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Kidney Week

Abstract: SA-PO331

Kidney Organoid Transplantation Promotes Endothelial Cell Proliferation and Transition Toward a Human Fetal Arterial/Afferent Arteriolar-Like Phenotype

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Dumas, Sébastien J., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Koning, Marije, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Meta, Elda, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • Lievers, Ellen, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Borri, Mila, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • Luo, Yonglun, Aarhus Universitet, Aarhus, Denmark
  • van den Berg, Bernard, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Carmeliet, Peter, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • Van den Berg, Cathelijne W., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Rabelink, Ton J., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
Background

Kidney organoids (KORs) derived from induced pluripotent stem cells hold promise for regenerative medicine and kidney modeling. However, KORs lack proper vascularization, hindering maturation despite the emergence of endothelial cells (ECs). In vivo KOR transplantation prevents EC regression, enabling chimeric vascularization, blood perfusion, and nephron maturation. This study aimed to characterize the molecular effects of KOR transplantation on ECs.

Methods

Day7+12 KORs were transplanted into chicken embryos for 1 or 8 days, or further cultured in vitro for the same time period. FACS-sorted CD31+ KOR ECs underwent scRNA-seq (11,966 ECs). A human fetal kidney EC reference (8-17 weeks of gestation, >3,000 ECs) was created from publicly available scRNA-seq data. Immunostainings were performed to validate the findings.

Results

Both time and transplantation altered KOR EC transcriptomes, with the latter having a greater impact. KOR transplantation induced a metabolic transcriptome switch from oxidative phosphorylation to glycolysis, associated with hypoxia response geneset enrichment at day 1. At day 8, KOR transplantation prevented DNA damage response and decreased nuclear division, while upregulating antigen presentation, matrix deposition, angiogenesis, blood coagulation/circulation genesets, indicating response to blood perfusion. Consistent with angiogenesis, EC proliferation was increased in that condition (especially in M phase), as confirmed by Ki67 staining. ECs also underwent a major vein-to-arterial phenotypic transition, with a decreased pool of NR2F2+ ECs and the emergence of arterial ECs, and upregulated EC tissue-specific genes (especially kidney-related). Arterial ECs characterized by laminar shear stress response and Notch signaling, showed a similar transcriptome as human fetal kidney arterial/afferent arteriolar ECs. Transplantation-induced EC reprogramming involved SOX7 transcription factor upregulation and regulon enrichment.

Conclusion

KOR transplantation led to the development of arterial ECs alike human fetal kidney artery/afferent arteriolar ECs, likely via SOX7 and blood flow exposure. These findings provide insights for the development of KOR vascularization strategies.