Investigating mechanical regulation of nephrogenesis using viscoelastic biomaterials and kidney organoids

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PROJECT SUMMARY Chronic kidney disease (CKD) affects ~15% of adults in the US and is associated with the irreversible loss of nephrons, which form the basic functional unit of the kidney. There is currently no cure for CKD, and treatments such as kidney transplantation and dialysis have a high morbidity and mortality. Developing strategies for repairing or replacing nephrons will address this significant public health problem by providing an alternative treatment for patients and a new model of kidney development and disease for drug screening. Mechanical properties of the extracellular matrix, such as stiffness and viscoelasticity, regulate key aspects of cell behavior that drive nephrogenesis in vivo, including proliferation, differentiation, and migration. However, while the molecular mediators that drive nephrogenesis have been studied extensively, the role of matrix mechanics in nephrogenesis remains unclear. Beyond elucidating the role of biomechanics in kidney development, understanding the functional role of the mechanical microenvironment in nephrogenesis will help to inform engineering strategies to reproduce nephrogenesis in vitro. The goal of this proposal is to integrate 3D viscoelastic alginate hydrogels and kidney organoids to test the hypothesis that the mechanical microenvironment regulates nephrogenesis. The first aim is to determine the role of matrix stiffness and viscoelasticity in the differentiation of human pluripotent stem cells into multipotent nephron progenitor cells and the subsequent cellular organization of nephrons in kidney organoids. The second aim is to investigate how hydrogel architecture affects the morphology and maturation of kidney organoids. These aims will be accomplished by integrating bioengineering, biomaterials, developmental biology, computational modeling, and mechanical characterization techniques. Completion of this project will deepen our understanding of the role of the mechanical microenvironment in the formation of nephrons and will fill a substantial knowledge gap regarding our fundamental understanding of kidney development and stem cell differentiation in vivo. This work will also illuminate design principles for engineering new biomaterials that support nephrogenesis in culture and the regeneration of nephrons in vivo. The training will take place in the Mooney Lab at Harvard University in collaboration with the Mahadevan Lab at Harvard University and the Bonventre Lab at Brigham and Women's Hospital. The training plan will enhance the applicant’s skills in biomaterials design, quantitative biology, and kidney organoid culture and provide a broad understanding of kidney development and disease.