Regenerating white matter using human iPSC-derived immature astroglia.

Abstract

Astrocytes traditionally were thought to have merely a support function, but are now understood to be important regulators of neural development and function. The immature and mature astrocytes have stage-specific roles in neuronal development. However, it is largely unclear whether human astrocytes also serve stage-specific roles in oligodendroglial development. Owing to the broad and diverse roles of astroglia in the central nervous system, transplantation of astroglia also could be of therapeutic value in promoting regeneration after CNS injury or disease. Our recent study (Jiang et al., 2016) explores the developmental interactions between astroglia and oligodendroglia, using a human induced pluripotent stem cell (hiPSC) model. By generating immature and mature human astrocytes from hiPSCs, we reveal previously unrecognized effects of immature human astrocytes on oligodendrocyte development. Notably, tissue inhibitor of metalloproteinase-1 (TIMP-1) is differentially expressed in the immature and mature human astrocytes, and mediates at least in part the effects of immature human astrocytes on oligodendroglial differentiation. Furthermore, we demonstrate that hiPSC-derived astroglial transplants promote cerebral white matter regeneration and behavioral recovery in a neonatal mouse model of hypoxic-ischemic injury. Our study provides novel insights into the astro-oligodendroglial cell interaction and has important implications for possible therapeutic interventions for human white matter diseases.