Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development

TLDR

Human stem cell‑derived models of development and neurodegenerative diseases suffer from cellular immaturity, and while micro‑engineered Organ‑Chip systems emulate microvolume cytoarchitecture to enable co‑culture, the role of brain microvascular endothelial cells in early neuronal maturation remains largely unknown. The study aimed to investigate how co‑culturing spinal motor neurons with BMECs in micro‑scale Organ‑Chips affects neuronal maturation, compared to conventional 96‑well plates. Human iPSC‑derived spinal motor neurons and BMECs were co‑cultured in micro‑engineered Organ‑Chips that emulate microvolume cytoarchitecture, and their functional and gene‑expression profiles were compared to 96‑well plate cultures. Seeding BMECs in Organ‑Chips induced vascular‑neural interactions and gene activation that enhanced neuronal function and in vivo‑like signatures, demonstrating that the vascular system specifically promotes maturation of spinal cord neural tissue and brings stem‑cell models closer to in vivo conditions.

Abstract

Human stem cell-derived models of development and neurodegenerative diseases are challenged by cellular immaturity in vitro. Microengineered organ-on-chip (or Organ-Chip) systems are designed to emulate microvolume cytoarchitecture and enable co-culture of distinct cell types. Brain microvascular endothelial cells (BMECs) share common signaling pathways with neurons early in development, but their contribution to human neuronal maturation is largely unknown. To study this interaction and influence of microculture, we derived both spinal motor neurons and BMECs from human induced pluripotent stem cells and observed increased calcium transient function and Chip-specific gene expression in Organ-Chips compared with 96-well plates. Seeding BMECs in the Organ-Chip led to vascular-neural interaction and specific gene activation that further enhanced neuronal function and in vivo-like signatures. The results show that the vascular system has specific maturation effects on spinal cord neural tissue, and the use of Organ-Chips can move stem cell models closer to an in vivo condition.