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WIREs Dev Biol
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Stress and stem cells

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Abstract The unique properties and functions of stem cells make them particularly susceptible to stresses and also lead to their regulation by stress. Stem cell division must respond to the demand to replenish cells during normal tissue turnover as well as in response to damage. Oxidative stress, mechanical stress, growth factors, and cytokines signal stem cell division and differentiation. Many of the conserved pathways regulating stem cell self‐renewal and differentiation are also stress‐response pathways. The long life span and division potential of stem cells create a propensity for transformation (cancer) and specific stress responses such as apoptosis and senescence act as antitumor mechanisms. Quiescence regulated by CDK inhibitors and a hypoxic niche regulated by FOXO transcription factor function to reduce stress for several types of stem cells to facilitate long‐term maintenance. Aging is a particularly relevant stress for stem cells, because repeated demands on stem cell function over the life span can have cumulative cell‐autonomous effects including epigenetic dysregulation, mutations, and telomere erosion. In addition, aging of the organism impairs function of the stem cell niche and systemic signals, including chronic inflammation and oxidative stress. WIREs Dev Biol 2012 doi: 10.1002/wdev.56 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging

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Stem cells reside in protected locations and many rarely divide. (a) Hair follicle stem cells. Hair follicle structure with quiescent (bulge) and active (hair germ) stem/progenitor cells. Bulge area typically maintains quiescent stem cells, whereas DP provides stimulatory signals. Only during development and under injury condition, bulge stem cells give rise to stem cells in epidermis label‐retaining cells (LRC). (b) Intestinal crypt and intestinal stem cells. Intestinal crypt structure with quiescent (+4) and active crypt‐based columnar (CBC) (Lgr5+) stem cells, as well as TA and mesenchymal cells. (c) Bone marrow and hematopoietic stem cells (HSCs). Quiescent HSCs located in the endosteal region where osteoblastic lining, endothelial, CXCL12‐abundant reticular (CAR), and other cells form the endosteal region and active HSCs located in the central marrow region, which lacks osteoblastic cells. (Reprinted with permission from Ref 11. Copyright 2010 The American Association for the Advancement of Science)

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Feedback regulation of intestinal stem cell (ISC) proliferation in response to stress. Stressed or dying enterocytes induce the expression of fly cytokines (such as Upd3 and Upd2) and EGFs (such as Krn and Vn) in the midgut, which activate the JAK/STAT and EGFR pathways in the midgut progenitor cells. Whereas EGFR signaling functions mainly to promote ISC proliferation, Jak/Stat signaling functions to promote both ISC proliferation and enteroblast differentiation. (Reprinted with permission from Ref 92. Copyright 2011 Elsevier)

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An escargot‐GFP transgenic reporter marks the Drosophila ISC lineage and stress dysplasia. Confocal images of guts dissected from 2‐day old (2d) and 50‐day old (50d) flies expressing GFP in the ISCs and enteroblasts (EBs) (genotype: w1118; esg‐Gal4, UAS‐GFP). ISCs and EBs are labeled by GFP expression (green). Cell boundaries are labeled by immunostaining against Armadillo (membrane marker, red). Enteroendocrine cells are labeled by nuclear pros staining (nuclear marker, red). (Reprinted with permission from Ref 90. Copyright 2008 Elsevier)

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Diagram of Drosophila intestinal stem cell (ISC) lineage and intestinal dysplasia. (a) Diagram of ISC lineage. (a) Normal conditions. The ISCs divide to produce an ISC and an enteroblast (EB) cell; the EB then differentiates into either an enterocyte (EC) or an enteroendocrine (EE) cell. (b) Dysplasia. During normal aging and in response to the dietary oxidative stressor paraquat, the ISCs hyperproliferate to produce undifferentiated and misdifferentiated EBs, coincident with disruption of normal gut structure (intestinal dysplasia). The escargot gene is abundantly expressed in the ISCs and EBs, and escargot‐GFP transgenic reporter constructs allow the ISCs and intestinal dysplasia to be visualized using fluorescence microscopy (indicated in green).

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Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease
Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells
Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging