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Kidney Week

Abstract: PO0883

Successful Introduction of Renovascular Units into the Mammalian Kidney

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Pleniceanu, Oren, Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
  • Gnatek, Yehudit, Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
  • Rosenzweig, Barak, Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
  • Eisner, Alon, Assuta Ashdod Hospital, Ashdod, South, Israel
  • Dotan, Zohar A., Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel
  • Fine, Leon G., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Greenberger, Shoshana, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
  • Dekel, Benjamin, Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
Background

Various cell-based therapies, aimed at replenishing renal parenchyma, have been proposed as means to treat chronic kidney disease (CKD). However, a key limitation to the applicability of these strategies is the failure of in-vivo administered cell types to develop donor-derived vessels, resulting in poor graft survival. Similarly, such strategies do not address renal hypoxia, a key factor in CKD progression. We hypothesized that administering self-organizing human renal tubule-forming cells (RTFCs) derived from adult and fetal kidneys, previously shown to exert a functional effect in CKD mice, alongside mesenchymal stromal cells (MSCs) and endothelial colony-forming cells (ECFCs), would result in generation of both vessels and tubules with potential interaction.

Methods

NOD-SCID mice were injected with either RTFCs or a mix of RTFCs, MSCs and ECFCs in Matrigel into the sub-cutis (SC), under the renal capsule or into the renal parenchyma. The resulting grafts were analyzed after 2 weeks.

Results

While RTFC-derived grafts harbored few host-derived vessels, injection of MSC, ECFCs and RTFCs into the SC, sub-renal capsular space, or renal parenchyma, resulted in robust formation of donor-derived reno-vascular units. These consisted of both well-developed renal tubules tubular epithelia of different nephron segments, and human vascular networks, which connect to host vasculature. The latter demonstrated the presence of both CD31+ endothelium and αSMA+ pericytes, originating from administered ECFCs and MSCs, respectively. Notably, MSC/ECFC-derived vessels augmented in-vivo tubulogenesis by RTFCs while in vitro co-culture experiments showed MSC/ECFCs to induce self-renewal and mesenchymal-epithelial transition-associated genes in RTFCs, disclosing paracrine effects.

Conclusion

Combined cell therapy of vessel-forming cells and RTFCs aimed at enhancing tubulogenesis and potentially alleviating renal hypoxia may serve as the basis for new renal regenerative therapies.