Cortical neurogenesis from pluripotent stem cells: complexity emerging from simplicity

Abstract

The cerebral cortex contains dozens of neuronal subtypes grouped in specific layers and areas. Recent studies have revealed how embryonic and induced pluripotent stem cells (PSC) can differentiate into a wide diversity of cortical neurons in vitro, while recapitulating many of the temporal and spatial features that characterize corticogenesis. PSC-derived neurons can integrate into the brain following in vivo transplantation and display patterns of morphology and connectivity specific of cortical neurons. PSC-corticogenesis thus emerges as a robust model that provides new ways to link cortical development, evolution, and disease.

Figure 1. Modelling temporal and spatial patterning of cortical neuron neurogenesis

(A) PSC cultured under minimal conditions or in the presence of Wnt/Tgfβ/BMP morphogen inhibitors, undergo differentiation towards forebrain/telencephalic identity. In absence or low levels of Shh-signalling, PSC will mostly differentiate into a collection of progenitors of dorsal telencephalon/cortical identity. Subsequent generation of cortical pyramidal neurons follows a temporal patterning, with deep layer neurons being generated earlier than upper layer neurons, eventually followed by a switch to astrocyte production, like in vivo. Human PSC-derived corticogenesis follows a much more protracted time-course than the mouse counterpart, highly reminiscent of the in vivo situation. (B) Schematics of the relationships between the various cellular players of corticogenesis found in vivo. OSVZ/ISVZ, outer/inner subventricular zone. 3D models can recapitulate in a strikingly faithful way the in vivo organization of cortical progenitors and neurons, thereby providing unique tools to study spatial patterning and cytoarchitecture formation.

Figure 2. Comparison of Mouse and Human In Vivo and ESC-based In Vitro PV and SST Interneuron Development

Schematic of a mouse (A) and a human (B) half coronal section at comparable ages during neurodevelopment, embryonic day 13.5 and 15 gestational weeks (not to scale) showing in red the Nkx2.1-expressing medial ganglionic eminence (MGE). The MGE is the progenitor domain for both PV and SST expressing cortical interneurons and is relatively well conserved across species (A, B), as is the progression (C) from Nkx2.1-expressing progenitors, to Lhx6 and then GABA-expressing migratory precursors, then finally to terminally differentiated interneurons. Mouse ESC derived PV and SST expressing cells mature at analogous rates, with both makers detectable by approximately 4 weeks post transplantation into mouse neonatal cortex (D). Conversely human ESC-derived PV and SST expressing cells mature very slowly- also analogously to their in vivo counterparts (E). E=Embryonic Day, DD=Differentiation Day, GW=Gestational Weeks, P=Days After Birth.