Human Kidney Organoids Underscore Importance of Microenvironment in Polycystic Kidney Disease

MedicalResearch.com Interview with:
Benjamin Freedman, Ph.D
.
Assistant Professor | University of Washington
Department of Medicine | Division of Nephrology
Member, Kidney Research Institute
Member, Institute for Stem Cell and Regenerative Medicine
Seattle WA 98109

MedicalResearch.com: What is the background for this new technology and study? What are the main findings?

Response: Polycystic kidney disease (PKD) is the leading genetic cause of end stage renal disease, affecting approximately twelve million people. The hallmark of the disease is the massive expansion of kidney tubules into large, fluid-filled cysts. Although we know the genes that are mutated in this disease, we do not have a firm grasp on what they do to protect the body from disease.

We used a new system, human kidney organoids with gene-edited PKD mutations, to discover how factors outside the cell affect cyst formation. We found that liberating the organoids from plastic dishes into floating cultures greatly increased the number and size of cysts that formed. We also found that PKD organoids had problems in their ability to change the shape of collagen scaffolds surrounding them, compared to control organoids of the same genetic background.

MedicalResearch.com: What should readers take away from your report?

Response: Our findings point to a critical role for microenvironment – the factors around the tubule – in PKD. There have been hints that this might be happening in the past, but for the most part the field has focused on other aspects of PKD. In general, our study nicely illustrates the power of organoid systems for adding and subtracting components to discover their contribution to disease.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We would like to figure out what exactly the proteins encoded by the Polycystic kidney disease genes are doing that is being affected by their surroundings. Now that we have a highly efficient system for generating PKD cysts, we can add in soluble factors, including drug candidates, to see whether they impact cyst formation in the system. Also, the cysts get very large, which opens the opportunity to study them in an unbiased way (e.g. whole transcriptome analysis) to identify unknown contributors toPolycystic kidney disease.

MedicalResearch.com: Is there anything else you would like to add?

Response: We just published another paper in Stem Cells that explores disease modeling in a different type of kidney cell, the podocyte. As in Polycystic kidney disease, we found that studying gene-edited cells in podocytes could provide new insights into the molecular processes that cause kidney disease. We verified these findings in a knockout mouse model as well. Going back and forth between human organoids and tissue samples is a useful approach for studying disease, that will hopefully help us develop therapies that treat the root causes. For the nephrology, a specialty in which effective small molecule therapeutics for specific disorders are not available, this is especially important.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Nat Mater. 2017 Oct 2. doi: 10.1038/nmat4994.

Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.

Cruz NM1,2,3,4, Song X5,6, Czerniecki SM1,2,3,4, Gulieva RE1,2,3,4, Churchill AJ1,2,3,4, Kim YK1,2,3,4, Winston K1,2,3,4, Tran LM1,2,3,4, Diaz MA1,2,3,4, Fu H3,4,7,8, Finn LS9,10, Pei Y5,6, Himmelfarb J1,2,4, Freedman BS1,2,3,4.

https://www.ncbi.nlm.nih.gov/pubmed/28967916

 

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