Thinking out of the dish: what to learn about cortical development using pluripotent stem cells

Abstract

The development of the cerebral cortex requires the tightly coordinated generation of dozens of neuronal subtypes that will populate specific layers and areas. Recent studies have revealed how pluripotent stem cells (PSC), whether of mouse or human origin, can differentiate into a wide range of cortical neurons in vitro, which can integrate appropriately into the brain following in vivo transplantation. These models are largely artificial but recapitulate a substantial fraction of the complex temporal and regional patterning events that occur during in vivo corticogenesis. Here, we review these findings with emphasis on the new perspectives that they have brought for understanding of cortical development, evolution, and diseases.

Neural commitment of human pluripotent stem cells under defined conditions recapitulates neural development and generates patient‐specific neural cells

“…In conclusion, our defined culture system provides a way to recapitulate some of the temporal and regional patterning events that occur during in vivo cortical neurogenesis [52]. Also, by deconstructing the natural complexity of neural development into a simpler experimental approach, we could mimic several aspects of Rett syndrome pathology potentially contributing to a better understanding of cortical development and disease.…”

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

“…The cell population in RA/FGF-2 group was more similar to the Cyclo group, indicating that this condition favored the generation of cortical neurons [24]. The loss of pluripotency marker Oct-4 during neural ectoderm induction and neural patterning was also confirmed (Figure 3).…”

“…As a ventralization factor, SHH influences neural patterning (D-V axis) in forebrain, midbrain, and hindbrain [52]. SHH activation plus Wnt inhibition results in the generation of ventral telencephalic cells [25], while SHH inhibition leads to the generation of dorsal telencephalic progenitors and helps cortical tissue development [24]. On the contrary, Wnt activation enriches neural progenitor populations from posterior (P) hindbrain/spinal cord and is used for deriving motor neurons, while low Wnt signaling is required for generating anterior (A) forebrain neurons (affecting A-P axis) [15,44,53].…”

“…Additional characterizations were performed on day 35 cells using neural patterning marker TBR1 (a deep cortical layer VI marker [24]) and ISL1 (Islet-1, another marker for motor neurons [43]) (Figure 4Ai, 4Aii). Here, the Cyclo and Purmo groups were compared with RA/FGF-2 as well as no growth factor control (no GFs).…”

“…In neural patterning of brain tissues, i.e., the process through which neural progenitors acquire brain regional identity, activation of sonic hedgehog (SHH) signaling induces ventral (V) identity of the developing neural ectoderm while SHH inhibition generates dorsal (D) telencephalic progenitors (i.e., affects D-V patterning) [24,25]. Thus, differential levels of SHH signaling, in combination with other signaling such as Wnt and retinoic acid, influence neural regional specification of hPSCs into forebrain cortical tissues, midbrain tissues, and hindbrain/spinal cord tissues [6].…”