Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI. [Display omitted] • GH treatment promotes myelin repair and functional recovery after hypoxia • GHR is selectively expressed by a subpopulation of pericytes • GHR-positive pericyte-tip cells lead blood vessel bridging and branching • GHR-positive pericytes modulate angiogenesis and govern myelination indirectly Ren et al. report increased growth hormone level in hypoxic brains and identify growth-hormone-receptor-expressing cells as a sub-group of pericytes that mediate angiogenesis in developing brains. Growth hormone treatment promotes myelination and functional recovery after hypoxia, demonstrating growth hormone receptor as a potential therapeutic target against hypoxic insults. [ABSTRACT FROM AUTHOR]