Macrophages in cardiovascular fibrosis: novel subpopulations, molecular mechanisms, and therapeutic targets.

Cardiovascular fibrosis is a common pathological process that contributes to the development and progression of various cardiovascular diseases. Despite being widely believed to be an irreversible and relentless process, both preclinical models and clinical trials have demonstrated that cardiovascular fibrosis is an extremely dynamic process. Additionally, as part of the innate immune system, macrophages are heterogeneous cells that are pivotal in tissue regeneration and fibrosis. They participate in fibroblast activation, extracellular matrix remodeling, and the regression of fibrosis. Although we have made some advances in understanding macrophages in cardiovascular fibrosis, a gap still remains between their identification and conversion into effective treatments. Moreover, the traditional M1/M2 paradigm faces many challenges as it does not sufficiently clarify macrophages diversity and their functions. Exploring novel macrophage-based therapies is urgent for cardiovascular fibrosis treatment. Single-cell techniques have shed light on identifying novel subpopulations that differ in function and molecular signature under steady-state and pathological conditions. In this review, we outline the developmental origins of macrophages, which underly their functions; recent technology development in the single-cell era. In addition, we describe the markers and mediators of the newly defined macrophage subpopulations and the molecular mechanisms involved to elucidate potential approaches for targeting macrophages in cardiovascular fibrosis.