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This week we profile a recent publication in Nature Communications from the laboratory of Dr. Dario Lemos (pictured, third from left) at Brigham and Women’s Hospital, Harvard Medical School, and Harvard Stem Cell Institute.

Can you provide a brief overview of your lab’s current research focus?

Work in our lab located at the Harvard Institutes of Medicine is focused on tissue regeneration and bioengineering. We employ a combination of approaches, including the use of hPSCs and in vivo models to investigate kidney injury and renal disease.

What is the significance of the findings in this publication?

Our recent publication in Nature Communications showcases a bioengineering approach to model renal diseases associated with Tuberous Sclerosis Complex, using transplanted human iPSC-derived renal organoids. Renal manifestations occur in over 80% of TSC patients, with renal angiomyolipoma and cystic disease representing the most frequent renal lesions. The findings represent the first experimental model of renal angiomyolipoma (AML), a tumor with potential lethality whose mechanisms remain obscure due to the previous lack of appropriate models. We show that AML organoids mimicking kidney AML anatomically and transcriptionally, can be generated from iPSCs derived from a patient, after introduction of a loss-of-function mutation in the TSC2 gene. Using these AML organoids, we further identify a molecular mechanism of tumor resistance previously unknown in these tumors. Key to the entire concept is the use of AML organoid xenografts with which we tested local delivery of rapamycin-loaded nanoparticles as a therapeutic approach to rapidly ablate AMLs without affecting neighboring healthy tissues. Overall the work represents the first iPSC-based bioengineering approach to model rare kidney disease in vivo for therapeutic research purposes.

 

What are the next steps for this research?

The next steps will involve: 1) Getting a deeper understanding of the developmental origin of these tumors, which is currently unknown. 2) Developing novel therapies by targeting signaling pathways that we believe contain good druggable candidate molecules, with the ultimate goal of expanding the therapeutic options for the patients. 3) Exploring the role of the vasculature in the process of tumorigenesis, and for this we are investigating a variety of orthogonal methods in vivo and in vitro.

If you’d like to mention your funding sources, please list them.

Current funding for this project: Paul Teschan Research Fund from Dialysis Clinic, Inc.

 

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