The 4D nucleome of muscle regeneration in ischemia-induced tissue damage and repair

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ABSTRACT: Ischemia, caused by restriction of blood flow, often results in severe tissue damage. Critical limb ischemia (CLI) is a serious condition in which peripheral artery disease (PAD) leads to irreversible limb muscle damage. About 40% of CLI patients undergo limb amputation one year after diagnosis, and 50% die after five years. Current treatment options focus on improving limb perfusion but these often fail to prevent disease progression, pointing to a critical need for a deeper understanding of the basic mechanisms regulating human muscle regeneration and how they are disrupted by ischemic damage. In the long-term, this information may lead to new regenerative treatment strategies for limb salvage that are independent of limb perfusion. Recent studies suggest that failure of skeletal muscle regeneration is key to determining tissue loss in CLI versus repair. Successful muscle regeneration requires the orchestrated activation, proliferation and differentiation of muscle stem cells (MuSCs, also known as satellite cells) that are normally quiescent. In our preliminary analysis of MuSCs from one representative CLI patient, we found that the transcription of genes important for MuSC regeneration are dysregulated in ischemia, and that these changes are associated with rearrangements in 3D chromatin organization. These finding support the hypothesis that CLI involves a failure in the normal dynamic reorganization of 3D chromatin structure that orchestrates the regeneration of MuSCs. The overall objectives of this study are to identify the spatial-temporal changes of chromatin organization (the 4D nucleome, 4DN) normally associated with regenerative human MuSCs, and to understand the functional consequences of defects in this mechanism for muscle damage in CLI.