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Flexible fate determination ensures robust differentiation in the hair follicle.

ABSTRACT: Tissue homeostasis is sustained by stem cell self-renewal and differentiation. How stem cells coordinately differentiate into multiple cell types is largely unclear. Recent studies underline the heterogeneity among stem cells or common progenitors, suggesting that coordination occurs at the stem cell/progenitor level1-4. Here, by tracking and manipulating the same stem cells and their progeny at the single-cell level in live mice, we uncover an unanticipated flexibility of homeostatic stem cell differentiation in hair follicles. Although stem cells have been shown to be flexible upon injury, we demonstrate that hair germ stem cells at the single-cell level can flexibly establish all of the differentiation lineages even in uninjured conditions. Furthermore, stem cell-derived hair progenitors in the structure called matrix, previously thought to be unipotent, flexibly change differentiation outcomes as a consequence of unexpected dynamic relocation. Finally, the flexible cell fate determination mechanism maintains normal differentiation and tissue architecture against an ectopic differentiation stimulus induced by Wnt activation. This work provides a model of continual fate channelling and late commitment of stem cells to achieve coordinated differentiation and robust tissue architecture.

SUBMITTER: Xin T

PROVIDER: S-EPMC6314017 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Flexible fate determination ensures robust differentiation in the hair follicle.

Xin Tianchi T Gonzalez David D Rompolas Panteleimon P Greco Valentina V

Nature cell biology 20181112 12

Tissue homeostasis is sustained by stem cell self-renewal and differentiation. How stem cells coordinately differentiate into multiple cell types is largely unclear. Recent studies underline the heterogeneity among stem cells or common progenitors, suggesting that coordination occurs at the stem cell/progenitor level<sup>1-4</sup>. Here, by tracking and manipulating the same stem cells and their progeny at the single-cell level in live mice, we uncover an unanticipated flexibility of homeostatic ...[more]

PMID: 30420661

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Project description:Rationale: β-catenin signaling controls multiple fibroblast subsets, with its overactivity promoting the differentiation of hair follicle dermal stem cells (hfDSCs) and the hyperactivation of interfollicular fibroblasts. Understanding the concept of hfDSC activation and modulation offers hope towards the therapeutic armamentarium in dermatology and related comorbidities, as well as their potential applications in gerontology (the study of physiological aging). Having a comprehensive understanding in this stochastic process could also further yield important, novel insights into the molecular basis of skin aging to improve lifespan and preventing aging-related diseases. Methods: A new CD34CrePGR mouse line was generated. Through fate-tracing models and a series of β-catenin genetic experiments, our study depicts how the wound environment increases phosphorylated β-catenin in hfDSCs and facilitates their differentiation into dermal papilla (DP) and dermal sheath (DS). In mice carrying hfDSC-specific activated allele of β-catenin, hfDSCs accelerated their differentiation into DP cells. Results: Notably, with β-catenin stabilization in CD34-expressing cells and potential activation of canonical Wnt signaling, the mutant mice showed a brief increase of hair density in the short term, but over time leads to a senescence phenotype developing premature canities and thinning [hair follicle (HF) miniaturization]. Conclusion: β-catenin signaling drove HF senescence by accelerating differentiation of CD34+ hfDSCs, resulting in phenotypes attributable to the differentiation of the hfDSCs into DP cells and the loss of their stem cell potential. Therefore, our study reveals that the regulation of β-catenin signaling in hfDSCs may potentially become an important subject for future exploration in development of clinically effective therapies for hair loss treatment and an excellent model for revealing new therapeutic approaches to reverse aging or retarding the development of alopecia.

Dataset Information

Flexible fate determination ensures robust differentiation in the hair follicle.

Publications

Flexible fate determination ensures robust differentiation in the hair follicle.

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