Immunomodulatory effects of HUC-MSCs therapy: enhancing adaptive and innate immune responses in aging frailty

Frailty associated with aging, characterized by chronic inflammation and immune dysfunction, poses a significant public health challenge. Human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) exhibit immunomodulatory properties; however, their mechanism of action in frail elderly populations remains unclear. Building on a prior clinical trial investigating HUC-MSCs for elderly frailty (Trial Registration: ClinicalTrials.gov, NCT04314011; PubMed ID: 38679727), this study was conducted to further elucidate the mechanism of action of HUC-MSCs.

We performed a longitudinal single-cell RNA sequencing (scRNA-seq) study on peripheral blood mononuclear cells (PBMCs) from frail elderly patients before and after HUC-MSCs therapy. Immune cell dynamics were analyzed across multiple time points, and cell-cell communication networks were reconstructed. Spearman correlation analyses were performed to link immune changes with clinical frailty and physical performance metrics.

HUC-MSCs induced a time-dependent recalibration of the immune system. An early, transient expansion of MAIT cells (p=0.049) was followed by a sustained reduction in B cell hyperactivity (p=0.032) and a phenotypic shift in naïve B cells. NK cell cytotoxicity was enhanced (increased GNLY), while NKT cells showed modulated stress-response signatures. Cell-cell communication was reorganized, with the EPHA/NRG pathways highlighting CD4⁺ TEM, MAIT, and NKT cells as central signaling hubs. Critically, these immunomodulatory changes were quantitatively associated with clinical improvement: reductions in B cell and innate immune subsets correlated with gains in grip strength and gait speed, while regulatory T cell expansion was linked to improved lower-limb function.

HUC-MSCs restore immune homeostasis in aging frailty through sequential, multi-faceted immunomodulation. The association between specific immune remodeling features and functional recovery positions HUC-MSCs as a promising mechanism-based therapy for aging frailty.