Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

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.

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…Previously it was shown that high‐density NSC cultures spontaneously form neural aggregates that recapitulate several NSC niche components 37. In line with this, large neural aggregates or neural organoids exhibiting CNS tissue architecture have recently been described 38, 39. It has also been proposed that MICs could offer further benefits for culturing NSCs and NSC‐derived cells.…”

Translational potential of human brain organoids

“…Current brain organoids closely resemble fetal brains,28, 30, 66 and can only partially represent the diverse functional cell types of the brain, making them less ideal for studying complex network activities and circuit formations. It also raises the question as in to what extent can brain organoids effectively model neuropsychiatric or neurodegenerative diseases.…”

From stem cells to comparative corticogenesis: a bridge too far?

“…This human specific control could be due to genetic mutation in the human lineage (7) as illustrated by the gene Arhgap11b arisen from a duplication specific to the human lineage and involved in cortical expansion (3). This cell-autonomous control of precursor dynamics could also be due to specific regulation of gene expression [lnRNA (50,51); miRNA (52); different timings of gene expression (1,6,53)]. …”

“…Despite a wealth of recent influential studies addressing the specific features of the human gene regulatory network of corticogenesis (1)(2)(3)(4)(5)(6)(7), the question of what makes us human is still unresolved. The human cerebral cortex has achieved a unique degree of complexity considered to underlie the emergence of unrivaled cognitive abilities compared to other species including non-human primates (8,9).…”