The aging skin microenvironment dictates stem cell behavior

Abstract

Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.

Glycome profiling by lectin microarray reveals dynamic glycan alterations during epidermal stem cell aging

“…An age‐related decline in tissue regeneration and function could be attributed to an impaired stem cell function, a theory known as “stem cell aging” (López‐Otín, Blasco, Partridge, Serrano, & Kroemer, 2013); however, it remains elusive what are the crucial drivers for aging at cellular and molecular levels. An aged epidermis shows histological and functional changes, including a decreased proliferative capacity (Charruyer et al, 2009; Gilchrest, 1983) and lower success in epidermal engraftment (Piccin & Morshead, 2010), a decrease in epidermal thickness, flattening of epidermal–dermal junction (Changarathil, Ramirez, Isoda, Sada, & Yanagisawa, 2019; Giangreco, Goldie, Failla, Saintigny, & Watt, 2010; Langton, Halai, Griffiths, Sherratt, & Watson, 2016; Makrantonaki & Zouboulis, 2007), delayed wound healing (Keyes et al, 2016), decreased barrier function (Gonzales & Fuchs, 2017), increased risk of cancer (Adams, Jasper, & Rudolph, 2015; López‐Otín et al, 2013), impaired HF stem cell lineages (Matsumura et al, 2016), and interaction with their niche (Ge et al, 2020). Mutant mouse studies and transcriptome analyses have suggested that the age‐related epidermal dysfunction could be due to defects in IFE and HF stem cells to interact with other cell types or extracellular matrix in skin (Ge et al, 2020; Giangreco, Qin, Pintar, & Watt, 2008; Keyes et al, 2016; Liu et al, 2019; Matsumura et al, 2016; Watanabe et al, 2017).…”

Wound Induced Hair Neogenesis – A Novel Paradigm for Studying Regeneration and Aging

“…This increase in regenerative capacity with improved crosstalk between HFSCs and the wound environment underscores the importance of the microenvironment on the plasticity of HFSCs. Interestingly, similar lineage infidelity is also evident in HFSCs mobilized in both young and old animals during the healing response to partial thickness wounds ( Ge et al, 2020 ). In aged animals, these HFSCs migrate from the bulge and express both IFE and HF markers.…”

“…As discussed below, major cytokine pathways driving this decline in cutaneous wound healing are also implicated in WIHN. Further, this same group examined the response of young (2 month) and old (2 year) mice to partial thickness cutaneous wounds ( Ge et al, 2020 ). Skin was removed to the depth of epidermis and partial dermis but with hair follicle bulges left intact.…”

Defining the Skin Cellular Community Using Single-Cell Genomics to Advance Precision Medicine

“…Embryonic single-layered epithelium eliminates unfit cells through apoptosis and/or engulfment in contrast to asymmetric division and/or differentiation by mature epidermal cells (Ellis et al, 2019). Age and the microenvironment have been shown to impact hair regeneration following wounding, as well as rejuvenation of aged stem cells by neonatal dermal cells (Ge et al, 2020).…”