Pluripotent stem cells for the study of CNS development

Abstract

The mammalian central nervous system is a complex neuronal network consisting of a diverse array of cellular subtypes generated in a precise spatial and temporal pattern throughout development. Achieving a greater understanding of the molecular and genetic mechanisms that direct a relatively uniform population of neuroepithelial progenitors into diverse neuronal subtypes remains a significant challenge. The advent of pluripotent stem cell (PSC) technology allows researchers to generate diverse neural populations in vitro. Although the primary focus of PSC-derived neural cells has been their therapeutic potential, utilizing PSCs to study neurodevelopment is another frequently overlooked and equally important application. In this review, we explore the potential for utilizing PSCs to study neural development. We introduce the types of neurodevelopmental questions that PSCs can help to address, and we discuss the different strategies and technologies that researchers use to generate diverse subtypes of PSC-derived neurons. Additionally, we highlight the derivation of several thoroughly characterized neural subtypes; spinal motoneurons, midbrain dopaminergic neurons and cortical neurons. We hope that this review encourages researchers to develop innovative strategies for using PSCs for the study of mammalian, and specifically human, neurodevelopment.

Keywords: derivation; development; embryonic; nervous system; neurons; pluripotent; stem cells.

Figure 1

Schematic depicts the origin of embryonic stem cells from the inner cell mass of the blastocyst (A), the stem cell niches in the subventricular zone and the hippocampus in the adult mouse brain (B), and the induced pluripotent stem cells and induced neural cells derived from human fibroblasts (C).

Figure 2

Schematic depicts important secreted signaling factors that pattern the rostro-caudal and dorso-ventral neuraxis during embryonic development. A coronal section through the developing telencephalon is depicted (dotted line, arrow). BMP, bone morphogenetic protein; FGF, fibroblast growth factor; RA, retinoic acid; Shh, Sonic hedgehog

Figure 3

Schematic depicts the general procedure for deriving different neuronal subtypes from PSCs by utilizing secreted patterning factors identified in the developing embryo. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; RA, retinoic acid; Shh, Sonic hedgehog.

Figure 4

Comparison of different techniques for deriving three of the more studied neural cell types: spinal motor neurons (A), midbrain dopaminergic neurons (B), and cortical cells (C). FGF, fibroblast growth factor; RA, retinoic acid; Shh, Sonic hedgehog; IGF, insulin growth factor; AA, arachidonic acid; PN, projection neurons; IN, interneurons; MMC, median motor neurons; LMC, lateral motor neurons; HMC, hypaxial motor neurons; DA, dopaminergic.