Abstract: Methods for testing the effects of therapeutic compound candidates on a phenotypic organoid model is provided. Such a method includes steps of generating the phenotypic organoid model on a high throughput screening platform, treating the organoid with a therapeutic compound candidate, and testing one or more effects resulting from treatment with each of the therapeutic compound candidates. The testing method that has led to identification of a method for treating or preventing cysts is provided. That method may include contacting a population of cells with an inotrope, wherein the inotrope prevents cyst formation, shrinks existing cysts, or both. That method may be used to treat cystogenic diseases or conditions such as Polycystic Kidney Disease (PKD).

Abstract: Described herein are methods related to generating intermediate mesoderm (IM) cells, including using sequential treatment of small molecules and growth factors, and composition produced by the described methods. Using small molecules such as CHIR99021 in combination with FGF2 and RA, efficient differentiation of human pluripotent stem cells (hPSCs) into intermediate mesoderm, such as PAX2+LHX1+ cells, is achieved. The method is extensible different hPSC cell lines and does not require flow sorting. Importantly, resulting PAX2+LHX1+ cells, are capable of WT1 expression and addition of FGF9 and activin, PAX2+LHX1+ cells specifically differentiates cells into SIX2, SALL1, and WT1 expressing cells representative of cap mesenchyme nephron progenitor cells. The described methods and compositions facilitate and improve the directed differentiation of hPSCs into cells of the kidney lineage for the purposes of bioengineering kidney tissue and iPS cell disease modeling.