Molecular mechanisms and regulation of adipose-derived stem cell differentiation into vascular endothelial cells

Adipose-derived stem cells (ADSCs) possess key advantages including wide availability and robust in vitro expansion. Their multipotency makes them promising seed cells for tissue engineering. Although the adipogenic and osteogenic differentiation of ADSCs is well characterized, their potential for endothelial cell (EC) differentiation and the associated regulatory mechanisms remain comparatively unexplored. Recent studies have demonstrated that endothelial commitment is a multifaceted process that is regulated by the physicochemical microenvironment, bioactive factors, signaling pathways, and biomaterial scaffolds. At the same time, many of these regulatory conditions can also enhance the paracrine activity of ADSCs, thereby promoting angiogenic responses in recipient endothelial cells. A key challenge is that these indirect proangiogenic effects may produce phenotypic and functional outcomes that overlap with those used to evaluate endothelial differentiation, making the two processes difficult to distinguish experimentally. To address this, this review proposes a conceptual framework to clearly differentiate direct endothelial differentiation from paracrine-mediated angiogenic effects. Furthermore, this review critically evaluates the major regulatory strategies reported to influence ADSC endothelial differentiation, summarizes the principal findings and limitations of current evidence, discusses emerging issues in the field, and identifies priorities for clinical translation. Ultimately, this review aims to provide a theoretical foundation and strategic framework for the application of ADSCs in vascular tissue engineering and the treatment of ischemic diseases.