The immunoregulation of dying cell components on macrophages and their therapeutic potential in ischemic muscle regeneration

Date

2021-11-29

Authors

Huang, Wenbai

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Abstract

Skeletal muscle regeneration after serious injury highly relies on local stem cell proliferation and differentiation which are processes that are tightly regulated by macrophages. Utilization of tissue-derived and ex-vivo expanded mesenchymal stromal cells (MSCs) in skeletal muscle regeneration has been heavily researched for the past decades but the results have not been consistent and the potential therapeutic mechanism or mechanisms remains unclear. In this project, we characterized the cell components of MSCs after inducing cell death under different conditions and confirmed their anti-inflammatory and pro-regenerative effects on macrophage polarization in vitro. We further investigated the underlying mechanisms of macrophage polarization by different components resulting from cell death. We found potent therapeutic effects from freeze and thaw (F&T) induced cell debris, and these effects are dependent on the externalization of phosphatidylserine (PtS) on the plasma membrane. In contrast, effects from the supernatant of F&T induced cell death primarily depends on the released protein content. Based on the findings from our in vitro studies, we applied the F&T induced cell supernatant to an animal model of peripheral artery disease (PAD) to treat muscle injury caused by a severe ischemia. This treatment resulted in significantly improved muscle functional and histological recovery as well as increased blood flow to the affected muscles 2 weeks after the injury procedure, validating the therapeutic potential of cell components of MSCs induced by F&T process, obviating the need for a viable cell population to treat injury. This result has implications for cell-free therapeutic approaches for ischemic injury to muscle.

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