The Role of Fat Cells (Adipocytes) in Wound Healing

The study of dermal adipocytes in the skin is leading to a new understanding of skin phsyiology, how the skin maintains and heals itself, and in the development of new procedures and products for wound healing.  Dr. Valerie Horsley, Ph.D., professor of Molecular, Cellular and Developmental Biology and Dermatology at Yale University has pioneered the work of adipocytes in the skin. Her lab has revealed that adipocytes regenerate in the skin and are essential for regeneration of the hair follicle during its normal growth cycle and following injury (Festa et al., 2011; Schmidt and Horsley, 2013). Working with Dr. Matthew Rodeheffer, Ph.D., professor of comparative medicine at Yale University, has identified mesenchymal adipose progenitor cells in the skin and showed that these cells are necessary to induce hair follicle growth (Festa et al., 2011).  These studies showed that the progenitor cells were activated after injury and required for dermal fibroblast migration during wound healing (Schmidt and Horsley, 2013). Her lab has also shown that dermal adipocyte precursor cell self-renewal process decreases as we age and that this process is dependent on PDGF and IGF-1 signaling from macrophages (Gonzalez et al., 2016).  Further, her lab showed that CD301b marks a portion of midphase macrophages and that depletion of CD301b-expressing macrophages was sufficient to induce skin repair defects observed by depletion of myeloid cells more broadly. Transplanting CD301b⁺ macrophages was sufficient to enhance re-epithelialization, dermal proliferation, and fibroblast repopulation during the midstage wound repair. Additionally, they showed that CD301b-expressing macrophage gene expression was enriched for growth factors and cytokines involved in skin regeneration. Therefore, their results identify a subset of CD301b⁺ macrophages critical for activating skin repair during midstage wound healing.  CD301b⁺ macrophage–derived signaling selectively activated the proliferation of adipocyte progenitor cells and not other myofibroblasts.  PDGFC and IGF1 released from macrophages promoted myofibroblast heterogeneity and repair (Shook et al, 2016; Shook et al, 2018). These data are compatible with the function of macrophages in tissue fibrosis, the ability of exogenous PDGFC to rescue delayed skin wound healing in diabetic mice, and the promotion of fibroblast proliferation and repair by IGF1. Further, the importance of adipose derived mesenchymal stem cells in the skin to polarize macrophages from the M1 inflammatory to a M2 anti-inflammatory phenotype may be important in this adipocyte-mediated process of wound healing (Li et al, 2015).

Another important aspect of adipocytes in the skin is to fight infection. Dr. Richard Gallo, MD, PhD, professor and chief of dermatology at UC San Diego School of Medicine, and colleagues have uncovered a previously unknown role for dermal adipocytes – they produce antimicrobial peptides (AMPs) that help fend off invading bacteria, viruses, and fungi.

So contrary to what many people have been told, Fat Isn’t All Bad, especially when considering adipocytes in the skin.

References

Festa, E et al (2011), Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–71 doi:10.1016/j.cell.2011.07.019pmid:21884937

Gonzalez GC et al (2016) Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell19, 738–751 pmid:27746098

Li Q et al (2015) Skin-Derived Mesenchymal Stem Cells Alleviate Atherosclerosis via Modulating Macrophage Function. Stem Cells Transl Med. 4(11): 1294–1301.

Schmidt V and Horsley V (2013) Intradermal adipocytes mediate fibroblast recruitment during skin wound healing.Development 140, 1517–1527 (2013). doi:10.1242/dev.087593pmid:23482487

Shook,B et al (2016) CD301b+ macrophages are essential for effective skin wound healing. J. Invest. Dermatol. 136, 1885–1891 (2016).doi:10.1016/j.jid.2016.05.107pmid:27287183

Shook B et al (2018) Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science, DOI: 10.1126/science.aar2971