Adipose tissue-derived stromal cells stimulated macrophages-endothelial cells interactions promote effective ischemic muscle neovascularization

Neovascularization, the process of new blood vessels formation in response to hypoxia induced signals, is an essential step during wound healing or ischemia repair. It follows as a cascade of consecutive events leading to new blood vessels formation and their subsequent remodeling to a mature and functional state, enabling tissue regeneration. Any disruption in consecutive stages of neovascularization can lead to chronic wounds or impairment of tissue repair. In the study we try to explain the biological basis of accelerated blood vessels formation in ischemic tissue after adipose tissue-derived stromal cells (ADSCs) administration. Experiments were performed on mouse models of hindlimb ischemia. We have evaluated the level of immune cells (neutrophils, macrophages) infiltration. The novelty of our work was the assessment of bone marrow-derived stem/progenitor cells (BMDCs) infiltration and their contribution to the neovascularization process in ischemic tissue. We have noticed that ADSCs regulated immune response and affected the kinetics and ratio of macrophages population infiltrating ischemic tissue. Our research revealed that ADSCs promoted changes in the morphology of infiltrating macrophages and their tight association with forming blood vessels. We assume that recruited macrophages may take over the role of pericytes and stabilize the new blood vessel or even differentiate into endothelial cells, which in consequence can accelerate vascular formation upon ADSCs administration. Our findings indicate that administration of ADSCs into ischemic muscle influence spatio-temporal distribution of infiltrating cells (macrophages, neutrophils and BMDCs), which are involved in each step of vascular formation, promoting effective ischemic tissue neovascularization.