The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.

The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB^−/− and MTTP^−/− organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.

The development of microglia: Microglia are the brain's immune cells, and they play important roles in health and neurodegenerative disease. Kracht et al. performed single-cell analysis of human microglial gene expression and chromatin accessibility and compared the results with those of other studies of human and mice microglial development. By using in situ validation, these data identify fetal microglial subsets that appear to be distinct from adult human microglia, suggesting functional differences between the developing and mature brain. Science , this issue p. 530

The current understanding of mammalian kidney development is largely based on mouse models. Recent landmark studies revealed pervasive differences in renal embryogenesis between mouse and human. The scarcity of detailed gene expression data in humans therefore hampers a thorough understanding of human kidney development and the possible developmental origin of kidney diseases. In this paper, we present a single-cell transcriptomics study of the human fetal kidney. We identified 22 cell types and a host of marker genes. Comparison of samples from different developmental ages revealed continuous gene expression changes in podocytes. To demonstrate the usefulness of our data set, we explored the heterogeneity of the nephrogenic niche, localized podocyte precursors, and confirmed disease-associated marker genes. With close to 18,000 renal cells from five different developmental ages, this study provides a rich resource for the elucidation of human kidney development, easily accessible through an interactive web application. Regenerative medicine offers an exciting avenue to potential cures of kidney disease. However, a detailed knowledge of the structure and embryonic development of the kidney is crucial, both for stimulating regeneration in the body and for growing healthy kidney tissue in a dish. Most of such knowledge has been obtained from mice, whose development differs in crucial ways from that of humans. We therefore studied the composition of human fetal kidney tissue from five developmental ages, using a technique that can measure gene expression in individual cells. Our measurements revealed 22 distinguishable cell types, some of which we localized in the tissue by fluorescence microscopy. We found several subpopulations of nephron progenitors—cells that give rise to the nephron, the functional unit of the kidney. Our study also focused on the development of podocytes, a cell type that is crucial for the filtration function of the kidney, and our results might inform attempts to recreate these cells in a dish. We hope that our data set, made conveniently accessible through a web application, will help scientists develop new regenerative medicine approaches to kidney disease.