, EPO, VEGF, SFC, Flt-3 ligand and various extracellular matrices. Specific micro-niches were created for generation of CFU-E, BFU-E, CFU-GM, CFU-GEMM, CFU-M, CFU-G, and CFU-MK progenitors from human ES-derived hemangioblast. Kinetic uploading of TPO, EPO, SCF and VEGF created a niche-sustaining growth of ES-derived hemangioblast with high efficiency and low apoptosis rate. These niches used pulse -delivery of anti-apoptotic bcl-2 gene and hematopoiesis-enhancing Hoxb4 gene. The model of artifical niche sustaing growth and differentiation of human ES-derived hemangioblast was established. In the future, this system will allow optimized and upscaled generation of early hematopoietic progenitors from human ES cells, as a first step towards clinical applications of human embryonic stem cells. Figure Figure
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Bianco, Paolo. "Minireview: The Stem Cell Next Door: Skeletal and Hematopoietic Stem Cell “Niches” in Bone." Endocrinology 152, no. 8 (May 24, 2011): 2957–62. http://dx.doi.org/10.1210/en.2011-0217.
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Long known to be home to hematopoietic stem cells (HSC), the bone/bone marrow organ and its cellular components are directly implicated in regulating hematopoiesis and HSC function. Over the past few years, advances on the identity of HSC “niche” cells have brought into focus the role of cells of osteogenic lineage and of marrow microvessels. At the same time, the identity of self-renewing multipotent skeletal progenitors (skeletal stem cells, also known as mesenchymal stem cells) has also been more precisely defined, along with the recognition of their own microvascular niche. The two sets of evidence converge in delineating a picture in which two kinds of stem cells share an identical microanatomical location in the bone/bone marrow organ. This opens a new view on the manner in which the skeleton and hematopoiesis can cross-regulate via interacting stem cells but also a novel view of our general concept of stem cell niches.
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Li, Tian, and Yaojiong Wu. "Paracrine Molecules of Mesenchymal Stem Cells for Hematopoietic Stem Cell Niche." Bone Marrow Research 2011 (September 22, 2011): 1–8. http://dx.doi.org/10.1155/2011/353878.
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Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are both adult stem cells residing in the bone marrow. MSCs interact with HSCs, they stimulate and enhance the proliferation of HSCs by secreting regulatory molecules and cytokines, providing a specialized microenvironment for controlling the process of hematopoiesis. In this paper we discuss how MSCs contribute to HSC niche, maintain the stemness and proliferation of HSCs, and support HSC transplantation.
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Arai, Fumio. "Hematopoietic stem cells and niche cell populations." Inflammation and Regeneration 32, no. 4 (2012): 152–57. http://dx.doi.org/10.2492/inflammregen.32.152.
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Rahnemoon, Ahmad Reza. "Why Is Importance the Reprogramming and Remodeling In Malignant Hematopoietic Microenvironment and Its Hematopoietic Stem Cells Too." Cancer Research and Cellular Therapeutics 5, no. 2 (June 9, 2021): 01–04. http://dx.doi.org/10.31579/2640-1053/086.
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Hematopoietic microenvironment or niche keeps stem cells in multi-potent/ uni-potent state which prevents precocious differentiation. The niche employs a variety of factors includes growth factors, cytokines and cell adhesion molecules too. In this section, we try to have a better understanding about the role of hematopoietic stem cells, niche and hematopoiesis as well as we demonstrate that leukemia induced reprogramming initially and then remodeling of the bone marrow (BM) microenvironment which can be a major part of leukemogenesis and is a potential prognostic parameter in malignant hematopoietic disease as well.
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Nishida, Chiemi, Kaori Sato-Kusubata, Yoshihiko Tashiro, Ismael Gritli, Aki Sato, Makiko Ohki-Koizumi, Yohei Morita, et al. "MT1-MMP Plays a Critical Role in Hematopoiesis by Regulating HIF-Mediated Chemo-/Cytokine Gene Transcription within Niche Cells." Blood 120, no. 21 (November 16, 2012): 2351. http://dx.doi.org/10.1182/blood.v120.21.2351.2351.
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Abstract Abstract 2351 Stem cells reside in a physical niche. The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation, stem cell maintenance and regeneration. Various stem cell niches have been shown to be hypoxic, thereby maintaining the stem cell phenotype of e.g. hematopoietic stem cells (HSCs) or cancer stem cells. The bone marrow (BM) niche is a rich reservoir of tissue-specific pluripotent HSCs. Proteases such as matrix metalloproteinases (MMPs) have been implicated in cell movement, partly due to their proteolytic function, and they have been linked to cellular processes such as cell proliferation and differentiation. The proteolytic function of Membrane-type 1 MMP (MT1-MMP/MMP-14) is essential for angiogenesis, arthritis and tumour growth. Recently, it has been reported that MT1-MMP is highly expressed in HSCs and stromal/niche cells. However the clear function of MT1-MMP in hematopoiesis is not well understood. To reveal the functional consequences of MT1-MMP deficiency for post-natal hematopoiesis in vivo, we have taken advantage of MT1-MMP−/− mice to demonstrate that MT1-MMP deficiency leads to impaired steady state hematopoiesis of all hematopoietic cell lineages. In a search for factors whose deficiency could cause this hematopoietic phenotype, we found not only reduced protein release, but also reduced transcription of the following growth factors/chemokines in MT1-MMP−/− mice: erythropoietin (Epo), stromal cell-derived factor-1 (SDF-1a/CXCL12), interleukin-7 (IL-7) and Kit ligand (KitL, also known as stem cell factor). All of these factors, except for Epo, are typical stromal cell-derived factors. To ensure that impaired gene transcription in vivo was not due to a lower number of stromal cells in vivo, we demonstrated that MT1-MMP knockdown in stromal cells in vitro also reduced transcription of the stromal cell derived factors SDF-1a/CXCL12, IL-7 and KitL. In contrast, overexpression of MT1-MMP in stromal cells enhanced gene transcription of these factors. All genes, whose transcription was altered in vitro and in vivo due to MT1-MMP deficiency, had one thing in common: their gene transcription is regulated by the hypoxia inducible factor-1 (HIF-1) pathway. Further mechanistic studies revealed that MT1-MMP activates the HIF-1 pathway via factor inhibiting HIF-1 (FIH-1) within niche cells, thereby inducing the transcription of HIF-responsive genes, which induce terminal hematopoietic differentiation. Thus, MT1-MMP in niche cells regulates postnatal hematopoiesis by modulating hematopoietic HIF-dependent niche factors that are critical for terminal differentiation and migration. Disclosures: No relevant conflicts of interest to declare.
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Calvi, Laura M., and Daniel C. Link. "The hematopoietic stem cell niche in homeostasis and disease." Blood 126, no. 22 (November 26, 2015): 2443–51. http://dx.doi.org/10.1182/blood-2015-07-533588.
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Abstract The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.
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Mazzon, Cristina, Achille Anselmo, Javier Cibella, Cristiana Soldani, Annarita Destro, Natalie Kim, Massimo Roncalli, et al. "The critical role of agrin in the hematopoietic stem cell niche." Blood 118, no. 10 (September 8, 2011): 2733–42. http://dx.doi.org/10.1182/blood-2011-01-331272.
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Abstract Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called “hematopoietic niches,” through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin−Sca1+c-Kit+ (LSK) cells express the α-dystroglycan receptor for agrin. In vitro, agrin-deficient MSCs were less efficient in supporting proliferation of mouse Lin−c-Kit+ cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn−/−). Agrin-deficient mice displayed in vivo apoptosis of CD34+CD135− LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells.
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Chute, John P. "Regenerative Niche-Hematopoietic Stem Cell Interactions." Blood 136, Supplement 1 (November 5, 2020): SCI1. http://dx.doi.org/10.1182/blood-2020-133083.
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Kfoury, Youmna, Francois Mercier, and David T. Scadden. "SnapShot: The Hematopoietic Stem Cell Niche." Cell 158, no. 1 (July 2014): 228–228. http://dx.doi.org/10.1016/j.cell.2014.06.019.
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Arai, Fumio. "Introduction of hematopoietic stem cell niche." Experimental Hematology 43, no. 9 (September 2015): S28. http://dx.doi.org/10.1016/j.exphem.2015.06.016.
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Hira, Vashendriya V. V., Jill R. Wormer, Hala Kakar, Barbara Breznik, Britt van der Swaan, Renske Hulsbos, Wikky Tigchelaar, et al. "Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins." Journal of Histochemistry & Cytochemistry 66, no. 3 (January 3, 2018): 155–73. http://dx.doi.org/10.1369/0022155417749174.
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In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell–derived factor-1α (SDF-1α), C-X-C chemokine receptor type 4 (CXCR4), osteopontin (OPN), and cathepsin K (CatK) are expressed in hypoxic GSC niches around arterioles in five human glioblastoma samples. In HSC niches, HSCs are retained by binding of SDF-1α and OPN to their receptors CXCR4 and CD44, respectively. Protease CatK cleaves SDF-1α to release HSCs out of niches. The aim of the present study was to reproduce the immunohistochemical localization of these GSC markers in 16 human glioblastoma samples with the addition of three novel markers. Furthermore, we assessed the type of blood vessels associated with GSC niches. In total, we found seven GSC niches containing CD133-positive and nestin-positive GSCs as a single-cell layer exclusively around the tunica adventitia of 2% of the CD31-positive and SMA-positive arterioles and not around capillaries and venules. Niches expressed SDF-1α, CXCR4, CatK, OPN, CD44, hypoxia-inducible factor-1α, and vascular endothelial growth factor. In conclusion, we show that GSC niches are present around arterioles and express bone marrow HSC niche proteins.
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Vodyanoy, Vitaly, Oleg Pustovyy, Ludmila Globa, Randy J. Kulesza, and Iryna Sorokulova. "Hemmule: A Novel Structure with the Properties of the Stem Cell Niche." International Journal of Molecular Sciences 21, no. 2 (January 14, 2020): 539. http://dx.doi.org/10.3390/ijms21020539.
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Stem cells are nurtured and regulated by a specialized microenvironment known as stem cell niche. While the functions of the niches are well defined, their structure and location remain unclear. We have identified, in rat bone marrow, the seat of hematopoietic stem cells—extensively vascularized node-like compartments that fit the requirements for stem cell niche and that we called hemmules. Hemmules are round or oval structures of about one millimeter in diameter that are surrounded by a fine capsule, have afferent and efferent vessels, are filled with the extracellular matrix and mesenchymal, hematopoietic, endothelial stem cells, and contain cells of the megakaryocyte family, which are known for homeostatic quiescence and contribution to the bone marrow environment. We propose that hemmules are the long sought hematopoietic stem cell niches and that they are prototypical of stem cell niches in other organs.
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Flynn, Catherine M., and Dan S. Kaufman. "Donor cell leukemia: insight into cancer stem cells and the stem cell niche." Blood 109, no. 7 (November 28, 2006): 2688–92. http://dx.doi.org/10.1182/blood-2006-07-021980.
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Abstract Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.
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Nishida, Chiemi, Kaori Kusubata, Yoshihiko Tashiro, Ismael Gritli, Aki Sato, Makiko Ohki-Koizumi, Motoharu Seiki, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori. "MT1-MMP Regulates Hematopoiesis Through HIF-Mediated Chemo-/Cytokine Release From the Bone Marrow Niche,." Blood 118, no. 21 (November 18, 2011): 3409. http://dx.doi.org/10.1182/blood.v118.21.3409.3409.
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Abstract Abstract 3409 Stem cells reside in a physical niche, a particular microenvironment. The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation, stem cell maintenance and regeneration. Various stem cell niches have been shown to be hypoxic, thereby maintaining the stem cell phenotype, e.g. for hematopoietic stem cells (HSCs) or cancer stem cells. The bone marrow (BM) niche is a rich reservoir for tissue-specific pluripotent HSCs. Proteases, such as matrix metalloproteinases (MMPs) can modulate stem cell fate due to their proteolytic or non-proteolytic functions (abilities). We have investigated the role of membrane-type1 matrix metalloproteinase (MT1-MMP), known for its role in pericellular matrix remodeling and cell migration, in hematopoiesis. MT1-MMP is highly expressed in HSCs and stromal cells. In MT1-MMP−/− mice, release of kit ligand (KitL), stromal cell derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo) and interleukin-7 were impaired resulting in erythroid, myeloid and T and B lymphoid differentiation. Addition of exogenous rec. KitL and rec. SDF-1 restored hematopoiesis in vivo and in vitro. Further mechanistic studies revealed that MT1-MMP in a non-proteolytic manner activates the HIF-1 pathway, thereby inducing the transcription of the HIF-responsive genes KitL, SDF-1 and Epo. These results suggested MT1-MMP as a critical regulator of postnatal hematopoiesis, which as a modulator of the HIF pathway alters critical hematopoietic niche factors necessary for terminal differentiation and or migration. Thus, our results indicate that MT1-MMP as a key molecular link between hypoxia and the regulation of vital HSC niche factors. Disclosures: No relevant conflicts of interest to declare.
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He, Ningning, Lu Zhang, Jian Cui, and Zongjin Li. "Bone Marrow Vascular Niche: Home for Hematopoietic Stem Cells." Bone Marrow Research 2014 (April 14, 2014): 1–8. http://dx.doi.org/10.1155/2014/128436.
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Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs). As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.
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Gonzalez-Nieto, Daniel, Gabriel Ghiaur, Lina Li, Jorden Arnett, Susan Dunn, Glenn Fishman, David Gutstein, Roberto Civitelli, and Jose Cancelas. "Connexin-43 Regulates the Cell Cycle Entry of Hematopoietic Stem Cells within the Stem Cell Niche." Blood 114, no. 22 (November 20, 2009): 1500. http://dx.doi.org/10.1182/blood.v114.22.1500.1500.
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Abstract Abstract 1500 Poster Board I-523 Bone marrow (BM) osteoblasts and stromal (O/S) cells are crucial in the establishment of the hematopoietic niches in the BM. Connexin 43 (Cx43) is expressed by BM stromal cells and by hematopoietic stem cells and progenitors (HSC/P) and is overexpressed in the BM endosteal space upon administration of chemotherapy or radiotherapy. We have previously reported that Cx43 is critical in fetal liver and in BM hematopoiesis. Since Cx43 is expressed by both HSC and the hematopoietic microenvironment, we dissected out the cellular mechanisms responsible for Cx43 function in the BM. We analyzed the hematopoiesis of mice deficient in Cx43 in the O/S cells (Collagen 1α-Creflox/flox; O/S-Cx43-deficient) or in the hematopoietic cells (Vav1-Creflox/flox; H-Cx43-deficient). Upon basal conditions, analysis of the HSC compartment of H-Cx43-deficient mice showed a ∼30% decreased content of immunophenotypically defined long-term HSC (LT-HSC) in BM of H-Cx43KO mice compared with their WT littermates, whereas there was not significant variation in the ST-HSC population content. The reduced LT-HSC population in H-Cx43KO mice was associated with a modest increased quiescence (∼12% increase of LT-HSC in G0). Interestingly, the expression of cyclin D1 and p21cip1 in the H-Cx43KO LT-HSC were 50% reduced and 4-fold increased, respectively, suggesting a decreased ability to enter cell cycle. While we found no significant engraftment difference in primary recipients of competitive repopulation assays, we found a marked reduction (>50%) in the engraftment ability of LT-HSC Cx43-deficient cells when transplanted into secondary recipients. When submitted to stress by 5-fluorouracil (5-FU) administration, H-Cx43KO mice showed a severely decreased hematopoietic recovery of peripheral blood (PB) counts for neutrophils and platelets accompanied with a marked reduction in the BM cellularity and hematopoietic progenitor content on day +14 after treatment. This defect was associated with a dramatic decreased (∼75 %) in the proliferation of the Cx43-deficient, LT-HSC population by 48 hours post-5-FU administration and a relative decrease of the expansion of the ST-HSC/MPP pool as early as 6 days post-5-FU administration. Interestingly, O/S-Cx43-deficient mice also showed severely delayed hematological recovery after 5-FU administration, with reduction in cellularity and hematopoietic progenitor content, suggesting that the increased hematopoietic toxicity induced by 5-FU in the context of Cx43 deficiency may depend on HSC-to-O/S Cx43 homotypic communication. This communication would be responsible of control of the G1 restriction checkpoint in LT-HSC. In summary, our findings suggest that Cx43 expression plays a crucial role controlling the LT-HSC pool size and fitness in response to stress. Disclosures: Cancelas: CERUS CO: Research Funding; CARIDIAN BCT: Research Funding; HEMERUS INC: Research Funding.
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Mayack, Shane R., and Amy J. Wagers. "Osteolineage niche cells initiate hematopoietic stem cell mobilization." Blood 112, no. 3 (August 1, 2008): 519–31. http://dx.doi.org/10.1182/blood-2008-01-133710.
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Abstract Recent studies have implicated bone-lining osteoblasts as important regulators of hematopoietic stem cell (HSC) self-renewal and differentiation; however, because much of the evidence supporting this notion derives from indirect in vivo experiments, which are unavoidably complicated by the presence of other cell types within the complex bone marrow milieu, the sufficiency of osteoblasts in modulating HSC activity has remained controversial. To address this, we prospectively isolated mouse osteoblasts, using a novel flow cytometry–based approach, and directly tested their activity as HSC niche cells and their role in cyclophosphamide/granulocyte colony-stimulating factor (G-CSF)–induced HSC proliferation and mobilization. We found that osteoblasts expand rapidly after cyclophosphamide/G-CSF treatment and exhibit phenotypic and functional changes that directly influence HSC proliferation and maintenance of reconstituting potential. Effects of mobilization on osteoblast number and function depend on the function of ataxia telangiectasia mutated (ATM), the product of the Atm gene, demonstrating a new role for ATM in stem cell niche activity. These studies demonstrate that signals from osteoblasts can directly initiate and modulate HSC proliferation in the context of mobilization. This work also establishes that direct interaction with osteolineage niche cells, in the absence of additional environmental inputs, is sufficient to modulate stem cell activity.
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Yao, Juo-Chin, and Daniel C. Link. "Concise Review: The Malignant Hematopoietic Stem Cell Niche." STEM CELLS 35, no. 1 (September 23, 2016): 3–8. http://dx.doi.org/10.1002/stem.2487.
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Nie, Yuchun, Yoon-Chi Han, and Yong-Rui Zou. "CXCR4 is required for the quiescence of primitive hematopoietic cells." Journal of Experimental Medicine 205, no. 4 (March 31, 2008): 777–83. http://dx.doi.org/10.1084/jem.20072513.
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The quiescence of hematopoietic stem cells (HSCs) is critical for preserving a lifelong steady pool of HSCs to sustain the highly regenerative hematopoietic system. It is thought that specialized niches in which HSCs reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by the niche and how these niche signals regulate such a balance. We report that CXCL12 produced by bone marrow (BM) stromal cells is not only the major chemoattractant for HSCs but also a regulatory factor that controls the quiescence of primitive hematopoietic cells. Addition of CXCL12 into the culture inhibits entry of primitive hematopoietic cells into the cell cycle, and inactivation of its receptor CXCR4 in HSCs causes excessive HSC proliferation. Notably, the hyperproliferative Cxcr4−/− HSCs are able to maintain a stable stem cell compartment and sustain hematopoiesis. Thus, we propose that CXCR4/CXCL12 signaling is essential to confine HSCs in the proper niche and controls their proliferation.
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Guidi, Novella, Gina Marka, Vadim Sakk, Yi Zheng, Maria Carolina Florian, and Hartmut Geiger. "An Aged Bone Marrow Niche Restrains Rejuvenated Hematopoietic Stem Cells." Stem Cells 39, no. 8 (April 13, 2021): 1101–6. http://dx.doi.org/10.1002/stem.3372.
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Abstract Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.
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Camargo, Fernando D. "In vivo Stem Cell Clonal Dynamics." Blood 126, no. 23 (December 3, 2015): SCI—40—SCI—40. http://dx.doi.org/10.1182/blood.v126.23.sci-40.sci-40.
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Abstract Tremendous progress has been achieved in the characterization of the hematopoietic system over the past two decades. Historically, the main experimental approach used to elucidate and define these cellular relationships in the bone marrow (BM) has been the transplantation assay. For this reason, most of our knowledge about the in vivo properties of hematopoietic stem cells (HSCs) and progenitor cells has been derived from studies in the transplant context. Because of the lack of tractable systems, the mechanistic nature of non-transplant hematopoiesis has remained largely unexplored. Over the past several years, my laboratory has developed novel genetic tools for the clonal tracing and imaging of hematopoietic populations in the unperturbed niche that aim to bring insight into the biology of stem and progenitor cells in situ. Our work using a transposon-mediated cellular tagging approach indicated that progenitors, and not the classical long-term HSCs, are the cells mainly responsible for the day-to-day production of blood cells in the adult. Our data also suggested that lineage restricted progenitors are the main contributors to hematopoiesis at steady state. These data represent the first systematic analysis of clonal fate in an unperturbed hematopoietic niche and revealed a novel cellular mechanism for homeostatic blood regeneration. We have now utilized this clonal tracing model to bring insight into the dynamics of stem and progenitor biology during embryonic hematopoiesis and in the severely aged hematopoietic system. These data will be discussed at the meeting. Disclosures Camargo: Cell Signaling Technologies: Consultancy; Vital Therapies: Consultancy.
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Lataillade, Jean-Jacques, Olivier Pierre-Louis, Hans Carl Hasselbalch, Georges Uzan, Claude Jasmin, Marie-Claire Martyré, and Marie-Caroline Le Bousse-Kerdilès. "Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence." Blood 112, no. 8 (October 15, 2008): 3026–35. http://dx.doi.org/10.1182/blood-2008-06-158386.
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Abstract Primary myelofibrosis (PMF) is the rarest and the most severe Philadelphia-negative chronic myeloproliferative syndrome. By associating a clonal proliferation and a mobilization of hematopoietic stem cells from bone marrow to spleen with profound alterations of the stroma, PMF is a remarkable model in which deregulation of the stem cell niche is of utmost importance for the disease development. This paper reviews key data suggesting that an imbalance between endosteal and vascular niches participates in the development of clonal stem cell proliferation. Mechanisms by which bone marrow niches are altered with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver are examined. Differences between signals delivered by both endosteal and vascular niches in the bone marrow and spleen of patients as well as the responsiveness of PMF stem cells to their specific signals are discussed. A proposal for integrating a potential role for the JAK2 mutation in their altered sensitivity is made. A better understanding of the cross talk between stem cells and their niche should imply new therapeutic strategies targeting not only intrinsic defects in stem cell signaling but also regulatory hematopoietic niche–derived signals and, consequently, stem cell proliferation.
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Hosokawa, Kentaro, Fumio Arai, Hiroki Yoshihara, Hiroko Iwasaki, Yuka Nakamura, Yumiko Gomei, and Toshio Suda. "Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells." Blood 116, no. 4 (July 29, 2010): 554–63. http://dx.doi.org/10.1182/blood-2009-05-224857.
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Abstract During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA. Inhibition of N-cadherin expression accelerated cell division in vitro and reduced the lodgment of donor HSPCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. Cotransduction of N-cadherin shRNA and a mutant N-cadherin that introduced the silent mutations to shRNA target sequences rescued the accelerated cell division and reconstitution phenotypes. In addition, the requirement of N-cadherin for HSPC engraftment appears to be niche specific, as shN-cad–transduced lineage−Sca-1+c-Kit+ cells successfully engrafted in spleen, which lacks an osteoblastic niche. These findings suggest that N-cad–mediated cell adhesion is functionally required for the establishment of hematopoiesis in the BM niche after BM transplantation.
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Mansour, Anna, Grazia Abou-Ezzi, Ewa Sitnicka, Sten Eirik W. Jacobsen, Abdelilah Wakkach, and Claudine Blin-Wakkach. "Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow." Journal of Experimental Medicine 209, no. 3 (February 20, 2012): 537–49. http://dx.doi.org/10.1084/jem.20110994.
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Formation of the hematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondral ossification, but little is known about the mechanisms involved. We used the oc/oc mouse, a mouse model with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigate the role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resulted in a defective HSC niche associated with an increased proportion of mesenchymal progenitors but reduced osteoblastic differentiation, leading to impaired HSC homing to the BM. Restoration of OCL activity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required for establishing HSC niches and that osteoblastic development is induced by OCLs. These findings broaden our knowledge of the HSC niche formation, which is critical for understanding normal and pathological hematopoiesis.
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Calvi, Laura M. "Hematopoietic-osteoblastic interactions in the hematopoietic stem cell niche." BoneKEy-Osteovision 3, no. 5 (May 2006): 10–18. http://dx.doi.org/10.1138/20060210.
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Asada, Noboru, Yuya Kunisaki, Takashi Nagasawa, and Paul S. Frenette. "Distinct Contributions By Perivascular Niche Cells in Hematopoietic Stem Cell Maintenance." Blood 126, no. 23 (December 3, 2015): 661. http://dx.doi.org/10.1182/blood.v126.23.661.661.
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Abstract Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood types in response to various demands through life. HSC functions are tightly and finely tuned by a specialized microenvironment called "niche" in the bone marrow (BM). Using Nestin-GFP transgenic mice, we have identified Nestin-GFP+ perivascular stromal cells exhibiting a mesenchymal stem/progenitor cell activity as niche cells. Furthermore, we found two types of Nestin-GFP+ cells expressing different surface markers, Nerve/glial antigen 2 (NG2) and Leptin receptor (Lepr) that are associated with arterioles and sinusoid, respectively, in the BM (Kunisaki et al. Nature, 2013). Both arteriolar and sinusoidal niche cells have been reported to show high gene expression of cytokines essential for HSC maintenance such as CXCL12 and stem cell factor (SCF), however, it remains unknown how the distinct niche cells differentially regulate HSC functions. To investigate the mechanisms, we utilized genetic mouse models, in which CXCL12 or SCF can be deleted in specific cell types. CXCL12 deletion in sinusoidal niche cells by using Lepr-cre/Cxcl12fl/− mice mobilized HSCs and lineage− Sca-1+ c-kit+ (LSK) progenitors into spleen (HSC, CT: Control/DL: Deleted: 760±165 / 2193±557 / spleen, n=6, p<0.05) and blood (LSK, CT/DL: 177±36 / 668±156 / mL blood, n=5, p<0.05), but had no effect on HSC numbers in the BM (CT/DL: 1435±101 / 1194±75 / femur, n=6, p=0.085), which is consistent with a previous report (Ding and Morrison, Nature, 2013). Furthermore, assessments of endogenous HSC localization using whole-mount 3D imaging technology revealed that the deletion of CXCL12 in Lepr+ niche cells had no impact on HSC location (KS-test: Two-sample Kolmogorov-Smirnov test, p=0.9981). By contrast, deletion of CXCL12 in NG2-cre derived cells, which recombines efficiently in the entire Nestin-GFP+ non-endothelial stromal fraction including both peri-arteriolar and peri-sinusoidal cells (96.9±1.3%), and overlapping with Lepr+ cells (88.5±1.6%) and CXCL12-abundant reticular cells (90.7±1.4%), led to a robust reduction of HSC numbers in the BM (CT/DL: 1487±87 / 179±40 / femur, n=10, p<0.0001) with HSC and progenitor mobilization into spleen (HSC, CT/DL: 705±262 / 3550±540 / spleen, n=6-8, p<0.01) and blood (LSK, CT/DL: 494±178 / 5357±896 / mL blood, n=5-7, p<0.01). In addition, deletion of CXCL12 in NG2-cre targeted cells led to HSC displacement away from arterioles (KS-test: Two-sample Kolmogorov-Smirnov test; p=0.001). To examine further a role of CXCL12 produced by NG2+ arteriolar niches on HSC maintenance, we generated tamoxifen-inducible NG2-creERTM/Cxcl12fl/− mice. Deletion of CXCL12 postnatally in NG2+ arteriolar niche cells significantly reduced the number of HSCs in the BM (CT/DL: 1617±160 / 960±95 / femur, n=10-13, p=0.0013), which was confirmed functionally by a competitive repopulation assay. Moreover, 3D imaging revealed that HSCs were located further away from arterioles in NG2-creERTM/Cxcl12fl/− marrow (KS-test: p<0.0001), suggesting a role for arteriolar niches in CXCL12-mediated HSC maintenance. As niche cells synthesize several factors, we evaluated the contribution of arteriolar niches in SCF synthesis, a cytokine shown to be critical for HSC maintenance. As expected, deletion of SCF in NG2-cre targeted cells led to a significant reduction of HSC numbers in the BM (CT/DL: 606±85 / 96±23 / femur, n=5-7, p<0.0001). To further evaluate functions of SCF produced by distinct vascular niches, we also compared these mice with deletions using Lepr-cre or tamoxifen-inducible NG2-creERTM mice. We found that deletion of SCF in Lepr-cre targeted cells showed a significant reduction of HSC numbers in the BM (CT/DL: 690±84 / 220±83 / femur, n=3-4, p<0.0118), consistent with previous studies (Ding et al., Nature, 2012), whereas there was no significant change observed in NG2-creERTM/SCFfl/− mice, suggesting that Lepr+ vascular niches rather than NG2+ arteriolar niches are the most important source of SCF in the BM. These results highlight distinct contributions of perivascular cells primarily located in separate vascular niches, arteriolar and sinusoidal, in HSC maintenance and mobilization. Disclosures No relevant conflicts of interest to declare.
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Bianco, Paolo. "Bone and the hematopoietic niche: a tale of two stem cells." Blood 117, no. 20 (May 19, 2011): 5281–88. http://dx.doi.org/10.1182/blood-2011-01-315069.
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Abstract The revived interest in (hematopoietic) stem cell (HSC) niches has highlighted the role of multiple cellular players found in the bone environment. Initially focused on the role of osteoblasts and sinusoid endothelial cells, the quest for HSC niche cells has recently focused on a unique role for osteoprogenitor cells (skeletal stem cells, mesenchymal stem cells). Strongly validated by observations of HSC dysregulation dictated by the dysregulation of osteoprogenitors, the role of osteoprogenitors in the HSC niche integrates data from different studies into a unified view. As preosteoblastic, periendothelial cells residing at the sinusoid wall, skeletal progenitors reconcile the notions of “osteoblastic” and “sinusoidal” niches with one another. In addition, they bring into focus the cross-regulation of skeletal and hematopoietic physiology as rooted into the interplay of two stem cells (hematopoietic and skeletal) sharing a single niche. As direct regulators of hematopoietic space formation, sinusoid development, and hematopoietic function(s), as well as direct progenitors of positive and negative regulators of HSCs such as osteoblasts and adipocytes, skeletal progenitors have emerged as pivotal organizers of a complex, highly plastic niche. This development seems to represents an evolutionary advance over the deterministic stem cell niches found in archetypal invertebrate systems.
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Stier, Sebastian, Yon Ko, Randolf Forkert, Christoph Lutz, Thomas Neuhaus, Elisabeth Grünewald, Tao Cheng, et al. "Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size." Journal of Experimental Medicine 201, no. 11 (May 31, 2005): 1781–91. http://dx.doi.org/10.1084/jem.20041992.
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Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.
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Schepers, Koen, Edward C. Hsiao, Trit Garg, Mark J. Scott, and Emmanuelle Passegué. "Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice." Blood 120, no. 17 (October 25, 2012): 3425–35. http://dx.doi.org/10.1182/blood-2011-11-395418.
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Abstract Adult hematopoiesis occurs primarily in the BM space where hematopoietic cells interact with stromal niche cells. Despite this close association, little is known about the specific roles of osteoblastic lineage cells (OBCs) in maintaining hematopoietic stem cells (HSCs), and how conditions affecting bone formation influence HSC function. Here we use a transgenic mouse model with the ColI(2.3) promoter driving a ligand-independent, constitutively active 5HT4 serotonin receptor (Rs1) to address how the massive increase in trabecular bone formation resulting from increased Gs signaling in OBCs impacts HSC function and blood production. Rs1 mice display fibrous dysplasia, BM aplasia, progressive loss of HSC numbers, and impaired megakaryocyte/erythrocyte development with defective recovery after hematopoietic injury. These hematopoietic defects develop without compensatory extramedullary hematopoiesis, and the loss of HSCs occurs despite a paradoxical expansion of stromal niche cells with putative HSC-supportive activity (ie, endothelial, mesenchymal, and osteoblastic cells). However, Rs1-expressing OBCs show decreased expression of key HSC-supportive factors and impaired ability to maintain HSCs. Our findings indicate that long-term activation of Gs signaling in OBCs leads to contextual changes in the BM niche that adversely affect HSC maintenance and blood homeostasis.
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Sharma, Shilpa, and Gurudutta Gangenahalli. "Adult Hematopoietic Stem Cells: Niche Cross-Talks to Affect the Cell Fate." Niche Journal 3, no. 1 (January 6, 2016): 12–23. http://dx.doi.org/10.5152/niche.2015.215.
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Ema, Hideo, and Toshio Suda. "Two anatomically distinct niches regulate stem cell activity." Blood 120, no. 11 (September 13, 2012): 2174–81. http://dx.doi.org/10.1182/blood-2012-04-424507.
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Abstract The niche microenvironment controls stem cell number, fate, and behavior. The bone marrow, intestine, and skin are organs with highly regenerative potential, and all produce a large number of mature cells daily. Here, focusing on adult stem cells in these organs, we compare the structures and cellular components of their niches and the factors they produce. We then define the niche as a functional unit for stem cell regulation. For example, the niche possibly maintains quiescence and regulates fate in stem cells. Moreover, we discuss our hypothesis that many stem cell types are regulated by both specialized and nonspecialized niches, although hematopoietic stem cells, as an exception, are regulated by a nonspecialized niche only. The specialized niche is composed of 1 or a few types of cells lying on the basement membrane in the epithelium. The nonspecialized niche is composed of various types of cells widely distributed in mesenchymal tissues. We propose that the specialized niche plays a role in local regulation of stem cells, whereas the nonspecialized niche plays a role in relatively broad regional or systemic regulation. Further work will verify this dual-niche model to understand mechanisms underlying stem cell regulation.
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Rafii, Shahin, Jason M. Butler, Ginsberg Michael, Jennifer L. Gori, Hans-Peter Kiem, and Scandura Jospeh. "Vascular Niche-Derived Angiocrine Factors Specify and Maintain Hematopoietic Stem Cells." Blood 126, no. 23 (December 3, 2015): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v126.23.sci-25.sci-25.
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Abstract Organ-specific endothelial cells (ECs) are both conduits for delivery of nutrients and also establish an instructive vascular niche. The vascular niche produces paracrine factors, (i.e., angiocrine factors), that balance self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) (1,2). Activation of Akt-mTOR pathway in sinusoidal ECs (SECs) stimulates physiological expression of angiocrine factors, including Kit-ligand, Notch-ligands, Wnts, FGFs, BMPs and TGFb, that expand long-term repopulating HSPCs. Activation of MAPkinase in ECs upregulates expression of GM-CSF, M-CSF, IL6, IL7, SDF-1 and G-CSF (..others) to accelerate HSPC multi-lineage differentiation. We developed an ex vivo vascular niche in which HSPC/EC co-cultures are maintained and expanded in serum-free conditions. This vascular niche platform produces physiologic levels of angiocrine factors that balance expansion/differentiation of human cord blood, mobilized peripheral blood, and steady state bone marrow HSPCs that maintain their ability to reconstitute hematopoiesis in vivo. In contrast to our vascular platform, co-culture with bone marrow-derived mesenchymal does not support long-term expansion of HSPCs. In collaboration with Drs. Kiem and Gori at Hutchinson Cancer Center, we have shown that ECs expand repopulating nonhuman primate marrow-derived HSPCs. Transplantation of the vascular-niche expanded gene-modified HSPCs reconstituted long-term multi-lineage hematopoiesis in autologous transplantation setting in nonhuman primates. Importantly, intravenous co-infusion of the vascular niche with HSPCs did not cause infusional toxicity. Vascular niche-expanded HSPCs supported robust hematopoietic recovery underscoring the essential function of vascular niche-signals in hematopoietic reconstitution without provoking fibrosis (3). The ECs also supplies key signals that induce emergence of HSPCs from hemogenic ECs. To prove this point, we transduced adult human or mouse ECs with Runx1/Spi1/Gfi1/FosB transcription factors along with vascular niche-induction allowing for conversion of these ECs into stable and long-term engraftable HSPCs, including functional immune cells (4). Importantly, transition through a pluripotent state results in poorly engraftable hematopoietic cells that are unstable and upon exposure to pathophysiological stressors differentiate aberrantly into other cell-types. Remarkably, signals from vascular niche support specification of repopulating multipotent-HSPCs from both human and nonhuman primate pluripotent stem cells (5). In summary, we developed and characterized a vascular niche platform that provides physiologically relevant levels of key angiocrine factors that stimulate safe clinical-scale expansion of authentic adult, cord blood, and primitive HSPCs under GMP-grade culture conditions. We are currently translating the vascular niche platform to the clinical setting, to evaluate the potential of co-transplantation of HSPCs with vascular niche cells to reconstruct injured EC niches thereby accelerating short- and long-term hematopoietic recovery. This first-in-man clinical application will set the stage for repopulation with true hematopoietic stem cells, thereby enabling use of a vascular niche for treatment of a wide range of acquired, inherited, and malignant hematopoietic diseases. 1. Butler JM …… Rafii S. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell, 3:251-64, 2010. 2. Nolan D........Rafii S. Molecular and cellular signatures of tissue-specific vascular heterogeneity in organ maintenance and regeneration. Developmental Cell, 26(2):204-19, 2013. 3. Ding BS …..Rafii S. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.Nature 505(7481):97-102, 2014. 4. Sandler VM, Lis R ...... Butler JM, Scandura JM, Rafii S. Reprogramming of Human Endothelium Into Engraftable Hematopoietic Progenitors by Vascular Niche Induction.Nature, 511(7509):312-8, 2014. 5. Gori J., Butler JM, .....Rafii S, Kiem HP. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. Journal of Clinical Investigation, 125(3): 1243-54, 2015. Disclosures Rafii: Angiocrine Bioscience: Consultancy, Equity Ownership.
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Day, Ryan B., and Daniel C. Link. "Megakaryocytes in the hematopoietic stem cell niche." Nature Medicine 20, no. 11 (November 2014): 1233–34. http://dx.doi.org/10.1038/nm.3745.
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Morikawa, Takayuki, and Keiyo Takubo. "Hypoxia regulates the hematopoietic stem cell niche." Pflügers Archiv - European Journal of Physiology 468, no. 1 (October 21, 2015): 13–22. http://dx.doi.org/10.1007/s00424-015-1743-z.
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Frenette, Paul. "Hematopoietic stem cell niche through the ages." Experimental Hematology 44, no. 9 (September 2016): S33. http://dx.doi.org/10.1016/j.exphem.2016.06.027.
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Khlusov, Igor A., Larisa S. Litvinova, Marina Yu Khlusova, and Kristina A. Yurova. "Concept of Hematopoietic and Stromal Niches for Cell-Based Diagnostics and Regenerative Medicine (a Review)." Current Pharmaceutical Design 24, no. 26 (November 14, 2018): 3034–54. http://dx.doi.org/10.2174/1381612824666180829154119.
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Background: R. Schofield (1978) proposed a hypothesis of hematopoietic stem cells (HSCs) niche (specialized cell microenvironment). An existence of osteoblastic and vascular niches for HSCs has been postulated since 2003. At the same time, the discussion about the existence and functioning of niche for multipotent mesenchymal stromal cells (MMSCs) is just beginning to develop. The design of artificial materials capable of biomimetical reproductionof the cellular and tissue microenvironment based on ideas and main elements borrowed from wildlife is an experimental approach in search of the stem cell niches. Results: Recent attempts to model the microterritories (niches) for HSCs have been undertaken and the behavior of cells in such structures has been investigated. However, the main quantitative factors involved in the original design of stem cell microterritories remain unknown. At the modern stage, the topography, hierarchy, and the size of the niches have to be determined, because the definition of the niches as morphological (structural and functional) units (microterritories), which provides the conditions for vital activity of stem cells, implies finite values of its parameters. The aim of this review was the critical review of key milestones of the niche concept for HSCs and MMSCs as we understood it. Conclusion: We speculated our definition of the stem cell niche, proposed and described certain stages (postulation; morphofunctional; topographical; quantitative; bioengineering) of the niche theory development. Prospective directions of the niche designing for cell-based diagnostics and regenerative medicine were noted.
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Köhler, Anja, Vince Schmithorst, Marie-Dominique Filippi, Marnie A. Ryan, Deidre Daria, Matthias Gunzer, and Hartmut Geiger. "Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones." Blood 114, no. 2 (July 9, 2009): 290–98. http://dx.doi.org/10.1182/blood-2008-12-195644.
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Abstract Aged hematopoietic stem cells (HSCs) are impaired in supporting hematopoiesis. The molecular and cellular mechanisms of stem cell aging are not well defined. HSCs interact with nonhematopoietic stroma cells in the bone marrow forming the niche. Interactions of hematopoietic cells with the stroma/microenvironment inside bone cavities are central to hematopoiesis as they regulate cell proliferation, self-renewal, and differentiation. We recently hypothesized that one underlying cause of altered hematopoiesis in aging might be due to altered interactions of aged stem cells with the microenvironment/niche. We developed time-lapse 2-photon microscopy and novel image analysis algorithms to quantify the dynamics of young and aged hematopoietic cells inside the marrow of long bones of mice in vivo. We report in this study that aged early hematopoietic progenitor cells (eHPCs) present with increased cell protrusion movement in vivo and localize more distantly to the endosteum compared with young eHPCs. This correlated with reduced adhesion to stroma cells as well as reduced cell polarity upon adhesion of aged eHPCs. These data support a role of altered eHPC dynamics and altered cell polarity, and thus altered niche biology in mechanisms of mammalian aging.
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Hira, V. V. V., J. R. Wormer, H. Kakar, B. Breznik, B. van der Swaan, R. Hulsbos, W. Tigchelaar, et al. "P04.45 Periarteriolar glioblastoma stem cell niches express bone marrow hematopoietic stem cell niche proteins." Neuro-Oncology 20, suppl_3 (September 2018): iii289. http://dx.doi.org/10.1093/neuonc/noy139.279.
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Akiyama, Haruyo, Leif R. Lund, Yohei Morita, Hiromitsu Nakauchi, Hideoki Ogawa, Ko Okumura, Keld Dano, Zena Werb, Beate Heissig, and Koichi Hattori. "Novel Functions for a Fibrinolytic Pathway in Controlling the Stem Cell Niche." Blood 108, no. 11 (November 16, 2006): 1394. http://dx.doi.org/10.1182/blood.v108.11.1394.1394.
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Abstract Hematopoietic stem cells (HSCs) reside within specific niches, where they are maintained by self-renewal and can be mobilized into circulation, but the underlying mechanisms are still unknown. The hematopoietic niche comprises of a local network of stromal cells (like fibroblasts, endothelial cells), accessory cells (T lymphocytes, monocytes), their products (extracellular matrix (ECM) and cytokines, capable of influencing self-renewal, proliferation and differentiation of HSCs. One such ECM molecule is fibrin, which can be found along surfaces in the bone marrow. Its precursor fibrinogen can maintain hematopoiesis in long-term bone marrow liquid cultures and increase the colony size of bone marrow cells cultured in semisolid medium containing serum. Plasmin, a serine protease, proteolytically degrades fibrin and fibrinogen. Plasminogen (Plg), its inactive proenzyme is present in the plasma, interstitial fluid or adherent to ECM proteins and can be activated by tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and other serine proteasesWe demonstrated previously that matrix metalloproteinase-9 (MMP-9) controls stem cell recruitment from the bone marrow niche. During fibrinolysis plasmin participates in the consecutive activation of MMPs. We initially wished to determine if this fibrinolytic cascade might be involved in regulating the stem cell niche. In this study we provide novel mechanistic data demonstrating that classical fibrinolytic factors-Plg/Plasmin are involved in recruitment of HSCs into the cell cycle following myelosuppression and their mobilization from the BM niche influencing cell differentiation, proliferation and migration by activating niche cells to secrete typical niche factors, including Kit-ligand and stromal cell-derived factor-1 (SDF-1, CXCL12). Deletion of Plg in mice prevented hematopoietic stem cells from entering the cell cycle and undergoing differentiation after myelosuppression, leading to the death of the mice. By Plg-dependent and Plg-independent pathways, tissue-type plasminogen activator activated matrix metalloproteinases and released Kit ligand and stromal cell-derived factor-1 from niche cells, thereby promoting stem cell recruitment and proliferation. We conclude that the fibrinolytic cascade plays a critical role in controlling the exit from the stem cell niche and that this represents a general stem cell regulatory axis.
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Taichman, Russell S., Younghun Jung, Benjamin Williams, Junhui Song, and Paul H. Krebsbach. "Hematopoietic Stem Cells Regulate Niche Development." Blood 108, no. 11 (November 16, 2006): 90. http://dx.doi.org/10.1182/blood.v108.11.90.90.
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Abstract Events localized to endosteal surfaces are critical for the maintenance of hematopoetic stem cells (HSCs). Here we explored whether HSCs themselves regulate their microenvironment directly by regulating cytokine expression by osteoblasts (OBs) in response to physiologic demands, or influence the developmental pattern of mesenchymal lineages and thereby indirectly modulate cytokine expression. To test the these possibilities, marrow was isolated from mice 48h after stressing the animals with a single acute bleed (removing 30% of the calculated blood volume by jugular vein venipucture) and in a second control group of non-stressed (puncture only) animals. The Sca-1(+) hematopoietic cells were co-cultured with confluent murine bone marrow stromal (BMSC) and calvarial digested OBs. The presence of HSCs stimulated the basal production of IL-6, SDF-1 and osteoclacin by OBs and BMSCs as determined by ELISA. Co-cultures of HSCs derived from the stressed group produced more IL-6, SDF-1 and osteocalcin relative to the non-stressed group. Newborn dermal fibroblasts did not respond in a similar fashion. To determine if HSCs influence the developmental pattern of the marrow, HSCs derived from stressed and non-stressed animals were separated from either murine OBs or BMSCs using TranswellR membranes and the ability of target cells to differentiate along the osteoblastic lineage was evaluated. A significant proportion of the colonies established from calvarial-derived OB cultures were able to mineralize their extracellular matrix relative whole BMSC population (CFU-OB). In the presence of HSCs, the proportion of non-mineralized (CFU-F) and mineralized colonies from the OB populations significantly increased. Further enhancement of both colony types were induced by the HSCs derived from stressed and non-stressed animals. Adherent cells derived from mixed BMSCs also responded to the presence of HSCs by increasing the generation of CFU-F and OBs relative to the No HSC groups. HSCs derived from stressed vs. the non-stressed groups of animals were better able to induce CFU-OB differentiation. Microarray of HSCs derived from stressed vs. the non-stressed groups, and QRT-PCR of highly purified HSCs (CD150(+), CD48(−), CD41(−), Sca-1(+), cKit(+)) suggested that BMP-2 and BMP-6 were responsible for the activities. Antibody neutralization studies confirmed these observations that BMP-2 and BMP-6 derived from the HSCs themselves alters the developmental pattern of the marrow microenvironment. In conclusion, cross-talk between HSCs-OBs is essential for the development of both cellular populations. These studies demonstrate that at least 2 mechanisms whereby HSCs might set up a paracrine loop with OBs to establish the HSC niche; (i) HSCs directly regulate cytokine expression by OBs in response to physiologic demands or, (ii) HSCs may influence the developmental pattern of mesenchymal lineages and thereby indirectly modulate cytokine expression in the marrow.