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Tissue-resident PDGFRα stromal cells modulate both fibrosis and tissue revascularization during wound repair

ABSTRACT: PDGFRα+ cells are interstitial/perivascular mesenchymal progenitor cells that have been associated with fibro-adipogenic processes. However, their function during tissue homeostasis or in response to revascularization and regeneration stimuli remains to be fully defined. Here, by high-throughput transcriptomic analysis, adoptive transfer and multicolor lineage tracking we showed that PDGFRα+ cells from skeletal muscle cluster as a population that is transcriptionally distinct from other mesenchymal stromal cells and with an essential role in tissue revascularization and restructuring of ischemic areas. We further showed that tissue regeneration involves the removal of differentiated PDGFRα+-derived cells, while pathological healing occurred if PDGFRα+-derived cells persisted as terminally differentiated mesenchymal cells (e.g. myofibroblasts). From the perspective of tissue regeneration, these studies support a context-dependent 'yin-yang' biology of PDGFRα+ cells, that possess an innate ability to stabilize newly formed blood vessels and concurrently limit injury expansion after ischemia, while also being capable of promoting fibrosis in an unfavorable environment.

ORGANISM(S): Mus musculus

PROVIDER: GSE101930 | GEO | 2019/07/01

REPOSITORIES: GEO

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Project description:Critical limb threatening ischemia (CLTI), the most severe manifestation of peripheral artery disease, results from the chronic blockade of peripheral vessels, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization and reversal of CLTI. However, the variety in cell types and cell combinations, administration routes or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” for these patients, prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties. Herein, we have evaluated and compared, for the first time, the regenerative and vasculogenic potential of endothelial colony forming cells (ECFCs) isolated from either adipose-tissue (AT-ECFCs) or umbilical cord blood (CB-ECFCs), in combination with AT-derived MSCs, in a murine model of CLTI. Furthermore, the long-term molecular changes in CLTI and in response to both combinations have been analyzed in a proteomic quantitative approach. Overall, the administration of AT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia, which appeared associated to an increased number of vessels in AT treated mice or with wider vessels in CB. Besides, they both modulated the inflammatory and necrotic processes, although the CB group presented the slowest ischemic progression along the assay. Furthermore, many of the protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs induced revascularization (immune response, vascular repair, muscle regeneration, etc).

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Tissue-resident PDGFRα stromal cells modulate both fibrosis and tissue revascularization during wound repair

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