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Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells.

ABSTRACT: In homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here, we examine the dynamic behavior of adult hair follicle stem cells in their normal setting by employing mice with repressible H2B-GFP expression to track cell divisions and Cre-inducible mice to perform long-term single-cell lineage tracing. We provide direct evidence for the infrequent stem cell division model in intact tissue. Moreover, we find that differentiation of progenitor cells occurs at different times and tissue locations than self-renewal of stem cells. Distinct fates of differentiation or self-renewal are assigned to individual cells in a temporal-spatial manner. We propose that large clusters of tissue stem cells behave as populations whose maintenance involves unidirectional daughter-cell-fate decisions.

SUBMITTER: Zhang YV

PROVIDER: S-EPMC2756832 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells.

Zhang Ying V YV Cheong Janice J Ciapurin Nichita N McDermitt David J DJ Tumbar Tudorita T

Cell stem cell 20090806 3

In homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here, we examine the dynamic behavior of adult hair follicle stem cells in their normal setting by employing mice with repressible H2B-GFP expression to track cell divisions and Cre-inducible mice to ...[more]

PMID: 19664980

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Project description:In homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here we examine the dynamic behaviour of adult hair follicle stem cells in their normal setting by employing mice with repressible H2B-GFP expression to track cell divisions and Cre inducible mice to perform long-term single cell lineage tracing. We provide direct evidence for the infrequent stem cell division model in intact tissue. Moreover, we find that differentiation of progenitor cells occurs at different times and tissue locations than self-renewal of stem cells. Distinct fates of differentiation or self-renewal are assigned to individual cells in a temporal-spatial manner. We propose that large clusters of tissue stem cells behave as populations, whose maintenance involves unidirectional daughter-cell fate decisions. We used microarrays to expression profile the stem cell progeny generated at distinct differentiation and self-renewal stages. Experiment Overall Design: We employed double transgenic mice, K5tTA x pTRE-H2B-GFP in which an epithelial Keratin 5 (K5) promoter drove repressible histone H2B-GFP expression. Repression is achieved by feeding the mice doxycycline for a period of time (chase), when the H2B-GFP dilutes in cells by 2-fold at division. This allowed us to quantify precise proliferation history in vivo, from the amount of H2B-GFP fluorescence retained in cells after chase. After various chase periods we sacrificed mice at different ages corresponding to distinct phases of hair cycle. We isolated skin cell suspensions from these mice and stained them for surface expression of stem cell niche bulge(Bu) markers CD34 and alpha 6-integrin. Fluorescence-activated cell sorting (FACS) revealed histograms with distinct peaks of 2-fold median H2B-GFP intensity corresponding to distinct divisions. For microarray, we FACS sorted bulge(Bu) and non-bulge(NonBu) cells based cell surface marker staining and their proliferation history with H2B-GFP intensity, after two doxycycline chase schemes (Postnatal Day 18-PD21 or PD22-PD25), then extract total RNA from each cell fractions. For microarrays 5 ng of high quality RNA (Bioanalyzer, Agilent) were amplified (Ovation Amplification; Nugene) in the Cornell Microarray Core Facility. GeneChip IVT labelling was followed by Gene Chip MOE 430 2.0 hybridization, GeneArray 3000 scanning, GCOS generation of present calls and signal values (Affymetrix).

Project description:Hair follicle regeneration is dependent on reciprocal signaling between epithelial cells and underlying mesenchymal cells within the dermal papilla. Hair follicle dermal stem cells reside within the hair follicle mesenchyme, self-renew in vivo, and function to repopulate the dermal papilla and regenerate the connective tissue sheath with each hair cycle. The identity and temporal pattern of signals that regulate hair follicle dermal stem cell function are not known. Here, we show that platelet-derived growth factor signaling is crucial for hair follicle dermal stem cell function and platelet-derived growth factor deficiency results in a progressive depletion of the hair follicle dermal stem cell pool and their progeny. Using αSMACreERT2:RosaYFP:Pdgfrαflox mice, we ablated Pdgfrα specifically within the adult hair follicle dermal stem cell lineage. This led to significant loss of hair follicle dermal stem cell progeny in connective tissue sheath and dermal papilla of individual follicles, and a progressive reduction in total number of anagen hair follicles containing YFP+ve cells. As well, over successive hair cycles, fewer hair follicle dermal stem cells were retained within each telogen hair follicle suggesting an impact on hair follicle dermal stem cell self-renewal. To further assess this, we grew prospectively isolated hair follicle dermal stem cells (Sox2GFP+ve αSMAdsRed+ve) in the presence or absence of platelet-derived growth factor ligands. Platelet-derived growth factor-BB enhanced proliferation, increased the frequency of Sox2+ve hair follicle dermal stem cell progeny and improved inductive capacity of hair follicle dermal stem cells in an ex vivo hair follicle formation assay. Similar effects on proliferation were observed in adult human SKPs. Our findings impart novel insights into the signals that comprise the adult hair follicle dermal stem cell niche and suggest that platelet-derived growth factor signaling promotes self renewal, is essential to maintain the hair follicle dermal stem cell pool and ultimately their regenerative capacity within the hair follicle.

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Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells.

Publications

Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells.

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