Spatiotemporal heterogeneity and patterning of developing renal blood vessels
The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3-dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10.5, and begin to show signs of specification by E13.5 when the first arteries can be identified. We then focus on how ECs pattern and remodel with respect to the developing nephron and collecting duct epithelia. ECs circumscribe nephron progenitor populations at the distal tips of the ureteric bud (UB) tree and form stereotyped cruciform structures around each tip. Beginning at the renal vesicle (RV) stage, ECs form a continuous plexus around developing nephrons. The endothelial plexus envelops and elaborates with the maturing nephron, becoming preferentially enriched along the early distal tubule. Lastly, we perform transcriptional and immunofluorescent screens to characterize spatiotemporal heterogeneity in the kidney vasculature and identify novel regionally enriched genes. A better understanding of development of the kidney vasculature will help instruct engineering of properly vascularized ex vivo kidneys and evaluate diseased kidneys.
KeywordsEndothelium Epithelium Blood vessel Nephron Vascular patterning Endothelial cell heterogeneity
We thank Janet Rossant for the Flk1-eGFP mouse line, as well as members of the Cleaver lab, including Caitlin Braitsch, Xiaowu Gu, and David Barry, for discussions and critical reading of the manuscript. We thank the Genepaint.org database for in situ hybridization data (where noted).
Experiments were performed by ED, DBA, ARR, TAW, CC, and GISTJC, DKM, and OC supervised the project and contributed to analysis. ED and OC wrote the text of this article with input from co-authors.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases DK099478 to DKM., DK080004, DK095057, DK106743 to TJC and DK106743, DK079862 to OC; CPRIT RP110405; and National Institute of Heart, Lung, and Blood HL113498 to OC. Deposited in PMC for release after 12 months.
Compliance with ethical standards
Conflict of interest
The authors declare no competing or financial interests.
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