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Skeletal muscle regeneration in the ischemic limb is a complex process dependent on coordinated intercellular communication involving an array of cell types. These interactions are not well-understood, and the development of novel regenerative therapies for peripheral arterial disease will require new insight into the cellular heterogeneity and intercellular signaling that occurs in the ischemic limb. Macrophages play a role in orchestrating critical events in muscle regeneration; hence we sought to characterize their transcriptional signature and identify candidate signaling pathways in the context of limb ischemia.
We applied single-cell RNA sequencing to skeletal muscle obtained from regenerative (C57BL/6) and nonregenerative (BALB/c) mouse limbs at multiple time points following ligation of the femoral artery. We used CellChat, a computation tool, to predict signaling pathway activity between macrophages and muscle satellite cells (MuSC) based on our single-cell data.
We identified 12 distinct macrophage populations in the regenerative and nonregenerative limb, including strain-specific macrophage clusters associated with the response to ischemia. Regenerative macrophages displayed a proliferative phenotype, while nonregenerative macrophages exhibited a persistent proinflammatory phenotype. Additionally, we identified several candidate signaling interactions between specific macrophage clusters and MuSCs. Notable potential interactions included enhanced FN1 to SDC4 and THBS1 to SDC4 signaling between regenerative macrophage and MuSCs, as well as OPN to CD44 signaling between nonregenerative macrophages and MuSCs.
Our study maps the dynamic macrophage response in the ischemic limb at single-cell resolution. This provides a valuable resource to investigate macrophage-mediated mechanisms of skeletal muscle regeneration in response to limb ischemia.
Published online: June 10, 2022
Author Disclosures: D. Peters: Nothing to disclose; Y. Xu: Nothing to disclose; X. Lin: Nothing to disclose; X. Wei: Nothing to disclose; Y. Diao: Nothing to disclose; K. Southerland: Nothing to disclose