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Repeal and Replace: Adipocyte Regeneration in Wound Repair

2017; Elsevier BV; Volume: 20; Issue: 4 Linguagem: Inglês

10.1016/j.stem.2017.03.015

1934-5909

Valerie Horsley, Fiona M. Watt,

Wound Healing and Treatments

Adipocyte precursor cells generate lipid-filled mature adipocytes in multiple tissues during a high-fat diet and in skin during hair follicle growth. In Science, Plikus et al. report that myofibroblasts can generate lipid-filled adipocytes in large skin wounds that regenerate hair follicles, suggesting a new source of adipogenic progenitor cells. Adipocyte precursor cells generate lipid-filled mature adipocytes in multiple tissues during a high-fat diet and in skin during hair follicle growth. In Science, Plikus et al. report that myofibroblasts can generate lipid-filled adipocytes in large skin wounds that regenerate hair follicles, suggesting a new source of adipogenic progenitor cells. Skin regeneration after injury requires the coordination of multiple cell types to regenerate epidermal keratinocytes and dermal cells. The epidermis provides an essential barrier against external pathogens and is supported structurally by fibroblasts that produce a rich extracellular matrix (ECM) within the dermis. The dermis also contains multiple other cell types including immune cells, neurons, and lipid-filled adipocytes. While fibroblasts and adipocytes both develop from the mesenchyme (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar), the cellular and molecular mechanisms by which mesenchymal cells regenerate after injury is not well understood. In the past several years, a growing area of inquiry is the role of dermal adipose tissue in skin regeneration. Adipocyte precursor cells (APCs) and/or mature adipocytes have been implicated in several regenerative and pathological processes in the skin including hair follicle regeneration (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar) and fibroblast regeneration after injury (Schmidt and Horsley, 2013Schmidt B.A. Horsley V. Development. 2013; 140: 1517-1527Crossref PubMed Scopus (193) Google Scholar). Despite the emerging importance of both APCs and their lipid-filled mature adipocyte progeny in skin regeneration, the lineages and molecular machinery that control the development and homeostasis of adipogenic cells in vivo remain poorly understood. In traditional models of wound repair in mice and in adult human patients, hair follicles and mature adipocytes do not regenerate. However, hair follicles can regenerate de novo (called wound-induced neogenesis) in the center of mouse wounds if the injury is sufficiently large (see references within Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Science. 2017; 355: 748-752Crossref PubMed Scopus (312) Google Scholar). In a recent study, Plikus and colleagues note that when newly regenerated hair follicles form in sizeable wounds, mature adipocytes are present (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Science. 2017; 355: 748-752Crossref PubMed Scopus (312) Google Scholar). To identify the cellular origins of adipocytes in these wounds, the authors examine the possibility that adipocytes are regenerated by myofibroblasts, which repopulate the dermis of skin wounds after injury (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar, Rinkevich et al., 2015Rinkevich Y. Walmsley G.G. Hu M.S. Maan Z.N. Newman A.M. Drukker M. Januszyk M. Krampitz G.W. Gurtner G.C. Lorenz H.P. et al.Science. 2015; 348: aaa2151Crossref PubMed Scopus (387) Google Scholar, Schmidt and Horsley, 2013Schmidt B.A. Horsley V. Development. 2013; 140: 1517-1527Crossref PubMed Scopus (193) Google Scholar) (Figure 1) and have been shown to generate mature adipocytes in other adipose depots (Jiang et al., 2014Jiang Y. Berry D.C. Tang W. Graff J.M. Cell Rep. 2014; 9: 1007-1022Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Using genetic lineage tracing with SMA-CreER and SM22-Cre mice crossed to a lacZ reporter animal, the authors identify lacZ+ cells adjacent to the regenerated adipose tissue in their large wound model, concluding that myofibroblasts are reprogrammed to generate adipocytes in the skin (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Science. 2017; 355: 748-752Crossref PubMed Scopus (312) Google Scholar). Transcriptional profiling of fibroblasts from these wounds identifies several molecular changes during wound repair, including BMP2 and BMP4 expression. Mice overexpressing the BMP inhibitor, Noggin, in keratinocytes; mice treated with a BMP antagonist, LDN-193189; or mice with a deletion of BMPR1A in myofibroblasts do not regenerate adipocytes, even when hair follicles regenerate. Thus, activation of BMP signaling in myofibroblasts is essential for the formation of mature adipocytes after repair of large wounds. By implicating myofibroblasts as adipogenic cells in the skin, this present study adds to the complexity of our current understanding of dermal mesenchymal cell heterogeneity. Distinct fibroblast cell populations in the skin have been highlighted by several recent studies (Figure 1). Lineage tracing studies in mice reveal that early in development, a common mesenchymal precursor prior to E12.5 generates fibroblasts and APCs later in development and that as the skin matures, these two lineages maintain their own precursors (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar, Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). Furthermore, recent work reveals that myofibroblasts in wounds and fibrotic skin are derived from embryonic precursors that express Engrailed (Rinkevich et al., 2015Rinkevich Y. Walmsley G.G. Hu M.S. Maan Z.N. Newman A.M. Drukker M. Januszyk M. Krampitz G.W. Gurtner G.C. Lorenz H.P. et al.Science. 2015; 348: aaa2151Crossref PubMed Scopus (387) Google Scholar). CD26 is dynamically expressed on fibroblast subpopulations (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar) and the Rinkevich study highlighted the expression of CD26 on myofibroblasts that contribute to ECM production after injury. These studies use standard wound models that fail to regenerate mature adipocytes during healing, and it will be interesting to define whether CD26+ and/or engrailed+ cells form adipocytes in this large wound model. The ability of cells that express myofibroblast markers to generate adipocytes seems contrary to the fibrotic events that reduce adipogenesis in the skin and other adipose depots. Defined as cells that express smooth muscle actin, myofibroblasts have been proposed to derive from fibroblast differentiation and/or the acquisition of contractile phenotypes by existing fibroblasts (Figure 1). Myofibroblast numbers increase within wound beds during skin regeneration and during fibrosis (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar, Rinkevich et al., 2015Rinkevich Y. Walmsley G.G. Hu M.S. Maan Z.N. Newman A.M. Drukker M. Januszyk M. Krampitz G.W. Gurtner G.C. Lorenz H.P. et al.Science. 2015; 348: aaa2151Crossref PubMed Scopus (387) Google Scholar, Schmidt and Horsley, 2013Schmidt B.A. Horsley V. Development. 2013; 140: 1517-1527Crossref PubMed Scopus (193) Google Scholar). Activation of β-catenin in the lower dermal fibroblast lineage leads to conversion of the adipocyte layer into fibrotic dermis (Mastrogiannaki et al., 2016Mastrogiannaki M. Lichtenberger B.M. Reimer A. Collins C.A. Driskell R.R. Watt F.M. J. Invest. Dermatol. 2016; 136: 1130-1142Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Since myofibroblasts may be derived from current mesenchymal populations in the skin and/or from specific myofibroblast progenitor cells, whether the adipogenic capacity of myofibroblasts is a true “reprogramming” event is unclear. Importantly, induction of Sma-CreER activity prior to induction of the sizeable wounds labels only vascular smooth muscle cells within the wounds (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Science. 2017; 355: 748-752Crossref PubMed Scopus (312) Google Scholar), suggesting that pre-existing myofibroblasts are not capable of adipogenesis in large wounds. A standard method in the field to identify APCs involves the analysis of cell surface markers on mesenchymal cells by flow cytometry (Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). APCs express several markers including PDGFRα, CD29, CD34, and Sca1 that when used in combination can purify APCs (Driskell et al., 2013Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Nature. 2013; 504: 277-281Crossref PubMed Scopus (714) Google Scholar, Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). Analysis of APCs in the skin has revealed that they proliferate during hair-cycle-associated adipogenesis (Donati et al., 2014Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Proc. Natl. Acad. Sci. USA. 2014; 111: E1501-E1509Crossref PubMed Scopus (103) Google Scholar, Festa et al., 2011Festa E. Fretz J. Berry R. Schmidt B. Rodeheffer M. Horowitz M. Horsley V. Cell. 2011; 146: 761-771Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar) and following standard injury paradigms (Schmidt and Horsley, 2013Schmidt B.A. Horsley V. Development. 2013; 140: 1517-1527Crossref PubMed Scopus (193) Google Scholar). It is unknown whether APCs are activated in the authors’ large wound model or whether APCs express SMA or SM22, the promoters used to lineage trace myofibroblasts in Plikus et al., thus leaving the residual possibility that APCs can generate myofibroblasts during wound healing. Using a large wound paradigm capable of hair follicle neogenesis (Plikus et al., 2017Plikus M.V. Guerrero-Juarez C.F. Ito M. Li Y.R. Dedhia P.H. Zheng Y. Shao M. Gay D.L. Ramos R. Hsi T.C. et al.Science. 2017; 355: 748-752Crossref PubMed Scopus (312) Google Scholar), this manuscript highlights an emerging theme that hair follicles can influence differentiation and/or maturation of adipocyte lineage cells. Others have shown that activation of hair cycling by hair plucking or keratinocyte-driven expression of activated β-catenin or Shh can induce dermal adipogenesis (Donati et al., 2014Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Proc. Natl. Acad. Sci. USA. 2014; 111: E1501-E1509Crossref PubMed Scopus (103) Google Scholar, Zhang et al., 2016Zhang B. Tsai P.C. Gonzalez-Celeiro M. Chung O. Boumard B. Perdigoto C.N. Ezhkova E. Hsu Y.C. Genes Dev. 2016; 30: 2325-2338Crossref PubMed Scopus (57) Google Scholar). While mesenchymal derived signals such as Pdgfa can also regulate APC proliferation (Rivera-Gonzalez et al., 2016Rivera-Gonzalez G.C. Shook B.A. Andrae J. Holtrup B. Bollag K. Betsholtz C. Rodeheffer M.S. Horsley V. Cell Stem Cell. 2016; 19: 738-751Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar), the work by Plikus et al. further supports the ability of dermal adipocyte lineage cells to respond to signals derived from hair follicles. Further investigation into the source of BMP signals and how hair follicle cells impinge on adipocyte lineage decisions will have implications for adipose regeneration in the skin and regulation in other adipose depots.