Abstract
Adult mammalian skin has a defective regenerative capacity following full-thickness cutaneous injury; this defect overshadows the complete physiological functions of the skin. Immune-mediated skin reconstruction driven by biological scaffolds is a recently developed innovative repair strategy to support regenerative wound healing. However, to date, little is known about how biological scaffolds orchestrate the immune response to promote regeneration. Here, using acellular dermal matrix (ADM) scaffolds, we discovered that the default pro-inflammatory response was altered in response to a pro-regenerative response characterized by specific M2 polarization. M2 macrophages subsequently produced a series of wound healing factors, including matrix metalloproteinases (Mmps), and growth factors which promoted cell proliferation, stabilized angiogenesis, and remodeled the extracellular matrix. Our investigations further revealed that the M2 polarization of macrophages arose from an ADM scaffold-derived amino acid sufficiency signal by collagen degradation via macrophage phagocytosis, which activated the acid-sensing pathway (v-ATPase, Lamtor1, and mTORC1). Lamtor1, the acid-sensing pathway-associated lysosomal adaptor protein was critical for inducing M2 polarization, while with the presence of extracellular interleukin 4 (IL4). Our results suggest that ADM scaffolds generate a pro-regenerative microenvironment during full-thickness cutaneous wound healing through M2 macrophage polarization via Lamtor1.
Highlights
Restoration of skin integrity and function following injury is crucial for maintaining the survival of most organisms because the skin performs multiple critical functions for the underlying organs
Whereas the acellular dermal matrix (ADM) scaffold-transplanted mice developed vascularized and cellular wound tissue by 10 days post-injury, in the saline-treated mice, the wound tissue was highly hemorrhagic (1.56- and 1.59-fold increase in the area encompassed by erythrocytes in the saline-treated mice compared with the area in the neonatal mouse skin ADM (N-ADM) and adult mouse skin ADM (A-ADM) mice, respectively), indicative of defective repair response (Figures 1D,E), which could be due to the absence of macrophages (Lucas et al, 2010)
We found that the scaffolds generated a proregenerative microenvironment through abundant production of wound healing factors by M2 macrophages, such as matrix metalloproteinases (Mmps) (Mmp3 and Mmp9) and a series of growth factors (Egf, Igf, Pdgf, Tgfβ, and Vegfα), which promoted cell proliferation, stabilized angiogenesis, and remodeled the extracellular matrix (Figure 8A)
Summary
Restoration of skin integrity and function following injury is crucial for maintaining the survival of most organisms because the skin performs multiple critical functions for the underlying organs. Skin-wound repair is a fundamental biological process that involves orchestrated cell signaling events and complex biochemical cascades. Skin has a natural ability to undergo spontaneous repair and regeneration, but the capacity for regeneration is distinctly variable among different species and at different ages (Tanaka and Reddien, 2011). The skin has an extraordinary regenerative capacity and is capable of undergoing complete recreation following injury (Yates et al, 2012). ADM Scaffolds Immune Microenvironment fibrotic scar tissue and an absence of functional skin appendages (Takeo et al, 2015). Achieving scarless wound healing and functional restoration of damaged skin tissue in adults remains a great challenge
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