Summary
MicroRNAs (miRNAs) are gene expression regulators and they have been implicated in acquired kidney diseases and in renal development, mostly through animal studies. We hypothesized that the
miR-199a/214
cluster regulates human kidney development. We detected its expression in human embryonic kidneys by
in situ
hybridization. To mechanistically study the cluster, we used 2D and 3D human embryonic stem cell (hESC) models of kidney development. After confirming expression in each model, we inhibited the miRNAs using lentivirally transduced miRNA sponges. This reduced the WT1
+
metanephric mesenchyme domain in 2D cultures. Sponges did not prevent the formation of 3D kidney-like organoids. These organoids, however, contained dysmorphic glomeruli, downregulated
WT1
, aberrant proximal tubules, and increased interstitial capillaries. Thus, the
miR-199a/214
cluster fine-tunes differentiation of both metanephric mesenchymal-derived nephrons and kidney endothelia. While clinical implications require further study, it is noted that patients with heterozygous deletions encompassing this miRNA locus can have malformed kidneys.