Microglial TGFb1 coordinates the multicellular post-stroke reparative process via regulating metabolic reprogramming, extracellular matrix, and immune infiltration
Ischemic stroke triggers complex multicellular responses that coordinate inflammation, tissueremodeling, and repair. Microglial TGFb signaling is known to maintain microglial homeostasisunder physiological conditions, but its role in shaping post-stroke recovery remains unclear. Herewe show that microglia derived TGFb1 is a key regulator of the injured brain environment instroke. Conditional deletion of Tgfb1 in microglia did not affect the infarct area in the acute stageof stroke. Instead, it impaired functional recovery following stroke and reshaped microglialtranscriptional states. scRNAseq analysis show that deletion of microglial Tgfb1 reestablishesmicroglia immature phenotype that persists in the ischemic environment. These changes wereaccompanied by marked alterations in lipid metabolic programs and by reduced Trem2 expression,indicating disruption of cholesterol-handling pathways. Loss of microglial TGFb signaling alsoaltered extracellular matrix responses in astrocytes and fibroblasts in the stroke glial scar andpromoted the accumulation of CD8 positive T cells in the post-ischemic brain. Depletion of CD8 positive T cellsrescued cognitive deficits in Tgfb1 deficient stroke mice while motor impairments remainedunchanged. Together, these findings identify microglial TGFb1 as a central regulator of metabolic,structural, and immune programs that shape tissue repair and functional recovery after ischemicstroke.