Vasculogenesis in kidney organoids upon transplantation
Human induced pluripotent stem cell-derived kidney organoids have potential for disease modeling and to be developed into clinically transplantable auxiliary tissue. However, they lack a functional vasculature, and the sparse endogenous endothelial cells (ECs) are lost upon prolonged culture in vitro, limiting maturation and applicability.
In embryology, the development of the kidney depends on the presence of perfused blood vessels. These supply the tissue with oxygen and nutrients and enable the interaction between podocytes and vascular endothelial cells (ECs) that is necessary for their maturation and development of the glomerular basement membrane (GBM). In kidney organoids maintained in vitro, this interaction does not occur, limiting their maturation as well as their resemblance to in vivo kidney tissue.
researchers have developed a new model to efficiently induce and study the development of a stabilized vascular network in kidney organoids through transplantation in the coelomic cavity of chicken embryos, and demonstrate the essential role of vascularization for organoid maturation and glomerular morphogenesis. This scalable model can be used to identify essential early cues for vasculogenesis and maturation of kidney organoids.
Endogenous organoid-derived ECs which diminish in vitro culture, thrive upon transplantation, invade glomerular structures, and form a chimeric vasculature with invading host-derived endothelial. This implies that organoid vascularization occurs through a combination of vasculogenesis (human,organoid-derived vessels) and angiogenesis (chicken-derived vessels), and is consistent with the main accepted theory that kidney vascularization in embryology depends on angiogenic as well as vasculogenic mechanisms.
Researchers demonstrate that the chimeric neovasculature in transplanted organoids is supported by perivascular stromal cells that interact with the ECs to stabilize and mature the vascular network.
Analysis of the effect of transplantation on the cellular composition of kidney organoids revealed an increase in proportion of mesenchymal cells in organoids. As concerns have been raised about the proliferation of off-target cell types upon transplantation, researchers analyzed the identity of the mesenchymal cells in our organoids. they found a lower percentage of off-target cells and a higher proportion of pericytes/mesangial cells and fibroblasts in transplanted organoids at d7+20 compared to untransplanted controls.
In the human kidney, pericytes play a role in angiogenesis, blood vessel stabilization, and blood pressure regulation and have been implied as a source of mesenchymal stem cells. Mesangial cells are specialized pericytes that interact with glomerular ECs and podocytes to enable glomerular functionality.
The researchers' findings demonstrate the beneficial effect of vascularization on not only epithelial cell types, but also the mesenchymal compartment, inducing the expansion of ´on target´ perivascular stromal cells, which in turn are required for further maturation and stabilization of new vessels.
Koning, M., Dumas, S.J., Avramut, M.C. et al. Vasculogenesis in kidney organoids upon transplantation. npj Regen Med 7, 40 (2022).
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