Engineering kidney organoids to study the interplay between Tissue Mechanics and Metabolism: from development to disease

Research with human pluripotent stem cells (hPSCs) has led to the development of miniorgan-like structures in culture, so called organoids.

Generally, organoids are generated exploiting cell-autonomous responses of hPSCs with minimal control over the external inputs supplied to the system.

The unrestrained nature of these approaches explains, in part, key shortcomings of the organoid technology, such as limited capacity to recreate all cell types within an organ, maturation and function.Data from my laboratory has shown, for the first time, that the presentation of a physical instruction (elastic modulus-stiffness) during the derivation of hPSCs-kidney progenitor cells results in the generation of hPSCs-kidney organoids with higher differentiation potential and functional attributes.

Similarly, our preliminary results show that boosting metabolic activities differentially regulated upon the presentation of controlled physical cues represents a new strategy to generate specific kidney cells on demand.ENGINORG proposes conceptual and technical advances to mechanistically link how the presentation of controlled physical and metabolic constrains during organoid generation are integrated and resolved through gene expression regulation and epigenetics.

To this end, we will combine micropatterning techniques, hPSCs-genome engineering, metabolomics, biomaterials design and microfluidics.

The identification of the molecular mechanisms connecting how metabolic and mechanical cues modulate cell fate and function will define minimal design principles for the proper control of cell-cell and cell-matrix interplay, and cell organization for organoid generation.

This knowledge will be implemented through three interconnected objectives to understand and model early steps of kidney morphogenesis and Congenital anomalies of the kidney and the urinary tract (CAKUT), which account for ~50% of the etiology of chronic kidney disease in children worldwide.