Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.

Matthieu Genestine,Gunnar Hargus,Edmund Au,Patrick Dummer,Gregg W Crabtree,Dritan Agalliu,Saptarshi Biswas,Michael Quintero,Daisy Ambriz,Anna Molotkova,Peter Canoll,Huijuan Feng,Angeliki Mela,Joseph A Gogos,Chaolin Zhang

doi:10.7554/elife.56063

Matthieu Genestine, Gunnar Hargus + Show 13 more

Open Access

https://doi.org/10.7554/elife.56063

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Abstract

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

Highlights

Cortical interneurons are inhibitory, locally projecting cells that form a distributed network of repetitive circuits throughout the cortex (Kepecs and Fishell, 2014; Tremblay et al, 2016)
Using embryonic mouse development as a model system, we found that interneuron migration coincides with vascularization of the medial ganglionic eminence (MGE), and that by manipulating the degree of MGE vascularization in vivo, it regulates the degree of interneuron migration into the cortex
Cortical interneurons are generated from a distal source and undergo long-distance migration to their final destination in the neocortex

Summary

Introduction

Locally projecting cells that form a distributed network of repetitive circuits throughout the cortex (Kepecs and Fishell, 2014; Tremblay et al, 2016). The process lasts days in mice (Lavdas et al, 1999; Marın and Rubenstein, 2001) and several months in humans (Arshad et al, 2016; Hansen et al, 2013; Ma et al, 2013). This species difference extends to stem cell-derived interneurons where mouse ES-derived interneurons develop rapidly

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