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Abstract: FR-PO360

Kidney Decellularized Extracellular Matrix Enhanced the Vascularization and Maturation of Human Kidney Organoids

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Kim, Jinwon, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Lee, Jong Young, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Jin, Ajou University, Suwon, Gyeonggi-do, Korea (the Republic of)
  • Kim, Yong Kyun, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Nam, Sun-ah, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
Background

Kidney organoids derived from human pluripotent stem cells have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of kidney organoids have been still remained to overcome.
In kidney development, kidney ECM regulate mesenchymal condensation, nephron formation, terminal differentiation of renal tubules, and glomerular basement membrane assembly. Kidney decellularized ECM (dECM) hydrogels contain ECM proteins to provide a microenvironment similar to that of a normal kidney. Our study highlights that kidney dECM hydrogels could be used to more accurately culture kidney organoids.

Methods

Porcine kidneys were decellularized to prepare kidney decellularized extracellular matrix hydrogels. Kidney organoids were differentiated using kidney dECM, and VEGF for enhancing the vascular network and SB-431542 for enhancing podocyte differentiation were added. α-galactosidase A(GLA) mutant iPSCs in which the GLA gene was knocked out were generated using the CRISPR/Cas9. To recapitulate of Fabry Nephropathy with Vasculopathy, GLA-mutant human iPSCs were differentiated into kidney organoids using kidney dECM. We transplanted kidney organoids derived from human iPSCs with kidney dECM beneath the kidney capsule of immunodeficient NOD-SCID mice for engraftment.

Results

The vascularization was extensively increased in the kidney organoids generated by using kidney dECM. Single-cell transcriptomics revealed that the vascularized kidney organoids cultured using the kidney dECM had more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of GLA knock-out hPSC generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulated Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerated the recruitment of endothelial cells from the host mouse kidney and maintained vascular integrity with the more organized slit diaphragm-like structures than those without kidney dECM.

Conclusion

Our data suggest that kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.