Editors' ChoiceWound Healing

Senescent Cells Promote Tissue Repair

Sci. Signal.  06 Jan 2015:
Vol. 8, Issue 358, pp. ec3
DOI: 10.1126/scisignal.aaa5983

Senescent cells no longer go through the cell cycle, contain specific markers (such as high amounts of the cell cycle inhibitor p16INK4a), and have a specific secretory phenotype [senescence-associated secretory phenotype (SASP)]. Although senescent cells have been associated with pathological characteristics of aging, they may also function in tissue remodeling (see Serrano). Demaria et al. engineered mice (p16-3MR) with a complex reporter construct that enabled the visualization of senescent cells in vivo by luminescence, their selective elimination with ganciclovir [(GCV), an otherwise nontoxic drug], and their isolation from other cells by fluorescence-activated cell sorting due to the expression of red fluorescent protein (RFP). Senescent cells identified by luminescence in p16-3MR mice were obvious within 3 days after skin wounding by punch biopsy, peaked in number at 6 days, and returned to barely detectable by 12 days; the abundance of mRNA markers of senescence and SASP changed with similar kinetics. GCV-mediated elimination of senescent cells delayed wound closure. Six days after wounding, GCV-treated wounds had necrotic debris in the gap, wide epithelial edges, reduced angiogenesis and inflammation, little collagen deposition, and few fibroblasts and endothelial cells, compared with wounds in untreated p16-3MR mice. By 15 days after wounding, GCV-treated mice had wounds that were more fibrotic than those from the control mice. Cells sorted from skin biopsies taken of the wound site 6 days after wounding showed that the senescent cells (2-5% of the total cells) were enriched for markers of fibroblast and endothelial cells and that a smaller subset were positive for a myofibroblast marker. Compared with RFP-negative cells, the RFP-positive senescent cells had high amounts of mRNA for the growth factor PDGF-A, and PDGF-A-positive cells were also RFP-positive in samples taken 6 days after wounding. Irradiation of cultured mouse skin fibroblasts and endothelial cells, but not of mouse embryonic fibroblasts, to induce senescence also stimulated the production of PDGF-AA (a homodimeric form of PDGF-A), but not homodimerized PDGF-B (PDGF-BB) or heterodimeric PDGF-AB. When added to nonsenescent murine skin fibroblasts, PDGF-AA increased the proportion of cells that became positive for a myofibroblast marker. Application of PDGF-AA topically to skin wounds in the GCV-treated mice increased the numbers of myofibroblasts at the wound site, increased the kinetics of wound healing, and reduced the collagen deposition at the healed site. Thus, although topical PDGF-B is approved clinically for treating skin ulcers, these results suggest that PDGF-AA may be a better option.

M. Demaria, N. Ohtani, S. A. Youssef, F. Rodier, W. Toussaint, J. R. Mitchell, R.-M. Laberge, J. Vijg, H. Van Steeg, M. E.T. Dollé, J. H. J. Hoeijmakers, A. de Bruin, E. Hara, J. Campisi, An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). [PubMed]

M. Serrano, Senescence helps regeneration. Dev. Cell 31, 671–672 (2014). [PubMed]

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