Vascular bioengineering of scaffolds derived from human discarded transplant kidneys using human pluripotent stem cell–derived endothelium

Abstract

The bioengineering of a replacement kidney has been proposed as an approach to address the growing shortage of donor kidneys for the treatment of chronic kidney disease. One approach being investigated is the recellularization of kidney scaffolds. In this study, we present several key advances toward successful re‐endothelialization of whole kidney matrix scaffolds from both rodents and humans. Based on the presence of preserved glycosoaminoglycans within the decelullarized kidney scaffold, we show improved localization of delivered endothelial cells after preloading of the vascular matrix with vascular endothelial growth factor and angiopoietin 1. Using a novel simultaneous arteriovenous delivery system, we report the complete re‐endothelialization of the kidney vasculature, including the glomerular and peritubular capillaries, using human inducible pluripotent stem cell –derived endothelial cells. Using this source of endothelial cells, it was possible to generate sufficient endothelial cells to recellularize an entire human kidney scaffold, achieving efficient cell delivery, adherence, and endothelial cell proliferation and survival. Moreover, human re‐endothelialized scaffold could, in contrast to the non‐re‐endothelialized human scaffold, be fully perfused with whole blood. These major advances move the field closer to a human bioengineered kidney.

Stem cells: a potential treatment option for kidney diseases

“…Scaffolds have become a hope for clinical translation due to their features of biocompatibility, biochemical and biological cues for cell adhesion, proliferation, migration, differentiation, and continued function [78,79]. Renal scaffolds were successfully produced from porcine, rat, and human kidneys [80][81][82][83][84]. Considering as a potent cell source for scaffold recellularization, embryonic stem cells and adipose tissue-derived stem cells have been seeded into renal scaffolds, achieving cell adherence, proliferation, differentiation, endothelialization, and vascularization [84][85][86][87].…”

“…Renal scaffolds were successfully produced from porcine, rat, and human kidneys [80][81][82][83][84]. Considering as a potent cell source for scaffold recellularization, embryonic stem cells and adipose tissue-derived stem cells have been seeded into renal scaffolds, achieving cell adherence, proliferation, differentiation, endothelialization, and vascularization [84][85][86][87]. Du et al have first attempted to repopulate a kidney scaffold using hiPSC-derived endothelial cells (hiPSC-ECs) [88].…”

Strategies based on organ decellularization and recellularization

“…Bonandrini et al . supplied these cells through renal artery at a concentration of 12 × 10 6 cells and dynamically perfused the scaffold with a recirculating medium for a maximum of 72 h. Adult‐derived iPSCs represent another inexhaustible but costly alternative . Abolbashiri et al .…”

“… isolated primary porcine renal cells to repopulate decellularized scaffolds and showed that these cells were capable of electrolyte absorption and erythropoietin production. Furthermore, endothelial cells have been used for the repopularization of the vascular tree in bioengineered kidneys to prevent the thrombosis of the otherwise exposed ECM . Song et al .…”

Kidney Organoids and Tubuloids

“…Endothelial cells were present in the cortex with expression levels comparable to normal human kidney. Moreover, hardly any occlusions where detected and the recellularized kidney was successfully perfused with blood [102]. Obviously, re-epithelialization with iPSC-derived renal epithelial cells would be the next step.…”