Modeling an unusual type of MCDK by human pluripotent stem cells derived kidney organoids

The WNT pathway plays a critical role in kidney development. In accordance, mutations in different components of this pathway are associated with diverse types of renal disorders.

We identified recently a mutation in LRP5, a co-receptor of Frizzled, in a patient with an unusual type of multicystic dysplastic kidney (MCDK). By contrast to other cases of MCDK where the kidneys grow to a certain size during fetal life and then regress after birth, this patient`s kidney continued to grow also after birth, until it reached a size that required a complete nephrectomy. Notably, mutations in LRP5 were not associated previously with MCDK development.

To generate an in-vivo model for this unique type of MCDK, we reprogrammed epithelial cells from the patient`s kidney into iPSCs. Teratoma assay revealed that the LRP5 mutation did not affect the pluripotency of the cells. In accordance with the patient`s phenotype, the kidney organoids differentiated from the LRP5-iPSCs were significantly bigger than the controls and contained structures that resembled cysts morphology. Moreover, immunostaining with markers for proximal and distal tubules showed a significant effect of the mutation on these structures. Finally, Ki67 immunostaining showed that the LRP5-organoids had much more proliferative cells than the controls.

Overall, our results show that the kidney organoids recapitulate the major phenotypes of the patient`s kidney, and thus can be used to explore the cellular and molecular mechanisms underlying the development of this unusual type of MCDK.