Single cell transcriptomics and chromatin accessibility in human fetal microglia

Microglia, the myeloid cells of the central nervous system (CNS), are heterogeneous and exhibit distinct stages during mouse development; however, human microglia development is not elucidated. Here, single cell gene expression profiles of 15,782 human microglia and bulk chromatin profiles were assessed in 23 fetuses during development from gestational week (GW) 9 to 18. Microglia are highly heterogeneous at all developmental stages and exhibit transcriptional profiles similar to a phagocytic microglia phenotype associated with disease. Microglia start to mature during this developmental period and increasingly express homeostatic and sensome markers at later gestational stages. Concomitantly, chromatin accessibility increases in microglia from older fetuses with underlying transcriptional networks reminiscent of adult microglia. In conclusion, this work demonstrates that microglia already progress to a more mature, immune-sensing competent phenotype during early human fetal development, which might render microglia vulnerable towards environmental or inflammatory perturbations during early pregnancy. Overall design: Single cell RNA sequencing was performed to obtain single cell transcriptomes of microglia from 20 fetal CNS samples derived during GW9-18 (GW9 n=4, GW10 n=3, GW11 n=3, GW12 n=3, GW13 n=1, GW15 n=3, GW16 n=1, GW17 n=1, GW18 n=1). Assay for transposase accessibility sequencing (ATACseq) was performed to obtain chromatin accessibility profiles of bulk microglia from 8 fetal CNS samples derived during GW9-18 (GW9 n=1, GW10 n=1, GW11 n=1, GW12 n=1, GW15 n=2, GW16 n=1, GW17 n=1).