Targeting mechanisms of kidney ontogenesis: Roles of endothelial progenitors and Wnt5a signaling

Kidney diseases are a serious global health concern, and there is a growing need for treatments, including transplantable organs. Scientists have been working on generating kidney organoids, but one of the main challenges is the lack of endothelial cells (ECs) and blood flow in the organoids, which limits their usability. This thesis focuses on two key questions in kidney development: how the kidney becomes vascularized and how Wnt signaling pathway genes regulate kidney development.
To study kidney vascularization, we developed an improved technique for grafting kidneys onto the chorioallantoic membrane of chicken embryos. We found that intrinsic progenitor- and fully differentiated ECs were mainly responsible for kidney vascularization during grafting. When ECs were depleted, the glomeruli were vascularized by chicken-derived blood vessels.
We also studied the effects of Wnt5a, a gene that plays a crucial role in embryonic development. We found that lack of Wnt5a caused basement membrane organization problems in the glomeruli and collecting duct, which affected extracellular matrix gene expression. Additionally, a variant of the WNT5A gene identified in a human renal disease cohort showed altered protein conformation and function, possibly contributing to congenital kidney disease.
The findings presented in this thesis highlight the significance of blood flow in kidney development and provide a better understanding of kidney development and vascularization, which are critical for developing functional kidney organoids and new therapies for kidney diseases.