Surface marker-defined functional subpopulations of mesenchymal stromal cells: mechanisms, applications, and clinical...

Mesenchymal stromal cells (MSCs) hold considerable promise in tissue regeneration due to their multilineage differentiation, paracrine signaling, and immunomodulatory capabilities, as evidenced by thousands of clinical trials. However, clinical translation is constrained by inconsistent and unpredictable efficacy. This primarily stems from MSC heterogeneity, including differences in tissue origin, functional subpopulations, donor age and disease status, and phenotypic drift and functional decline during in vitro expansion. Traditional markers recommended by the International Society for Cell Therapy (ISCT), such as CD73, CD90, and CD105, define MSC identity but cannot discriminate functional subpopulations for angiogenesis, bone repair, or immunomodulation. Thus, the absence of functional surface markers has become a fundamental obstacle to precision MSC therapy and robust quality control. Identifying and harnessing functional surface markers that enrich specific regenerative subpopulations represents a key strategy for overcoming heterogeneity and improving the predictability of clinical outcomes. This review focuses on bone and cartilage, adipose, vascular, neural, muscle, and epithelial regeneration. It systematically examines the mechanisms of action and therapeutic applications of these markers and their subpopulations, and discusses the challenges and future directions for clinical translation.