Abstract Body: Introduction: Chronic limb threatening ischemia (CLTI), the most advanced stage of peripheral arterial disease (PAD), is associated with high rates of amputation and mortality. Despite significant improvements in medical and surgical therapies, the natural history for CLTI patients remains quite poor.

Methods & Results: To uncover novel cell-specific mechanisms for this complex disease we profiled the transcriptome of 124,926 cells across 22 human patients. We integrated our institutional CLTI dataset (n = 12) which includes paired proximal and distal samples obtained from CLTI patients undergoing limb amputation with a publicly available human skeletal muscle dataset (n=10). We identified a CLTI-specific fibro-adipogenic population (FAP) subpopulation with a cellular senescence transcriptional signature. We identified Igfbp4 and Il-6 as marker genes for this senescent FAP cluster. Next, we profiled the plasma of 60 PAD patients and demonstrated that both Igfbp4 and Il-6 were positively correlated with amputation and death.

Conclusions: Collectively, these data identify a sub-population of FAPs as a candidate causal cell-type, in the CLTI limb, that promotes limb loss and death via cellular senescence.