Dedifferentiation of committed epithelial cells into stem cells in vivo

Tata, Purushothama Rao; Mou, Hongmei; Pardo–Saganta, Ana; Zhao, Rui; Prabhu, Mythili; Law, Brandon M.; Vinarsky, Vladimir; Cho, Josalyn L.; Breton, Sylvie; Sahay, Amar; Medoff, Benjamin D.; Rajagopal, Jayaraj

doi:10.1038/nature12777

Cited by 600 publications

(546 citation statements)

References 34 publications

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“…Results from several new studies in the adult trachea, stomach and liver have indicated that differentiated non-mitotic cells in these tissues can fully replace resident stem cells if the latter are selectively ablated (Stange et al, 2013;Tata et al, 2013;Yanger et al, 2013). These findings challenge the importance of an adult resident stem cell population, given that committed cells can replace the stem cells under specific conditions.…”

Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 56%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 56%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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“…Differentiation studies have suggested that maturity status is involved in the dedifferentiation process in committed airway secretory cells [17], as well as in terminally differentiated B lymphocytes [18] and the nuclear reprogramming process [19]. These results suggest that differentiation is actively maintained by maturation factors in mammalian cells.…”

Section: Introductionmentioning

confidence: 51%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

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“…The dogma suggests a strict cellular hierarchy within tissues in which somatic stem cells are able to both self-renew and asymmetrically divide leading to the generation of progenitors which can fully differentiate into the cell types resident in the tissue. This cellular hierarchy has been challenged by recent studies (Mannik et al 2010, Rompolas et al 2013, Tata et al 2013 which have shown that differentiated epithelial cells can dedifferentiate to assume the functions of the somatic stem cell. In addition, induction of epithelial-mesenchymal transition (EMT) by TGFb or by other means has been shown to increase the stemness of both mammary (Mani et al 2008) and ovarian surface epithelial cells .…”

Section: Somatic Stem Cells and Epithelial Cell Plasticitymentioning

confidence: 93%

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

Garson¹,

Vanderhyden²

2015

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The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC. In addition, considerable research has been reviewed, that has identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, epithelial cell adhesion molecule, LY6A, ALDH1 and side population (SP)), which are enriched for tumour initiating cells (TICs). While many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the identification of universal markers defining a CSC. The assay that forms the basis of quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is essential that some of the potential limitations be examined in this review. Highlighting such limitations or weaknesses is required to properly evaluate data and broaden our interpretation of potential mechanisms that might be contributing to the pathogenesis of ovarian cancer.

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Dedifferentiation of committed epithelial cells into stem cells in vivo

Cited by 600 publications

References 34 publications

Roles for Hedgehog signaling in adult organ homeostasis and repair

Roles for Hedgehog signaling in adult organ homeostasis and repair

MafA is critical for maintenance of the mature beta cell phenotype in mice

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

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