Developmental landscape of human forebrain at a single-cell level unveils early waves of oligodendrogenesis

Abstract

Oligodendrogenesis in the human central nervous system has been mainly observed at the second trimester of gestation, a much later developmental stage compared to mouse. Here we characterize the transcriptomic neural diversity in the human forebrain at post conceptual weeks (PCW) 8 to 10, using single-cell RNA-Seq. We find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level with single-cell ATAC-Seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of fifty key genes using In Situ Sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mouse and human and describe regulatory mechanisms required for human OPC specification.

Oligodendroglia heterogeneity in the human central nervous system

“…These developmental OPC generation routes appear conserved in humans [ 57 , 58 , 78 , 90 ], but there may also be an additional route as primates show an enlarged outer ventricular zone during development compared to rodents [ 29 , 111 , 125 ] and progenitor cells in this zone produce not only neurons [ 9 , 70 ] but also OPCs [ 49 ]. Furthermore, a recent study has shown the presence of OPCs in human embryos at post conception week 8–11 which is earlier than previously assumed and which supports the notion that human oligodendroglia develop in several waves in parallel to what is known in mice [ 14 ].…”

Marked regional glial heterogeneity in the human white matter of the central nervous system

“…COP_C expresses traditional COP markers such as GPR17 , but the other COP clusters (albeit very limited in number in this adult dataset) are low in GPR17 expression (2c). COP_B expresses genes of the astrocyte lineage including SPARCL1 (2c), which has previously been detected in human foetal astrocyte-oligodendrocyte precursor cells 22 and pre-OPCs 34 . As SPARCL1 and SPARC (a marker for Oligo_F) are highly related, and there are more COP_B and Oligo_F cells in the CSC compared to the other tissues (see below), this raises the question as to whether COP_Bs give rise to Oligo_F cells.…”

“…We found marked regional differences between the spinal cord and the brain, so that we can no longer assume parity of physiological, pathological or therapeutic response between the two. The clear difference between posterior (CSC and CB) and anterior OPCs (BA4), and the continued expression of PAX3 and HOX genes even in adulthood in these spinal cord OPCs, strongly suggests that these are derived similarly to in mouse where Pax3 identifies the third wave of OPCs from a dorsal origin 34 . We speculate that these OPCs differentiate into Oligo_F oligodendrocytes which are selective for the CSC and seem only present in humans.…”

“…Oligo_F also express the highest levels of HCN2 which is important for the formation of longer myelin sheaths in mice 33 (Figure 2d). We found two OPC clusters, OPC_A, expressing PAX3 and SLC22A3, suggesting a dorsal origin 34 and OPC_B, expressing NELL1 (Figure 2a-c, Table S2). COP_C expresses traditional COP markers such as GPR17, but the other COP clusters (albeit very limited in number in this adult dataset) are low in GPR17 expression (2c).…”

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

“…Importantly, oRG cells have been shown to give rise to oligodendrocyte progenitor cells (OPC) [ 66 ], although new studies suggest that other neural stem cell populations may generate OPCs at early developmental periods [ 67 ]. Astrocytes have been shown to be a major cellular output of oRG cells [ 68 , 69 ], but recent studies have revealed further complexity that exists within this cell class in both humans and mice [ 70 , 71 , 72 , 73 ], which underscores the need for further studies of their developmental cell lineage.…”