Diosgenin enhances transplanted human oligodendrocyte precursor cell-mediated myelination in preterm white matter injury by inhibiting matrix metalloproteinase-9–driven TGF-β/Smad2/3 signaling
Preterm white matter injury (PWMI) is a major cause of long-term motor and cognitive disability, and there are no therapies that directly promote oligodendrocyte-lineage maturation. Here, we identify the natural steroid sapogenin diosgenin as a potent pro-myelinating modulator for transplanted human oligodendrocyte precursor cells (hOPCs) using a hypoxia–ischemia mouse model of PWMI, together with in vitro microglia–OPC co-culture systems. Diosgenin crosses the blood–brain barrier and promotes the differentiation of both transplanted hOPCs and endogenous OPCs into myelinating oligodendrocytes, thereby accelerating remyelination and improving neurological function. Mechanistic investigations reveal that diosgenin inhibits MMP-9/2 activity. This suppression blunts TGFβ–Smad2/3 signaling in microglia and OPCs, which in turn mitigates microglia activation and upregulates myelin-associated proteins. These findings uncover a previously unrecognized MMP-9–TGFβ–Smad2/3 axis controlling hOPC-mediated myelin repair, and establish diosgenin as a promising adjunct therapeutic agent for cell-based strategies against PWMI and other white matter disorders.