Relevant bibliographies by topics / Fibroblasts reprogramming

Academic literature on the topic 'Fibroblasts reprogramming'

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Published: 14 March 2023

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Journal articles on the topic "Fibroblasts reprogramming"

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Roy, Bibhas, Luezhen Yuan, Yaelim Lee, Aradhana Bharti, Aninda Mitra, and G. V. Shivashankar. "Fibroblast rejuvenation by mechanical reprogramming and redifferentiation." Proceedings of the National Academy of Sciences 117, no. 19 (April 29, 2020): 10131–41. http://dx.doi.org/10.1073/pnas.1911497117.

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Over the course of the aging process, fibroblasts lose contractility, leading to reduced connective-tissue stiffness. A promising therapeutic avenue for functional rejuvenation of connective tissue is reprogrammed fibroblast replacement, although major hurdles still remain. Toward this, we recently demonstrated that the laterally confined growth of fibroblasts on micropatterned substrates induces stem-cell-like spheroids. In this study, we embedded these partially reprogrammed spheroids in collagen-I matrices of varying densities, mimicking different three-dimensional (3D) tissue constraints. In response to such matrix constraints, these spheroids regained their fibroblastic properties and sprouted to form 3D connective-tissue networks. Interestingly, we found that these differentiated fibroblasts exhibit reduced DNA damage, enhanced cytoskeletal gene expression, and actomyosin contractility. In addition, the rejuvenated fibroblasts show increased matrix protein (fibronectin and laminin) deposition and collagen remodeling compared to the parental fibroblast tissue network. Furthermore, we show that the partially reprogrammed cells have comparatively open chromatin compaction states and may be more poised to redifferentiate into contractile fibroblasts in 3D-collagen matrix. Collectively, our results highlight efficient fibroblast rejuvenation through laterally confined reprogramming, which has important implications in regenerative medicine.
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Bektik, Emre, Yu Sun, Adrienne T. Dennis, Phraew Sakon, Dandan Yang, Isabelle Deschênes, and Ji-Dong Fu. "Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming." Cells 10, no. 7 (June 22, 2021): 1572. http://dx.doi.org/10.3390/cells10071572.

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Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenge in heart regeneration. Efforts have focused on improving the efficiency by understanding fundamental mechanisms. One major challenge is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in primary cell cultures. Both forskolin, which increases cAMP levels, and TGFβ inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c, and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblasts could improve their plasticity for reprogramming and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold more iCMs than untreated control cells. In conclusion, suppression of CREB-CBP signaling improves fibroblast plasticity for direct cardiac reprogramming.
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Mueller, Lars, Michael D. Milsom, Kristina Brumme, Chad Harris, Kalindi Parmar, Kaya Zhu, London Wendy, et al. "Mechanisms of Resistance to Reprogramming of Cells Defective In the Fanconi Anemia DNA Repair Pathway." Blood 116, no. 21 (November 19, 2010): 196. http://dx.doi.org/10.1182/blood.v116.21.196.196.

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Abstract Abstract 196 Fanconi anemia (FA), the most common inherited bone marrow failure syndrome, is characterized by progressive loss of hematopoietic stem cells, aplastic anemia, genomic instability and cancer predisposition. Induced pluripotent stem (iPS) cells are a promising source of cells for disease-specific investigations and genetic correction. It has been reported that human FA dermal fibroblasts are resistant to direct reprogramming without prior genetic correction (Raya et al., Nature, 2009), but the mechanism remains unclear. In this study we aimed to define the role of the FA pathway during the transition from fibroblasts to iPS cells in murine cells. We transduced Fanca-/- and wild type (wt) tail-tip fibroblasts with four defined factors (Oct3/4, Klf4, Sox2, c-Myc) and enumerated the number of iPS colonies that were derived from 1×105 cells. We noted a >10-fold decrease in the reprogramming efficiency of Fanca-/- cells compared to wt controls [median (range): wt 132 (0 to 1296) colonies, efficiency 0.328%, n=17; Fanca-/- 4 (0 to 80) colonies, efficiency 0.019%, n=10, p<0.0001, Wilcoxon test]. Despite the markedly reduced reprogramming efficiency, Fanca-/- fibroblasts yielded iPS cells that expressed pluripotency markers (Oct3, Nanog, SSEA-1), gave rise to mature teratomas, and were able to generate chimeric mice. Given the defective DNA repair phenotype of FA cells, we compared baseline and reprogramming-induced DNA damage and senescence in wt and Fanca-/- cells. We observed that double strand DNA (dsDNA) breaks (γH2AX foci) and senescence were significantly increased in Fanca-/- cells four days following the transduction with the reprogramming viruses as compared to wt cells (p<0.0001 and p=0.0012, respectively; Table 1). Because reactive oxygen species (ROS) have been implicated as cellular mediators of DNA damage, senescence and genomic instability in FA cells, we measured the ROS levels during reprogramming and observed a 1.7-fold ROS induction in Fanca-/- fibroblasts. Addition of the ROS scavenger N-acetylcysteine (NAC, 100 μ M) reduced the number of dsDNA breaks in the Fanca-/- cells but failed to increase the reprogramming efficiency, possibly due to off-target toxicity. Therefore, to further assess the impact of oxidative DNA damage on the reprogramming of FA iPS cells, we compared the reprogramming efficiency of Fanca-/- and wt fibroblast that were derived concurrently in normoxic (21% O2) or hypoxic (5% O2) conditions. In both Fanca-/- and wt cells, we observed a significant increase of the reprogramming efficiency under hypoxic conditions (p=0.0098 and p=0.0462, respectively). Complementation of Fanca-/- fibroblasts with the FANCA gene in combination with reprogramming under hypoxic conditions led to a significant rescue of the reprogramming efficiency (p=0.0109, Table 2). This correlated with a significant reduction in senescence and a trend towards decreased dsDNA breaks. These data indicate that oxidative DNA damage engages the FA signaling pathway during the reprogramming process, and acts as a negative physiologic regulator of reprogramming in Fanca-/- cells. Our study implicates the FA pathway as essential to the repair of dsDNA breaks that are induced during the reprogramming process, and provides a plausible mechanism for the reduced efficiency of reprogramming in Fanca-/- cells.Table 1:Increased dsDNA breaks (γH2AX foci) and senescence (β-galactosidase) in Fanca-/- fibroblasts four days post infection with reprogramming viruses.Table 2:Comparison of the number of iPS colonies derived from 1×105 input fibroblasts at 5%O2.GenotypeNumber of Experiments (n)Median (range) number of iPS-like colonies per 1×105 input fibroblastsP-valueFA GFP1468 (0 to 488)0.0018WT GFP18494 (22 to 1812)FA GFP1468 (0 to 488)0.0109FA + FANCA15276 (12 to 1196)WT GFP18494 (22 to 1812)0.1514FA +FANCA15276 (12 to 1196) Disclosures: No relevant conflicts of interest to declare.
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Murry, Charles E., and William T. Pu. "Reprogramming Fibroblasts into Cardiomyocytes." New England Journal of Medicine 364, no. 2 (January 13, 2011): 177–78. http://dx.doi.org/10.1056/nejmcibr1013069.

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Whalley, Katherine. "Reprogramming fibroblasts to OPCs." Nature Reviews Neuroscience 14, no. 6 (May 9, 2013): 380. http://dx.doi.org/10.1038/nrn3512.

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Markov, Glenn J., Thach Mai, Surag Nair, Anna Shcherbina, Yu Xin Wang, David M. Burns, Anshul Kundaje, and Helen M. Blau. "AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency." Proceedings of the National Academy of Sciences 118, no. 23 (June 4, 2021): e2104841118. http://dx.doi.org/10.1073/pnas.2104841118.

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Somatic cell transcription factors are critical to maintaining cellular identity and constitute a barrier to human somatic cell reprogramming; yet a comprehensive understanding of the mechanism of action is lacking. To gain insight, we examined epigenome remodeling at the onset of human nuclear reprogramming by profiling human fibroblasts after fusion with murine embryonic stem cells (ESCs). By assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and chromatin immunoprecipitation sequencing we identified enrichment for the activator protein 1 (AP-1) transcription factor c-Jun at regions of early transient accessibility at fibroblast-specific enhancers. Expression of a dominant negative AP-1 mutant (dnAP-1) reduced accessibility and expression of fibroblast genes, overcoming the barrier to reprogramming. Remarkably, efficient reprogramming of human fibroblasts to induced pluripotent stem cells was achieved by transduction with vectors expressing SOX2, KLF4, and inducible dnAP-1, demonstrating that dnAP-1 can substitute for exogenous human OCT4. Mechanistically, we show that the AP-1 component c-Jun has two unexpected temporally distinct functions in human reprogramming: 1) to potentiate fibroblast enhancer accessibility and fibroblast-specific gene expression, and 2) to bind to and repress OCT4 as a complex with MBD3. Our findings highlight AP-1 as a previously unrecognized potent dual gatekeeper of the somatic cell state.
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Kwon, Erika M., John P. Connelly, Nancy F. Hansen, Frank X. Donovan, Thomas Winkler, Brian W. Davis, Halah Alkadi, et al. "iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations." Proceedings of the National Academy of Sciences 114, no. 8 (February 6, 2017): 1964–69. http://dx.doi.org/10.1073/pnas.1616035114.

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Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs–whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines. Targeted deep sequencing of parental fibroblasts revealed that most variants detected in clonal iPSCs and fibroblast subclones were rare variants inherited from the parental fibroblasts. Only a small number of variants remained undetectable in the parental fibroblasts, which were thus likely to be de novo. Importantly, the clonal iPSCs and fibroblast subclones contained comparable numbers of de novo variants. Collectively, our data suggest that iPSC reprogramming is not mutagenic.
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Bruzelius, Andreas, Srisaiyini Kidnapillai, Janelle Drouin-Ouellet, Tom Stoker, Roger A. Barker, and Daniella Rylander Ottosson. "Reprogramming Human Adult Fibroblasts into GABAergic Interneurons." Cells 10, no. 12 (December 8, 2021): 3450. http://dx.doi.org/10.3390/cells10123450.

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Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders.
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Zhou, Huanyu, Matthew E. Dickson, Min Soo Kim, Rhonda Bassel-Duby, and Eric N. Olson. "Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes." Proceedings of the National Academy of Sciences 112, no. 38 (September 9, 2015): 11864–69. http://dx.doi.org/10.1073/pnas.1516237112.

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Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardiac transcription factors [Gata4, Hand2, Mef2c, and Tbx5 (GHMT)], we screened 192 protein kinases and discovered that Akt/protein kinase B dramatically accelerates and amplifies this process in three different types of fibroblasts (mouse embryo, adult cardiac, and tail tip). Approximately 50% of reprogrammed mouse embryo fibroblasts displayed spontaneous beating after 3 wk of induction by Akt plus GHMT. Furthermore, addition of Akt1 to GHMT evoked a more mature cardiac phenotype for iCMs, as seen by enhanced polynucleation, cellular hypertrophy, gene expression, and metabolic reprogramming. Insulin-like growth factor 1 (IGF1) and phosphoinositol 3-kinase (PI3K) acted upstream of Akt whereas the mitochondrial target of rapamycin complex 1 (mTORC1) and forkhead box o3 (Foxo3a) acted downstream of Akt to influence fibroblast-to-cardiomyocyte reprogramming. These findings provide insights into the molecular basis of cardiac reprogramming and represent an important step toward further application of this technique.
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Esseltine, Jessica L., Qing Shao, Tao Huang, John J. Kelly, Jacinda Sampson, and Dale W. Laird. "Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients." Biochemical Journal 472, no. 1 (October 30, 2015): 55–69. http://dx.doi.org/10.1042/bj20150652.

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We have investigated gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia (ODDD) patients. Patient fibroblasts contain less functional Cx43 which results in changes in the production of extracellular matrix (ECM)-associated proteins, collagen-I secretion, gel contraction and overall fibroblast function.
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Dissertations / Theses on the topic "Fibroblasts reprogramming"

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Elyaderani, Parisa Javadian. "Reprogramming of fibroblasts by the Piwil2 gene." Thesis, University of Newcastle Upon Tyne, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613436.

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The Piwil2 gene belongs to the Piwi family of genes conserved during evolution from Arabidopsis to human. The Piwi family genes are considered as stem cell modulators functioning in meristem cell division in Arabidopsis and germ stem cell propagation in C.elegans and in mammals. Although some essential functions such as germ cell development, transposition repression, epigenetic modification and translational regulation, as well as stem cell and cancer stem cell maintenance, are attributed to this family of genes, the detailed mechanism of the function of these genes still remains elusive. In this study, by taking advantage of the gam of function technique, the coding sequence of the Piwil2 gene was introduced into fibroblasts and stable Piwil2 expressing fibroblasts were established. These cells were evaluated for expression of germ cell specific markers, since the Piwil2 gene is well known as a regulator of spermatogenesis. Piwil2 transfected cells did not express specific markers of spermatogenesis, except Stra8 and Fragilis, but they did express the pluripotent markers of Oct4, Nanog, c-Myc and Klf4 instead. Furthermore, Piwil2 transfected cells exhibited a high tendency to form colony-like structures, partial staining for alkaline phosphatise (AP) activity, expression of germ layer markers and markers of the blood lineage. In terms of teratoma formation, Piwil2 transfected cells showed tumour outgrowth when injected subcutaneously in SCID mice. However, histological observations of the tumour sections revealed that tumours were not teratomas; instead, they were highly malignant tumours with rare signs of differentiation. This result is consistent with the suggestion that the Piwil2 gene is a cancer stem cell gene that is ectopically expressed in a variety of mammalian tumours. Although these results do not show full germ cell or i~S cell conversion of fibroblasts, the dramatic changes that were induced in the Piwil2 transfected cells, compared to the control cells, suggest this gene can act as a modulator of fundamental pathways such as proliferation and differentiation and bestow an unusual phenotype on fibroblasts. It is worth pointing out that some of the findings of this study, such as Oct4 and Terl19 expression in transfected fibroblasts, were not stable in spite of stable expression of the Piwil2 gene. The underlying reason for this might be some sort of dynamic effect of the Piwil2 gene on cell behaviour
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Rohanisarvestani, Leili. "Integration-free mRNA reprogramming of human fibroblasts: The study of aging upon reprogramming." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-159985.

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The ability to reprogram adult somatic cells into induced pluripotent stem (iPS) cells could provide a valuable implement for in vitro disease modeling and drug discovery. More importantly, they may potentially serve as an unlimited source of cells for regenerative medicine. However, most of the iPS cells have been generated by retroviral vectors, and therefore they carry the risk of viral integration into the host genome. This problem prevents their use for clinical applications and regenerative medicine. mRNA-mediated delivery of reprogramming factors is an alternative approach for cellular reprogramming. mRNA-based reprogramming offers the advantage of being completely free of genomic integration and is therefore highly suitable for clinical translation. However, there are some limitations which must be overcome so that mRNA can be widely used for successful cellular reprogramming. In the current thesis, the attempt was to generate stable mRNA-iPS cells through overcoming those limitations. Several human donor cells were transfected with mRNA encoding reprogramming factors and the generation of two stable mRNA-iPS cell lines was shown. The resultant mRNA-iPS colonies were assessed for pluripotency markers. Their pluripotency features were evaluated by the viral-iPS cells produced by conventional retroviral vectors. It was noticed that the generation of mRNA-iPS cells was largely affected by the parental cells from which they were derived. However, characterization and evaluation of the generated mRNA-iPS cells proved their pluripotency states comparable to the viral-iPS cells. On the other hand, the aging hallmarks of the iPS cells were assessed in the second part of this thesis. The potential aging signatures of the iPS cells should be conducted before their use in clinical applications. Currently, there are controversial data regarding the ability of reprogramming to fully rejuvenate an aged somatic cell and reverse agerelated changes such as shortened telomeres, dysfunctional mitochondria and DNA damage. Moreover, mixed findings have been published regarding whether the iPS cells are fully rejuvenated or they might retain some of the aging hallmarks from the cells which they were derived. This thesis studied these controversies through the investigation of three hallmarks of aging including telomere length, mitochondrial alteration and DNA damage. Telomere elongation was indicated in the iPS cells. Furthermore, mitochondrial morphology and function were improved into more immature features in iPS cell lines than their corresponding fibroblasts. Moreover, the iPS cell lines were shown to have less amount of DNA damage compared to their parental fibroblasts. In summary, it can be concluded that generation of mRNA-iPS cells is largely affected by the primary donor cells from which they are derived. Furthermore, it seems that reprogramming enables reversion of aging signatures to a more youthful state.
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Karamariti, Eirini. "Direct reprogramming of fibroblasts into smooth muscle cells." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/direct-reprogramming-of-fibroblasts-into-smooth-muscle-cells(d0feb08f-4d4a-4ded-a2b3-00e41c575cec).html.

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The generation of induced pluripotent stem (iPS) cells is a useful tool for regenerative medicine. However, the risk of tumor development of the aforementioned cells should be addressed before they can be used for clinical applications. During the reprogramming process a number of signal pathways are activated, which may lead to direct differentiation of specific cell lineages prior to the cells reaching the pluripotent state. In order to test this hypothesis we designed a combined protocol of reprogramming and differentiation in an attempt to achieve direct differentiation of fibroblasts to specific cell lineages. Human fibroblasts were shortly reprogrammed by overexpression of four reprogramming factors (OCT4, SOX2, KLF4 and c-MYC) and maintained in reprogramming media on a gelatin substrate for four days. These cells were defined as partially induced pluripotent stem (PiPS) cells. PiPS cells did not form tumours in vivo and differentiated into smooth muscle cells (SMCs) when seeded on a Collagen IV substrate and maintained in differentiation media (DM). The PiPS-SMCs expressed a panel of SMC markers such as SMA, SM22 and Calponin at mRNA and protein levels. Immunofluorescent staining of PiPS-SMCs showed positive staining for the above markers, demonstrating a typical SMC morphology. These cells displayed a greater potential to differentiate into SMCs than iPS cells. In order to elucidate the mechanism of PiPS cell differentiation into SMCs, data from a series of experiments indicated that the gene DKK3 was involved in SMC differentiation of PiPS cells. DKK3 was expressed in parallel with SMC markers, while its overexpression or stimulation induced SMC marker expression. Furthermore, DKK3 silencing resulted in downregulation of SMC markers on both the mRNA and protein levels. Finally, additional experiments revealed that the upregulation of SMC markers by DKK3 is mediated by activation of Wnt signalling through interaction of DKK3 with the transmembrane receptor Kremen 1. Therefore, we developed a protocol to generate SMCs from PiPS cells through a DKK3 signal pathway. These findings provide a new insight into the mechanisms of SMC differentiation with therapeutic potential to vascular disease.
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Rohanisarvestani, Leili [Verfasser], Friedemann [Gutachter] Horn, and Torsten [Gutachter] Remmerbach. "Integration-free mRNA reprogramming of human fibroblasts: The study of aging upon reprogramming / Leili Rohanisarvestani ; Gutachter: Friedemann Horn, Torsten Remmerbach." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1238525598/34.

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Hao, Ru. "Reprogramming of mesenchymal stem cells and adult fibroblasts following nuclear transfer in rabbits." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-96652.

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MAZZARA, PIETRO GIUSEPPE. "TWO FACTOR BASED REPROGRAMMING OF FIBROBLASTS AND INDUCED PLURIPOTENT STEM CELLS INTO MYELINOGENIC SCHWANN CELLS." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199039.

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Le cellule di Schwann (SC) sono cellule derivate dalla cresta neurale (NC) in grado di produrre la guaina mielinica avvolgendo gli assoni neuronali nel sistema nervoso periferico (PNS). I trapianti di SC potrebbero diventare un'opportunità terapeutica interessante per il trattamento delle lesioni del midollo spinale, dei nervi periferici e delle malattie demielinizzanti del PNS. Tuttavia, questi approcci terapeutici sono fortemente limitati dall'attuale mancanza di una fonte rinnovabile di SC. Le strategie di riprogrammazione cellulare si sono rivelate efficaci nel fornire una varietà di cellule specifiche per la modellizzazione delle malattie e per le procedure di trapianto di cellule, ottenute mediante sovraespressione di fattori di trascrizione cardine nello sviluppo embrionale del tipo cellulare di interesse. Ho identificato i due fattori di trascrizione Sox10 ed Egr2 in grado di generare cellule di Schwann indotte (iSCs) ad alta efficienza quando co-espresse in fibroblasti murini. Le iSC assomigliano a SC primarie nel profilo globale di espressione genica ed esprimono marcatori specifici di SC, tra cui S100ß, O4 e MPZ. Quando co-coltivati con espianti di gangli della radice dorsale di topo (DRG), le iSCs hanno generato guaine di mielina compatte organizzate in internodi Mbp+ intervallati da domini paranodali caspr + e domini nodali con canali del sodio. Al contrario, le iSC derivate da topi Twitcher hanno mostrato una grave perdita del potenziale mielinogenico, indicando le iSC come un sistema attraente per la modellazione in vitro delle malattie del PNS. Quindi, ho derivato iSCs da ratti sottoposti ad assotomia del nervo mediano seguito da trapianto di condotti di chitosano precedentemente seminati con iSC autologhe. Questi condotti con le iSC supportano e accelerano la rigenerazione dei nervi con un migliorato contenuto di mielina. Allo stesso modo, Sox10 ed Egr2 sono sufficienti per convertire i fibroblasti umani in iSC. Inoltre, la loro espressione facilita fortemente la differenziazione in SC delle cellule staminali pluripotenti indotte umane (iPSC), includendo nella strategia di riprogrammazione pochi passaggi intermedi che forniscono diversi stimoli trofici alle cellule differenzianti. In particolare, dopo la trasduzione lentivirale con i lentivirus esprimenti Sox10 ed Egr2, ho aggiunto piccole molecole neuralizzanti (SB431542 e LDN193189 in terreno iPSC), insieme a un terreno di differenziazione della cresta neurale (B27, acido ascorbico e FGF2 in terreno neurobasico) e infine un medium specifico per la crescita delle cellule di Schwann (Forskoline, NRG1, FGF2 in DMEM 10% FBS), fornendo una semplice procedura per ottenere un gran numero di SC omogenee e ben differenziate. Complessivamente, Sox10 ed Egr2 sono una combinazione unica di fattori per la generazione efficace di iSC mielinogeniche da fibroblasti di roditori e umani e da iPSC. Il processo rapido e diretto per generare iSC faciliterà la modellazione in vitro e gli approcci di trapianto di cellule autologhe per le malattie del PNS.
Schwann cells (SCs) are neural crest (NC) derived cells able to produce the myelin sheaths, wrapping neuronal axons in the peripheral nervous system (PNS). Transplantations of SCs might become an interesting therapeutic opportunity for the treatment of spinal cord and peripheral nerves injuries and demyelinating diseases of the PNS. However, these therapeutic approaches are strongly limited by the current lack of a renewable source of SCs. Cell reprogramming strategies have proven to be effective in providing a variety of tissue-specific cells for disease modelling, and cell transplantation procedure by over expression of cardinal developmental transcription factors of the interest cell type. I have identified the two transcription factors Sox10 and Egr2 able to generate induced Schwann Cells (iSCs) when co-expressed in murine fibroblasts with high efficiency. iSCs resembled primary SCs in global gene expression profiling and expressed cardinal markers of SCs including S100ß, O4 and MPZ. When co-cultured with mouse dorsal root ganglion (DRG) explants, iSCs generated compact myelin sheaths organized in Mbp+ internodes spaced by Caspr+ paranodal and Na+ channel nodal domains. Conversely, iSCs from Twitcher mice showed a severe loss in the myelinogenic potential, indicating iSCs as an attractive system for in vitro modeling of PNS diseases. Then, I derived iSCs from rats that were subjected to median nerve axotomy followed by transplantation of chitosan conduits previously seeded with autologous iSCs. These iSC-seeded conduits supported accelerated nerve regeneration with improved myelin content. Similarly, Sox10 and Egr2 are sufficient to convert human fibroblasts into iSCs. Moreover, their expression strongly facilitate the SC differentiation of human induced pluripotent stem cells (iPSCs), including in the reprogramming strategy few intermediate steps that provide different trophic stimuli to the differentiating cells. In particular, after the lentiviral transduction with the Sox10 and Egr2 expressing lentiviruses, I added neuralizing small molecules (SB431542 and LDN193189 in hiPS medium), together with a neural crest differentiation medium (B27, Ascorbic Acid and FGF2 in neurobasal medium), and finally a specific medium for Schwann cell growth (Forskoline, NRG1, FGF2 in DMEM 10% FBS), providing a simple procedure for obtaining a large number of homogeneous and well-differentiated SCs. Altogether, Sox10 and Egr2 is a unique combination of factors for the effective generation of myelinogenic iSCs from rodent as well as human fibroblasts and iPSCs. The fast and straightforward process to generate iSCs will facilitate in vitro disease modeling and autologous cell transplantation approaches for PNS diseases.
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Tanabe, Koji. "Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts." Kyoto University, 2013. http://hdl.handle.net/2433/180465.

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Bachamanda, Somesh Dipthi [Verfasser]. "Induced cardiomyocyte precursor cells obtained by direct reprogramming of cardiac fibroblasts / Dipthi Bachamanda Somesh." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1223925676/34.

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Raciti, Marilena. "Reprogramming fibroblasts to neural-stem-like cells by structured overexpression of pallial patterning genes." Doctoral thesis, SISSA, 2012. http://hdl.handle.net/20.500.11767/3924.

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In this study, we assayed the capability of four genes implicated in embryonic specification of the cortico-cerebral field, Foxg1, Pax6, Emx2 and Lhx2, to reprogramm mouse embryonic fibroblasts toward neural identities. Lentivirus-mediated, TetON-dependent overexpression of Pax6 and Foxg1 transgenes specifically activated the neural stem cell (NSC) reporter Sox1-EGFP in a substantial fraction of engineered cells. The efficiency of this process was enhanced up to ten times by simultaneous inactivation of Trp53 and co-administration of a specific drug mix inhibiting HDACs, H3K27-HMTase and H3K4m2-demethylase. Remarkably, a fraction of the reprogrammed population expressed other NSC markers and retained its new identity, even upon transgenes switching off. When transferred into a pro-differentiative environment, Pax6/Foxg1-overexpressing cells activated the neuronal marker Tau-EGFP. Frequency of Tau-EGFP cells was almost doubled upon delayed delivery of Emx2 and Lhx2 transgenes. A further improvement of the neuron-like cells output was achieved by tonic inhibition of BMP and TGFb pathways. These Tau-EGFP cells showed a negative resting potential and displayed active electric responses, following injection of depolarizing currents.
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Kole, Denis. "Role of Fibroblast Growth Factor 2 in Maintenance of Multipotency in Human Dermal Fibroblasts Treated with Xenopus Laevis Egg Extract Fractions." Digital WPI, 2014. https://digitalcommons.wpi.edu/etd-dissertations/207.

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Current usage of human embryonic stem cells (hES) and induced pluripotent stem cells (iPS) in clinical therapies and personalized medicine are limited as a result of ethical, technical and medical problems that arise from isolation and generation of these cells. Isolation of hES cells faces ethical problems associated with their derivation from human pre-implantation embryos. The most controversial aspect of hES cell isolation targets the generation of autologous hES cell lines which requires the transfer of a somatic-cell nucleus from the patient to an enucleated oocyte. While already established embryonic stem cell lines from IVF embryos can be used in a similar manner, lack of genetic identity can cause therapy rejection from the host, and prevent their use in personalized medicine. Induced pluripotent stem cells on the other hand, are generated from somatic cells that have been reprogrammed in vitro to behave like stem cells. While these cells can potentially be used for personalized medicine without the risk of rejection by the host system, derivation methods prevent their therapeutic use. The most efficient method used to generate iPS cells involves usage of viral particles which can result in viral DNA being integrated in the host cell’s genome and render these cells non-compliant for clinical therapies. Other methods not involving viral particles exist as well, but the reprogramming efficiency is too low and technical problems with generating large enough numbers of cells prevent these methods from being feasible approaches for clinical therapies. Direct reprogramming of a differentiated cell into a developmentally more plastic cell would offer alternatives to applications in regenerative medicine that currently depend on either embryonic stem cells (ES), adult stem cells or iPS cells. We hypothesize that Xenopus laevis egg cytoplasmic extract contains critical factors needed for reprogramming that may allow for non-viral, chemically defined derivation of human induced pluripotent/multipotent cells which can be maintained by addition of exogenous FGF2. In this thesis we investigated a new method for generation of multipotent cells through determining the ability of select fractions of Xenopus laevis egg extract to induce multipotency in already differentiated cells. We were able to identify select fractions from the extract that in combination with exogenously added FGF2 can reprogram and maintain the reprogrammed cells in an undifferentiated state. The findings of this work also determined that Xenopus laevis egg extract mRNA is required for achieving full reprogramming. The body of work presented in this thesis showed the ability of FGF2 isoforms to bind and activate select FGF receptor tyrosine kinases, act as extracellular mitogenic factors to support growth of hES cells in an undifferentiated state as well bind to nuclear DNA and affect expression of endogenous genes. Moreover, we showed that all FGF2 isoforms can induce expression of stem cell specific proteins in human dermal fibroblasts as well as extend lifespan of human dermal fibroblasts in vitro. In this work we identified HECW1, the gene coding for E3 ubiquitin ligase NEDL1, as a novel nuclear target for all FGF2 isoforms and showed that overexpression of recombinant FGF2 isoforms in human dermal fibroblasts can down regulate expression of HECW1 gene.
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Book chapters on the topic "Fibroblasts reprogramming"

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Adrian-Segarra, Juan M., Bettina Weigel, and Moritz Mall. "Isolation and Neuronal Reprogramming of Mouse Embryonic Fibroblasts." In Methods in Molecular Biology, 1–12. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1601-7_1.

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Wang, Li, Jiandong Liu, and Li Qian. "In Vivo Lineage Reprogramming of Fibroblasts to Cardiomyocytes for Heart Regeneration." In In Vivo Reprogramming in Regenerative Medicine, 45–63. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-65720-2_4.

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Jayawardena, Tilanthi, Maria Mirotsou, and Victor J. Dzau. "Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes Using MicroRNAs." In Methods in Molecular Biology, 263–72. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-0512-6_18.

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Weltner, Jere, and Ras Trokovic. "Reprogramming of Fibroblasts to Human iPSCs by CRISPR Activators." In Methods in Molecular Biology, 175–98. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-1084-8_12.

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Zhu, Hui, and Joy Y. Wu. "Induction of Osteoblasts by Direct Reprogramming of Mouse Fibroblasts." In Stem Cells and Tissue Repair, 201–12. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0655-1_17.

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Tian, E., Mingzi Zhang, and Yanhong Shi. "Direct Reprogramming of Fibroblasts to Astrocytes Using Small Molecules." In Methods in Molecular Biology, 45–55. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1601-7_4.

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Karl, Robert T., Angela M. Lager, Fadi J. Najm, and Paul J. Tesar. "Reprogramming of Mouse Fibroblasts to Induced Oligodendrocyte Progenitor Cells." In Neuromethods, 79–93. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-7024-7_5.

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Wei, Chuijin, Shumin Xiong, and Lin Cheng. "Reprogramming of Fibroblasts to Neural Stem Cells by a Chemical Cocktail." In Methods in Molecular Biology, 265–70. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0301-7_16.

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Kidder, Benjamin L. "Direct Reprogramming of Mouse Embryonic Fibroblasts to Induced Trophoblast Stem Cells." In Methods in Molecular Biology, 285–92. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0301-7_18.

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Paoletti, Camilla, Carla Divieto, and Valeria Chiono. "Direct Reprogramming of Adult Human Cardiac Fibroblasts into Induced Cardiomyocytes Using miRcombo." In Methods in Molecular Biology, 31–40. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2707-5_3.

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Conference papers on the topic "Fibroblasts reprogramming"

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Kusumoto, T., M. Ishii, M. Yotsukura, A. E. Hegab, F. Saito, J. Hamamoto, T. Asakura, et al. "Direct Reprogramming of Mouse Fibroblasts into Pulmonary Epithelial-Like Cells." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5341.

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Dennys, Cassandra, Kathrin Meyer, Florence Roussel, Xiaojin Zhang, Rochelle Rodrigo, Annalisa Hartlaub, Andrea Sierra-Delgado, et al. "Rapid reprogramming of ALS patient fibroblasts differentiates CuATSM responders from nonresponders." In 1st International Electronic Conference on Brain Sciences. Basel, Switzerland: MDPI, 2020. http://dx.doi.org/10.3390/iecbs-08443.

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Singh, Ankur, Shalu Suri, Ted T. Lee, Jamie M. Chilton, Steve L. Stice, Hang Lu, Todd C. McDevitt, and Andrés J. Garcia. "Adhesive Signature-Based, Label-Free Isolation of Human Pluripotent Stem Cells." In ASME 2012 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/sbc2012-80044.

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Generation of human induced pluripotent stem cells (hiPSCs) from fibroblasts and other somatic cells represents a highly promising strategy to produce auto- and allo-genic cell sources for therapeutic approaches as well as novel models of human development and disease1. Reprogramming protocols involve transduction of the Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc into the parental somatic cells, followed by culturing the transduced cells on mouse embryonic fibroblast (MEF) or human fibroblast feeder layers, and subsequent mechanical dissociation of pluripotent cell-like colonies for propagation on feeder layers1, 2. The presence of residual parental and feeder-layer cells introduces experimental variability, pathogenic contamination, and promotes immunogenicity3. Similar to human embryonic stem cells (hESCs), reprogrammed hiPSCs suffer from the unavoidable problem of spontaneous differentiation due to sub-optimal feeder cultures4, growth factors5, and the feeder-free substrate6. Spontaneously differentiated (SD)-hiPSCs display reduced pluripotency and often contaminate hiPSC cultures, resulting in overgrowth of cultures and compromising the quality of residual pluripotent stem cells5. Therefore, the ability to rapidly and efficiently isolate undifferentiated hiPSCs from the parental somatic cells, feeder-layer cells, and spontaneously differentiated cells is a crucial step that remains a bottleneck in all human pluripotent stem cell research.
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Shu, Shin La, Cheryl L. Allen, Yunchen Yang, Orla Maguire, Hans Minderman, Arindam Sen, Michael J. Ciesielski, et al. "Abstract 5087: Human melanoma exosomes induce metabolic reprogramming in human adult dermal fibroblasts." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5087.

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Ritzenthaler, J., H. Shaghaghi, R. Summer, E. Torres-Gonzalez, W. H. Watson, and J. Roman. "Nicotine Promotes Cellular Metabolic Reprogramming in Lung Fibroblasts via a7 Nicotinic Acetylcholine Receptors." In American Thoracic Society 2022 International Conference, May 13-18, 2022 - San Francisco, CA. American Thoracic Society, 2022. http://dx.doi.org/10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a3204.

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Horowitz, J. C., I. DeVengencie, and J. Prasad. "Cellular IAP (cIAP) Family Proteins Regulate TGF-β1 Induced Metabolic Reprogramming of Lung Fibroblasts." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4407.

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Freeberg, M. A. T., B. Szmoju, S. V. Camus, B. Pinto-Pacheco, T. H. Thatcher, D. I. Walker, and P. J. Sime. "Piezo2 Mechanosensing Is Associated with Lactate Production and Metabolic Reprogramming in Human Lung Fibroblasts." In American Thoracic Society 2022 International Conference, May 13-18, 2022 - San Francisco, CA. American Thoracic Society, 2022. http://dx.doi.org/10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a5059.

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Yeung, Tsz-Lun, Cecilia S. Leung, Kwong-Kwok Wong, and Samuel C. Mok. "Abstract 5066: Reprogramming the TGF-beta signaling in cancer-associated fibroblasts inhibits ovarian cancer progression." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5066.

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Liu, Hao, William W. Ho, Kamila Naxerova, Jelena Grahovac, Hadi Nia, Ivy Chen, Jessica M. Posada, et al. "Abstract A18: Angiotensin receptor blockers normalize the pancreatic ductal adenocarcinoma stroma by reprogramming carcinoma-associated fibroblasts." In Abstracts: AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; September 6-9, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.panca19-a18.

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Miyazaki, Yoshihiro, Yutato Kumagai, Hiroko Kushige, Osamu Shimomura, Yasuyuki Kida, and Tatsuya Oda. "Abstract A32: Adipose-derived mesenchymal stem cell has the differentiation/reprogramming capacity towards two distinct cancer-associated fibroblasts." In Abstracts: AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; September 6-9, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.panca19-a32.

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