Human iPSC-Derived Immature Astroglia Promote Oligodendrogenesis by Increasing TIMP-1 Secretion.

Peng Jiang,Chen Chen,Wenbin Deng,Ying Liu,Xiao-Bo Liu,David E Pleasure

doi:10.1016/j.celrep.2016.04.011

Abstract

Astrocytes, once considered passive support cells, are increasingly appreciated as dynamic regulators of neuronal development and function, in part via secreted factors. The extent to which they similarly regulate oligodendrocytes or proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) is less understood. Here, we generated astrocytes from human pluripotent stem cells (hiPSC-Astros) and demonstrated that immature astrocytes, as opposed to mature ones, promote oligodendrogenesis invitro. In the PVL mouse model of neonatal hypoxic/ischemic encephalopathy, associated with cerebral palsy in humans, transplanted immature hiPSC-Astros promoted myelinogenesis and behavioral outcome. We further identified TIMP-1 as a selectively upregulated component secreted from immature hiPSC-Astros. Accordingly, in the rat PVL model, intranasal administration of conditioned medium from immature hiPSC-Astros promoted oligodendrocyte maturation in a TIMP-1-dependent manner. Our findings suggest stage-specific developmental interactions between astroglia and oligodendroglia and have important therapeutic implications for promoting myelinogenesis.

Highlights

Astrocytes play important roles in organizing and maintaining brain structure and function (Barres, 2008)
Generation of Immature and Mature hiPSC-Astros By using our established protocol (Jiang et al, 2013b), we derived astroglia from two hiPSC lines generated from healthy individuals (Chen et al, 2014a; Figures S1A and S1B)
On P11, we found that administration of both ContsiRNA and TIMP-1siRNA astrocyte-conditioned medium (ACM) significantly increased the number of Olig2+ oligodendroglia on the ipsilateral side and on the contralateral side of the brain compared with administration of Cont medium and mature hiPSC-Astro ACM (Figures 7B and 7E)

Summary

Introduction

Astrocytes play important roles in organizing and maintaining brain structure and function (Barres, 2008). Astrocytes go through prenatal and protracted postnatal maturation during development and can undergo a spectrum of functional changes associated with development (Molofsky et al, 2012; Pekny and Pekna, 2014), serving stage-specific roles in assisting neuronal development, such as synapse stabilization and elimination (Chung et al, 2013; Molofsky et al, 2012). It is unclear how astrocytes, at specific immature and mature stages, may differently regulate the development of oligodendrocytes, myelin-producing cells in the CNS. Astroglia derived from hPSCs provide an unprecedented opportunity to investigate the interaction between oligodendroglia and human astrocytes that are at defined immature and mature stages

Results

Discussion

Conclusion