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. 2022 Feb 10;18(6):1912–1925. doi: 10.1007/s12015-021-10295-8

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a The epidermis is a stratified structure that is composed of the basal cell layer and the underneath basement membrane, spinous layers, granular layers and stratum corneum layers. b Three stochastic and incompatible cell-proliferation models have been used to illustrate epidermal self-renewal, including the single-progenitor (SP) model, two stem-cell (2xSC) model and stem cell-committed progenitor (SC-CP) model. c The heterogeneity of stem cells in hair follicle. The hair follicle stem cells in junctional zone (J-Z) express Lrig1. Stem cell in isthmus express Lgr6. Stem cell in bulge (Bu) area express CD34 and Keratin15 (K15). Stem cells in lower bulge and hair germ express Lgr5, and Shh is uniquely expressed in hair germ. Hair follicle stem cells showed excellent plasticity during skin wounding. Shh+ hair germ cells could contribute to form new epidermis, and the progeny of Shh+ cells could survive in new epidermis over 16 weeks post wounding. K15+ bulge cells could contribute to both new epidermis and hair follicle within the wound. While only a minority of K15+ cell progeny remained at the 50th day post wound (Short-live hair follicle cell progeny, S-HFP). Both the Lgr5+ cells and Lgr6+ cells progeny contribute to from new epidermis and their progeny could been detected in new hair follicle within wound. And the progeny of both Lgr5+ and Lgr6+ follicular cells could been detected after 100 days post wound (Long-live hair follicle cell progeny, L-HFP). SG, sebaceous gland; DP, dermal papilla. d Compartmentalization of hair follicle stem cells underlies different responses to oncogene and skin tumor heterogeneity. Oncogenic β-catenin expression in Lgr5+ cells led to formation of pilomatricomas, while Lrig1+ cells formed trichoadenomas and Lgr6+ cells formed dermatofibromas. Expression of an activated form of Smoothened (SmoM2), a mediator of Hedgehog (Hh) signaling, by K15+ bulge does not produce basal cell carcinomas (BCCs). However, wounding induces these cells from the follicle to the wound site, where downstream Hh signal transduction is derepressed, and giving rise to superficial BCC-like tumors. △β-cat, active form of β-catenin; △Smo, active form of Smothened