Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

TLDR

Cerebral organoids are 3‑D cultures derived from pluripotent stem cells that model human cortical development, yet it remains unclear how faithfully they recapitulate in‑vivo neural progenitor proliferation and neuronal differentiation programs. The study uses single‑cell RNA sequencing to compare cell composition and progenitor‑to‑neuron lineage relationships between human cerebral organoids and fetal neocortex. The authors performed scRNA‑seq and covariation network analysis on fetal neocortex data to uncover known and novel gene interactions governing neural progenitor proliferation and neuronal differentiation. Organoid cultures contain diverse progenitors and differentiated neuronal and mesenchymal cells, with cortical cells employing gene expression programs remarkably similar to fetal tissue, highlighting genetic features of human cortical development that can be studied in organoids.

Abstract

Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.