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.