Successful introduction of human renovascular units into the Mammalian kidney

Oren Pleniceanu, Orit Harari-Steinberg, Dorit Omer, Yehudit Gnatek, Bat El Lachmi, Osnat Cohen-Zontag, Eugenia Manevitz-Mendelson, Aviv Barzilai, Matan Yampolsky, Yaron Fuchs, Barak Rosenzweig, Alon Eisner, Zohar Dotan, Leon G. Fine, Benjamin Dekel*, Shoshana Greenberger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background Cell-based therapies aimed at replenishing renal parenchyma have been proposed as an approach for treating CKD. However, pathogenic mechanisms involved in CKD such as renal hypoxia result in loss of kidney function and limit engraftment and therapeutic effects of renal epithelial progenitors. Jointly administering vessel-forming cells (human mesenchymal stromal cells [MSCs] and endothelial colony-forming cells [ECFCs]) may potentially result in in vivo formation of vascular networks. Methods We administered renal tubule–forming cells derived from human adult and fetal kidneys (previously shown to exert a functional effect in CKD mice) into mice, alongside MSCs and ECFCs. We then assessed whether this would result in generation of “renovascular units” comprising both vessels and tubules with potential interaction. Results Directly injecting vessel-forming cells and renal tubule–forming cells into the subcutaneous and subrenal capsular space resulted in self-organization of donor-derived vascular networks that connected to host vasculature, alongside renal tubules comprising tubular epithelia of different nephron segments. Vessels derived from MSCs and ECFCs augmented in vivo tubulogenesis by the renal tubule–forming cells. In vitro coculture experiments showed that MSCs and ECFCs induced self-renewal and genes associated with mesenchymal–epithelial transition in renal tubule–forming cells, indicating paracrine effects. Notably, after renal injury, renal tubule–forming cells and vessel-forming cells infused into the renal artery did not penetrate the renal vascular network to generate vessels; only administering them into the kidney parenchyma resulted in similar generation of human renovascular units in vivo. Conclusions Combined cell therapy of vessel-forming cells and renal tubule–forming cells aimed at alleviating renal hypoxia and enhancing tubulogenesis holds promise as the basis for new renal regenerative therapies.

Original languageEnglish
Pages (from-to)2757-2772
Number of pages16
JournalJournal of the American Society of Nephrology : JASN
Issue number12
StatePublished - Dec 2020


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