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

Elife. 2021 Apr 27;10:e56063. doi: 10.7554/eLife.56063.

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.

Keywords: brain development; developmental biology; human; interneuron; mouse; neovascularization; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Cell Movement / drug effects*
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / surgery
  • Endothelial Cells / metabolism
  • HEK293 Cells
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation
  • Interneurons / drug effects*
  • Interneurons / metabolism
  • Interneurons / transplantation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Median Eminence / blood supply*
  • Median Eminence / embryology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / transplantation
  • Neurogenesis / drug effects*
  • Osteonectin / metabolism
  • Osteonectin / pharmacology*
  • Paracrine Communication
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activator Inhibitor 1 / pharmacology*
  • Signal Transduction

Substances

  • Apcdd1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Osteonectin
  • Plasminogen Activator Inhibitor 1

Associated data

  • GEO/GSE146991