Hair Follicle Dermal Stem Cells Research Articles

β-Catenin Signaling Evokes Hair Follicle Senescence by Accelerating the Differentiation of Hair Follicle Mesenchymal Progenitors.

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.

Single-Cell RNA Profiling of Human Skin Reveals Age-Related Loss of Dermal Sheath Cells and Their Contribution to a Juvenile Phenotype.

The dermal sheath (DS) is a population of mesenchyme-derived skin cells with emerging importance for skin homeostasis. The DS includes hair follicle dermal stem cells, which exhibit self-renewal and serve as bipotent progenitors of dermal papilla (DP) cells and DS cells. Upon aging, stem cells exhibit deficiencies in self-renewal and their number is reduced. While the DS of mice has been examined in considerable detail, our knowledge of the human DS, the pathways contributing to its self-renewal and differentiation capacity and potential paracrine effects important for tissue regeneration and aging is very limited. Using single-cell RNA sequencing of human skin biopsies from donors of different ages we have now analyzed the transcriptome of 72,048 cells, including 50,149 fibroblasts. Our results show that DS cells that exhibit stem cell characteristics were lost upon aging. We further show that HES1, COL11A1, MYL4 and CTNNB1 regulate DS stem cell characteristics. Finally, the DS secreted protein Activin A showed paracrine effects on keratinocytes and dermal fibroblasts, promoting proliferation, epidermal thickness and pro-collagen production. Our work provides a detailed description of human DS identity on the single-cell level, its loss upon aging, its stem cell characteristics and its contribution to a juvenile skin phenotype.

Hair-Follicle Mesenchymal Stem Cell Activity during Homeostasis and Wound Healing

The mesenchymal components of the hair follicle-the dermal papilla (DP) and dermal sheath (DS)-are maintained by hair follicle dermal stem cells, but the position of this stem cell population throughout the hair cycle, its contribution to the maintenance of the dermis, and the existence of a migratory axis from the DP to the dermis remain unclear. In this study, we show that during homeostasis DP and DS cells are confined to their compartments, and during the regression phase of the hair cycle, some DP/DS cells undergo apoptosis and subsequently are internalized by nearby adipocytes. In contrast, during wound healing, DP/DS cells move toward the wound but do not directly participate in follicle neogenesis. Furthermore, hair follicle dermal stem cells, driving the cyclic renewal of the DS during the hair cycle, are heterogeneous and are housed during the growth phase within the most proximal part of the DS. Our analysis provides insight into the mechanisms of tissue maintenance and reveals a potential function of adipocytes in phagocytosis.

Dysfunction of Hair Follicle Mesenchymal Progenitors Contributes to Age-Associated Hair Loss.

Skin aging is accompanied by hair loss due to impairments in hair follicle (HF) epithelial progenitor cellsand their mesenchymal niche. This inductive mesenchyme, called dermal papilla (DP), undergoes progressive cell loss and eventual miniaturization that contributes to HF pathogenesis. Using laser ablation and fate mapping, we show that HF dermal stem cells (hfDSCs) reconstitute the damaged DP and maintain hair growth, suggesting that hfDSC dysfunction may trigger degeneration of the inductive niche. Fate mapping over 24months revealed progressive hfDSC depletion, and invivo clonal analysis of aged hfDSCs showed impaired self-renewal and biased differentiation. Single-cell RNA-seq confirmed hfDSCs as a central precursor, giving rise to divergent mesenchymal trajectories. In agedskin, hfDSCs exhibited senescent-like characteristics, and senescence-associated secretory phenotypes were identified in the aging HF mesenchyme. These results clarify fibroblast dynamics within the HF and suggest that progressive dysfunction within the mesenchymal progenitor pool contributes to age-related hair loss.

β-catenin activation in hair follicle dermal stem cells induces ectopic hair outgrowth and skin fibrosis.

Hair follicle dermal sheath (DS) harbors hair follicle dermal stem cells (hfDSCs), which can be recruited to replenish DS and dermal papilla (DP). Cultured DS cells can differentiate into various cell lineages in vitro. However, it is unclear how its plasticity is modulated in vivo. Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration. Here we report that activation of β-catenin in DS generates ectopic HF outgrowth (EF) by reprogramming HF epidermal cells and DS cells themselves, and endows DS cells with hair inducing ability. Epidermal homeostasis of pre-existing HFs is disrupted. Additionally, cell-autonomous progressive skin fibrosis is prominent in dermis, where the excessive fibroblasts largely originate from DS. Gene expression analysis of purified DS cells with activated β-catenin revealed significantly increased expression of Bmp, Fgf, and Notch ligands and administration of Bmp, Fgf, or Notch signaling inhibitor attenuates EF formation. In summary, our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors.

1314 Advanced age impairs self-renewal and biases fate choice of hair follicle dermal stem cells

1314 Advanced age impairs self-renewal and biases fate choice of hair follicle dermal stem cells

Hair follicle dermal stem cells and skin-derived precursor cells: Exciting tools for endogenous and exogenous therapies.

Understanding the cellular interactions and molecular signals underlying hair follicle (HF) regeneration may have significant implications for restorative therapies for skin disease that diminish hair growth, whilst also serving to provide fundamental insight into the mechanisms underlying adult tissue regeneration. One of the major, yet underappreciated, players in this process is the underlying HF mesenchyme. Here, we provide an overview of a mesenchymal progenitor pool referred to as hair follicle dermal stem cells (hfDSCs), discuss their potential functions within the skin and their relationship to skin-derived precursors (SKPs), and consider unanswered questions about the function of these specialized fibroblasts. We contend that dermal stem cells provide an important reservoir of renewable dermal progenitors that may enable development of novel restorative therapies following hair loss, skin injury or disease.

Platelet-derived growth factor signaling modulates adult hair follicle dermal stem cell maintenance and self-renewal

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.

Role of dermal stem cells in hair follicle cycling

The hair follicle is composed of the epidermal (epithelial) and dermal (mesenchymal) compartments, whose interaction plays an important role in the morphogenesis and growth of hair follicles, and is also a key factor for successful reconstruction of hair follicles. Generally, dermal cells are considered as inducers, and epithelial cells as responders during the process of hair formation. There are hair follicle dermal stem cells (HFDSCs) in the dermal sheath and hair papilla, which belong to adult stem cells, and are characterized by slow periodicity, undifferentiation, self-renewal and strong proliferative ability in vitro. HFDSCs in the dermal sheath show a relatively long life, and can survive several hair follicle cycles to reconstitute the dermal sheath. In the anagen phase of hair follicle cycles, stem cells in the dermal sheath generate new cells for the hair papilla. In the catagen phase, dermal stem cell progenies move out of the hair papilla or die. HFDSCs are of great significance for reconstruction and repair of hair follicles after occurrence of injuries and diseases. Key words: Hair follicle; Dermis; Stem cells; Biological processes; Hair diseases

Hair Sciences: Hair Follicle Dermal Stem Cells (hfDSCs)

Hair Sciences: Hair Follicle Dermal Stem Cells (hfDSCs)

Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla, and modulate hair type.

The dermal papilla (DP) provide instructive signals required to activate epithelial progenitors and initiate hair follicle regeneration. DP cell numbers fluctuate over the hair cycle, and hair loss is associated with gradual depletion/atrophy of DP cells. How DP cell numbers are maintained in healthy follicles remains unclear. We performed in vivo fate mapping of adult hair follicle dermal sheath (DS) cells to determine their lineage relationship with DP and found that a subset of DS cells are retained following each hair cycle, exhibit self-renewal, and repopulate the DS and the DP with new cells. Ablating these hair follicle dermal stem cells and their progeny retarded hair regrowth and altered hair type specification, suggesting that they function to modulate normal DP function. This work identifies a bipotent stem cell within the adult hair follicle mesenchyme and has important implications toward restoration of hair growth after injury, disease, and aging.

Enrichment and Characterization of Human Dermal Stem/Progenitor Cells by Intracellular Granularity

Adult stem cells from the dermis would be an attractive cell source for therapeutic purposes as well as studying the process of skin aging. Several studies have reported that human dermal stem/progenitor cells (hDSPCs) with multipotent properties exist within the dermis of adult human skin. However, these cells have not been well characterized, because methods for their isolation or enrichment have not yet been optimized. In the present study, we enriched high side scatter (SSC(high))-hDSPCs from normal human dermal fibroblasts using a structural characteristic, intracellular granularity, as a sorting parameter. The SSC(high)-hDSPCs had high in vitro proliferation properties and expressed high levels of SOX2 and S100B, similar to previously identified mouse SOX2+ hair follicle dermal stem cells. The SSC(high)-hDSPCs could differentiate into not only mesodermal cell types, for example, adipocytes, chondrocytes, and osteoblasts, but also neuroectodermal cell types, such as neural cells. In addition, the SSC(high)-hDSPCs exhibited no significant differences in the expression of nestin, vimentin, SNAI2, TWIST1, versican, and CORIN compared with non-hDSPCs. These cells are therefore different from the previously identified multipotent fibroblasts and skin-derived progenitors. In this study, we suggest that hDSPCs can be enriched by using characteristic of their high intracellular granularity, and these SSC(high)-hDSPCs exhibit high in vitro proliferation and differentiation potentials.

Comparative Characterization of Hair Follicle Dermal Stem Cells and Bone Marrow Mesenchymal Stem Cells

We compared the growth and differentiation characteristics of hair follicle-derived dermal stem cells with bone marrow mesenchymal stem cells (MSCs). Follicular dermal cells were isolated from whisker hairs of Wistar rats and bone marrow MSCs were isolated from femora of the same animals. The adherent hair follicle dermal cells showed a fibroblastic morphology in serum-containing culture medium, were CD44(+), CD73(+), CD90(+), and CD34(), and had a population doubling time of 27 h. MSCs isolated from the bone marrow showed a similar morphology and population doubling time and expressed the same cell-surface markers. Following exposure to appropriate induction stimuli, both cell populations had the capacity to differentiate into various mesenchymal lineages, such as osteoblasts, adipocytes, chondrocytes, and myocytes and expressed neuroprogenitor cell markers. The rate and extent of differentiation were remarkably similar for both hair follicleand bone marrow-derived cells, whereas interfollicular dermal cells failed to differentiate. We identified telomerase activity in follicle dermal stem cells and marrow MSCs and demonstrated that they were capable of clonal expansion. In ex vivo analyses, we identified the presence of putative dermal stem cells in the dermal sheath and dermal papillae of the hair follicle. Consequently, the hair follicle may represent a suitable, accessible source for MSCs.