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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 and Shoshana Greenberger
JASN December 2020, 31 (12) 2757-2772; DOI: https://doi.org/10.1681/ASN.2019050508
Oren Pleniceanu
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Orit Harari-Steinberg
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
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Dorit Omer
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
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Yehudit Gnatek
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
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Bat-El Lachmi
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
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Osnat Cohen-Zontag
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
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Eugenia Manevitz-Mendelson
3Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
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Aviv Barzilai
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
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Matan Yampolsky
4Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion–Israel Institute of Technology, Haifa, Israel
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Yaron Fuchs
4Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion–Israel Institute of Technology, Haifa, Israel
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Barak Rosenzweig
5Department of Urology, Sheba Medical Center, Tel Hashomer, Israel
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Alon Eisner
5Department of Urology, Sheba Medical Center, Tel Hashomer, Israel
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Zohar Dotan
5Department of Urology, Sheba Medical Center, Tel Hashomer, Israel
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Leon G. Fine
6Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
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Benjamin Dekel
1The Pediatric Stem Cell Research Institute and Pediatric Nephrology Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Shoshana Greenberger
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
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Visual Abstract

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Significance Statement

Most cell-based renal regenerative strategies are limited by an inability to generate donor-derived vascular networks upon in vivo transplantation, which is especially problematic in hypoxic CKD kidneys. The authors report that coadministering human renal tubule–forming cells and vessel-forming cells (mesenchymal stromal cells and endothelial colony-forming cells) into mice generates in vivo vascularized grafts comprising renal tubules of different nephron segments and donor-derived vessels connecting to host vasculature. The vessel-forming cells enhanced tubulogenic capacity of renal tubule–forming cells by improving graft perfusion and by inducing a protubulogenic state via paracrine mechanisms. These effects occurred with injection of cells into either the subcapsular renal or intraparenchymatic space. The findings suggest that augmenting the regenerative potential of renal cell–based methods through use of vessel-forming cells hold promise.

Abstract

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.

  • renal stem cell
  • vascular endothelial growth factor
  • renal tubular epithelial cells
  • kidney spheres
  • organoids
  • mesenchymal stem cell (MSC)
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (12)
Journal of the American Society of Nephrology
Vol. 31, Issue 12
December 2020
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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
JASN Dec 2020, 31 (12) 2757-2772; DOI: 10.1681/ASN.2019050508

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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
JASN Dec 2020, 31 (12) 2757-2772; DOI: 10.1681/ASN.2019050508
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  • A Comprehensive Map of mRNAs and Their Isoforms across All 14 Renal Tubule Segments of Mouse
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Keywords

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  • vascular endothelial growth factor
  • renal tubular epithelial cells
  • kidney spheres
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  • mesenchymal stem cell (MSC)

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