Dissecting Heterogeneity Reveals a Unique BAMBI^high MFGE8^high Subpopulation of Human UC-MSCs

Mixed human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are widely applied in clinical trials to treat various diseases due to their multipotent differentiation potential and immune regulatory activities. However, the lack of a clear understanding of their heterogeneity hampers their application to precisely treat diseases. Moreover, few studies have experimentally authenticated the functions of so-called UC-MSC subpopulations classified from scRNA-seq samples. Here, this work draws a large-scale single-cell transcriptomic atlas and identified three clusters (C1, C2, and C3), representing the primed, intermediate, and stem statuses individually. The C1 and C3 clusters feature higher expression of cytokines and stemness markers, respectively. Surprisingly, further experimental assays reveal that the BAMBI^high MFGE8^high C1 subgroup has a unique phenotype, distinct transcriptomic profile, and limited adipogenic differentiation potential but compromised immunosuppressive activity in vitro and in vivo in lupus mice. Thus, this work is helpful to clarify the nature of human UC-MSCs and to choose optimal MSC types to treat specific diseases in the future.