Internal organs heal injuries with new connective tissue, but the cellular and molecular events of this process remain obscure. By tagging extracellular matrix around the mesothelium lining in mouse peritoneum, liver and cecum, here we show that preexisting matrix was transferred across organs into wounds in various injury models. Using proteomics, genetic lineage-tracing and selective injury in juxtaposed organs, we found that the tissue of origin for the transferred matrix likely dictated the scarring or regeneration of the healing tissue. Single-cell RNA sequencing and genetic and chemical screens indicated that the preexisting matrix was transferred by neutrophils dependent on the HSF–integrin AM/B2-kindlin3 cascade. Pharmacologic inhibition of this axis prevented matrix transfer and the formation of peritoneal adhesions. Matrix transfer was thus an early event of wound repair and provides a therapeutic window to dampen scaring across a range of conditions.
Optimal tissue recovery and organismal survival1 are achieved by tight spatiotemporal tuning of tissue inflammation, contraction and scar-formation. Here, we discover a multipotent fibroblast progenitor marked by CD201 expression in the fascia, the deepest connective tissue layer of the skin. Using murine skin injury models, single-cell transcriptomics, and genetic lineage tracing and ablation models, we demonstrate that CD201+ progenitors pace wound healing by generating multiple specialized cell types from proinflammatory fibroblasts to myofibroblasts in a spatiotemporally tuned sequence. We identify retinoic acid and hypoxia signaling as differentiation checkpoints that control the graduated entry of fascia progenitor into the proinflammatory and myofibroblast states. Modulating their differentiation, with retinoic acid and hypoxia-inducible factor 1-alpha, or genetically ablating this cellular lineage, impaired the graduated appearances of specialized fibroblasts and chronically delayed wound healing. The discovery of fascia progenitors, their microenvironment, and the signaling pathways that control the graduated transitions thereof provides a new roadmap to understand and clinically treat impaired wound healing.
As the first barrier of the human body, the skin has been of great concern for its wound healing and regeneration. The healing of large, refractory wounds is difficult to be repaired by cell proliferation at the wound edges and usually requires manual intervention for treatment. Therefore, therapeutic tools such as stem cells, biomaterials, and cytokines have been applied to the treatment of skin wounds. Skin microenvironment modulation is a key technology to promote wound repair and skin regeneration. In recent years, a series of novel bioactive materials that modulate the microenvironment and cell behavior have been developed, showing the ability to efficiently facilitate wound repair and skin attachment regeneration. Meanwhile, our lab found that the fascial layer has an indispensable role in wound healing and repair, and this review summarizes the research progress of related bioactive materials and their role in wound healing.
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