Summary

In mammalian skin, multiple types of resident cells are required to create a functional tissue and support tissue homeostasis and regeneration. The cells that compose the epithelial stem cell niche for skin homeostasis and regeneration are not well defined. Here, we identify adipose precursor cells within the skin and demonstrate that their dynamic regeneration parallels the activation of skin stem cells. Functional analysis of adipocyte lineage cells in mice with defects in adipogenesis and in transplantation experiments revealed that intradermal adipocyte lineage cells are necessary and sufficient to drive follicular stem cell activation. Furthermore, we implicate PDGF expression by immature adipocyte cells in the regulation of follicular stem cell activity. These data highlight adipogenic cells as skin niche cells that positively regulate skin stem cell activity, and suggest that adipocyte lineage cells may alter epithelial stem cell function clinically.

Resident skin adipocytes regenerate de novo in parallel with the hair cycle Immature adipocytes are necessary and sufficient for hair follicle regeneration Immature adipocytes express PDGF ligands to promote hair regeneration

Tissue niches are essential for controlling stem cell self-renewal and differentiation (Voog and Jones, 2010). Epithelial lineages in the skin are maintained by stem cells that exist in multiple tissue microenvironments (Blanpain and Fuchs, 2006). In particular, the niche for hair follicle stem cells, which reside within the bulge region of the hair follicle, promotes continual and repetitive regeneration of the follicle during the hair cycle. Specialized mesenchymal cells, the dermal papillae (DP), that are associated with the hair follicle can specify epithelial identity, and are thought to control follicular stem cell activity by releasing signaling molecules (Blanpain and Fuchs, 2006, Greco etal., 2009andRendl etal., 2005). Extrinsic signals, such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs) and Wnts can activate stem cell activity in the hair follicle (Blanpain and Fuchs, 2006, Greco etal., 2009andKarlsson etal., 1999). Yet, it remains unclear which cells establish the skin stem cell niche.

Multiple changes within the skin occur during the hair follicle's regenerative cycle (Blanpain and Fuchs, 2006). Following hair follicle morphogenesis (growth phase, anagen), the active portion of the follicle regresses (death phase, catagen), leaving the bulge region with a small hair germ that remains dormant during the resting phase (telogen) (Greco etal., 2009). Anagen induction in the next hair cycle is associated with bulge cell migration and proliferation in the hair germ to generate the highly proliferative cells at the base of the follicle (Greco etal., 2009andZhang etal., 2009). The activated stem cells then differentiate to form the inner root sheath and hair shaft for the new hair follicle.

During activation of hair growth, the expansion of the intradermal adipocyte layer in the skin doubles the skin's thickness (Butcher, 1934, Chase etal., 1953andHansen etal., 1984). The growth of the intradermal adipose depot could occur through adipocyte hypertrophy or adipogenesis. While adipocyte hypertrophy involves lipogenesis, adipogenesis requires the proliferation and specification of adipocyte precursor cells into preadipocytes, which exit from the cell cycle and differentiate into mature, lipid-laden adipocytes (Rodeheffer etal., 2008andRosen and Spiegelman, 2000). Adipogenesis requires the upregulation and transcriptional activity of the nuclear receptor, PPAR in preadipoctyes (Rosen and Spiegelman, 2000), which can be blocked by specific antagonists, bisphenol A diglycidyl ether (BADGE) and GW9662 (Bendixen etal., 2001andWright etal., 2000). Whether intradermal adipocytes undergo hypertrophy and/or adipogenesis during the hair cycle is unknown.

Recent data shows that during the hair cycle, mature intradermal adipocytes express BMP2 mRNA ( Plikus etal., 2008), an inhibitory signal for bulge cell activity ( Blanpain and Fuchs, 2006andPlikus etal., 2008). In addition, reduced intradermal adipose tissue in transgenic mice overexpressing human apolipoprotein C-I in the skin (Jong etal., 1998), fatty acid transport protein (FATP)-4-deficient mice ( Herrmann etal., 2003), and Dgat1/ or Dgat2/ mice ( Chen etal., 2002andStone etal., 2004) results in abnormalities in skin structure and function such as hair loss, epidermal hyperplasia, and abnormal sebaceous gland function. While these data suggest a regulatory role for adipocytes in the skin, these mutations affect multiple cell types in the skin. Thus, the precise role of intradermal adipocytes in skin biology remains unclear.

In this study, we analyze the role of intradermal adipocytes on follicular stem cell activity. Using histological and functional analysis of cell populations of the adipocyte lineage in the skin, we identify a dynamic process of adipogenesis that parallels the activation of hair follicle stem cells. Functional analysis of adipocyte lineage cells in mice with defects in adipogenesis and in transplantation experiments revealed that immature adipocyte cells are necessary and sufficient to drive follicular stem cell activation. Finally, we implicate PDGF signals produced by immature intradermal adipocyte lineage cells in controlling hair regeneration. These data define active roles for intradermal adipocytes in the regulation of the skin tissue microenvironment.

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Adipocyte Lineage Cells Contribute to the Skin Stem Cell ...

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