Cellular recruitment by podocyte-derived pro-migratory factors in assembly of the human renal filter

Analysis of monogenic kidney disease-causing genes, and secondary pathology resulting from systemic diseases including diabetes and hypertension, highlight the importance of the kidney’s filtering system, the renal corpuscles. To elucidate the developmental processes that establish the renal corpuscle, we employed single-nucleus droplet-based sequencing to capture single nuclei from the human fetal kidney. This enabled the identification of distinct cell types of the nephron (podocytes), interstitial (mesangial cells) and vascular (glomerulus) lineages that together generate the renal corpuscles. Computational trajectory analysis identified transient gene expression in the development of these cell types, predicting early precursors or mature podocytes express FBLN2, BMP4 or NTN4, in conjunction with recruitment, differentiation, and modeling of vascular and mesangial cell types into a functional filter. In vitro studies provide evidence these factors exhibit angiogenic or mesangial recruiting and inductive properties consistent with a key organizing role for podocyte precursors in kidney development. Together these studies define a spatiotemporal developmental program for the primary filtration unit of the human kidney and provide novel insights into cell interactions regulating co-assembly of constituent cell types. With the goal of defining the developmental processes of nephron development, we used snDrop-seq to process human fetal kidney samples (n = 4) that included fetal nephrogenic cortex (14.4 and 16.5 week) and renal corpuscles (13 and 15 week). Altogether, we generated 7,018 single-nucleus data sets.