Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons
Matthieu Genestine,
Daisy Ambriz,
Gregg W Crabtree,
Patrick Dummer,
Anna Molotkova,
Michael Quintero,
Angeliki Mela,
Saptarshi Biswas,
Huijuan Feng,
Chaolin Zhang,
Peter Canoll,
Gunnar Hargus,
Dritan Agalliu,
Joseph A Gogos,
Edmund Au
Affiliations
Matthieu Genestine
Department of Pathology and Cell Biology, Columbia University, New York, United States
Daisy Ambriz
Department of Pathology and Cell Biology, Columbia University, New York, United States
Gregg W Crabtree
Department of Neurology, Columbia University Irving Medical Center, New York, United States
Patrick Dummer
Department of Pathology and Cell Biology, Columbia University, New York, United States
Anna Molotkova
Department of Pathology and Cell Biology, Columbia University, New York, United States
Michael Quintero
Department of Pathology and Cell Biology, Columbia University, New York, United States
Angeliki Mela
Department of Pathology and Cell Biology, Columbia University, New York, United States
Saptarshi Biswas
Department of Neurology, Columbia University Irving Medical Center, New York, United States
Huijuan Feng
Department of Department of Systems Biology, Columbia University Irving Medical Center, New York, United States
Department of Department of Systems Biology, Columbia University Irving Medical Center, New York, United States
Peter Canoll
Department of Pathology and Cell Biology, Columbia University, New York, United States
Gunnar Hargus
Department of Pathology and Cell Biology, Columbia University, New York, United States
Dritan Agalliu
Department of Pathology and Cell Biology, Columbia University, New York, United States; Department of Neurology, Columbia University Irving Medical Center, New York, United States
Joseph A Gogos
Department of Cellular Physiology and Biophysics, Columbia University, New York, United States; Department of Neuroscience, Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States
Department of Pathology and Cell Biology, Columbia University, New York, United States; Columbia Translational Neuroscience Initiative Scholar, New York, United States
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.
