Mechanisms of developmental gene activation in the regeneration and repair of acute kidney injury
Final Report Abstract
Acute Kidney Injury (AKI) is defined as a sudden but reversible decline in kidney function and is one of the most common diseases in hospitalized patients. The underlying molecular mechanisms of AKI remain elusive. One of the reasons for this lies in the differences between human and mouse or rat kidneys. Therefore, many questions regarding AKI could not be profoundly answered. One of these questions is why a re-activation of developmental genes like PAX2 that usually is not expressed in the adult kidney occurs, upon AKI. Since a couple of years human cell-derived 3D models serve as a relatively new platform for kidney research. Human pluripotent stem cells (hSPCS) are treated with various agents and factors in order to generate kidney organoids. These match genetically fetal kidneys and contain structures as glomeruli, tubuli, stromal cells etc. and are capable of mimicking physiological reactions of the adult kidney. This project’s aim was to investigate the role of PAX2 expression upon toxininduced AKI. During this project we differentiated wild-type hSPCs cells as well as hPSCs with a knock-out of the PAX2 gene to kidney organoids and characterized them. PAX2 KO organoids display a distinct phenotype that is indicative of a hampered mesenchymal-toepithelial transition with less glomerular and tubular structures. We also demonstrate that kidney organoids mimic PAX2 upregulation upon toxic injury which is accompanied by an upregulation of kidney injury markers. Furthermore, PAX KO organoids have higher expression levels of some fibrosis and proliferation markers. Upon addition of toxins a higher mitochondrial stress reaction can be detected in KO lines. This leads to the conclusion that Pax2 play a role in these processes. My work on kidney organoids has been mentioned by Bayerischer Rundfunk in a web article.
Publications
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IBEC Symposium - Bioengineering for Future and Precision Medicine, Barcelona 2020- Studying Wilms Tumor (WT1) function in human kidney development and disease using human pluripotent stem cells-derived organoids and genome editing
Wajima Safi
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Assessing kidney development and disease using kidney organoids and CRISPR engineering. Frontiers in Cell and Developmental Biology, 10.
Safi, Wajima; Marco, Andrés; Moya, Daniel; Prado, Patricia; Garreta, Elena & Montserrat, Nuria
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Dissecting nephron morphogenesis using kidney organoids from human pluripotent stem cells. Current Opinion in Genetics & Development, 72, 22-29.
Garreta, Elena; Nauryzgaliyeva, Zarina; Marco, Andres; Safi, Wajima & Montserrat, Nuria
