Conserved and Divergent Features of Human and Mouse Kidney Organogenesis

Abstract

Human kidney function is underpinned by approximately 1,000,000 nephrons, although the number varies substantially, and low nephron number is linked to disease. Human kidney development initiates around 4 weeks of gestation and ends around 34-37 weeks of gestation. Over this period, a reiterative inductive process establishes the nephron complement. Studies have provided insightful anatomic descriptions of human kidney development, but the limited histologic views are not readily accessible to a broad audience. In this first paper in a series providing comprehensive insight into human kidney formation, we examined human kidney development in 135 anonymously donated human kidney specimens. We documented kidney development at a macroscopic and cellular level through histologic analysis, RNA hybridization, immunofluorescence studies, and transcriptional profiling, contrasting human development (4-23 weeks) with mouse development at selected stages (embryonic day 15.5 and postnatal day 2). The high-resolution histologic interactive atlas of human kidney organogenesis generated can be viewed at the GUDMAP database (www.gudmap.org) together with three-dimensional reconstructions of key components of the data herein. At the anatomic level, human and mouse kidney development differ in timing, scale, and global features such as lobe formation and progenitor niche organization. The data also highlight differences in molecular and cellular features, including the expression and cellular distribution of anchor gene markers used to identify key cell types in mouse kidney studies. These data will facilitate and inform efforts to generate human kidney structures and comparative functional analyses across mammalian species.

A Comprehensive Molecular Portrait of Human Urine-derived Renal Progenitor Cells

“…At the anatomical level, human and mouse kidney development differ in timing, scale, and global features such as lobe formation and progenitor niche organization. 21,22,23 These are all further evidence in support of the need of a reliable and robust human renal cell culture model.…”

“…Comparing self-renewal of renal progenitor cells in both human (UdRPCs) and mouse, it is clear that an intricate balance is needed between SIX2, WT1, CITED1 expression and Wnt/β-catenin activity in order to determine the cell fate of nephron progenitor cells. 7,11,17,21 Furthermore, it remains to be determined if indeed there exist subtle human and mouse differences in the gene regulatory network needed to maintain a self-renewing renal progenitor pool in both species and we believe that human UdRPCs as described here will facilitate these studies.…”

“…19 To date, research related to transcriptional regulatory control of mammalian nephrogenesis has been limited to the mouse 6,12 or to transcriptome "snapshots" in human. 20 A recent study demonstrated conserved and divergent genes associated with human and mouse kidney organogenesis, 21 thus further highlighting the need for primary human renal stem cell models to better dissect nephrogenesis at the molecular level. Furthermore, species differences need to be considered, for example, mammalian nephrons arise from a limited nephron progenitor pool through a reiterative inductive process extending over days (mouse) or weeks (human) of kidney development.…”

Spatial Transcriptional Mapping of the Human Nephrogenic Program

“…The 3-D morphologies and protein patterns were consistently sharper in the human nephron across > twenty-five proteins. The size difference and the slower developmental pace of human nephrogenesis, roughly eight times slower to S-shaped body stage than the mouse kidney (Lindström et al, 2018c), likely contribute to the enhanced resolution of human nephrogenesis in our data.…”

Isolation and long-term expansion of a single adult human renal epithelial cell with efficient kidney regeneration capacity

“…Previous studies suggested that the progenitor-like cells identified in rodent systems may not formally extrapolate the situation in the human kidney [27][28][29] . Therefore our successful isolation of REC from the injured mouse kidney encouraged us to further test the "F-Clone" strategy to grow SOX9+ REC in human patients.…”