Abstract
Background:
Type 2 diabetes is strongly associated with impaired collateralization, which increases the risk of cardiovascular complications, such as myocardial infarction and heart failure. This study explored the immune cell dynamics in patients with type 2 diabetes with chronic total occlusion and their impact on collateralization.
Methods:
Peripheral blood mononuclear cells were extracted from patients with type 2 diabetes with chronic total occlusion, exhibiting either good or poor collateralization. Single-cell RNA sequencing was conducted to profile the quantitative and transcriptomic dynamics of immune cells in these 2 groups. Moreover, coculture experiments were executed, and ischemic models of the hindlimb and myocardium were induced in diabetic mice to corroborate the single-cell RNA sequencing findings. Additional validation was attained by conducting an analysis on a separate cohort of patients.
Results:
Single-cell RNA sequencing of peripheral blood mononuclear cells identified elevated levels of mucosal-associated invariant T (MAIT) cells in patients with poor collateralization. In diabetic mice, inhibition of MAIT cell activation significantly improved angiogenesis under ischemic conditions. In vitro, MAIT cell-derived CCL3L1 (C-C motif chemokine ligand 3-like 1) drove macrophage polarization toward a proinflammatory phenotype through CCR5 (C-C chemokine receptor type 5) interaction. Furthermore, an independent patient cohort confirmed that elevated MAIT cell levels represent an independent risk factor for poor collateralization.
Conclusions:
These findings highlight the critical role of MAIT cells in regulating collateralization in type 2 diabetes chronic total occlusion patients and propose circulating MAIT cell levels as a potential biomarker for predicting and intervening in poor collateralization.