Research Award Recipients

Human stem cell-derived kidney assembloids for modeling renal tuberous sclerosis complex

Co-applicant(s): Adrianna Douvris

Lay Abstract

Background: Genetic disorders are important causes of chronic kidney disease (CKD). Tuberous sclerosis complex (TSC) is a genetic disorder caused by loss of TSC expression in cells, causing them to grow and divide abnormally, resulting in the development of benign tumors affecting many organs. Notably, up to 4 out of 5 patients with TSC have kidney disease including cysts and benign tumors called renal angiomyolipomas (R-AML), and, rarely, kidney cancer. Importantly, R-AMLs contribute to chronic kidney disease progression by growing and invading into the normal kidney tissue, bleeding, and procedural interventions known as embolization. Understanding how kidney disease develops in people with TSC has been limited because current experimental models do not form R-AMLs. Further, therapies are not curative and are ineffective for some patients. We developed ‘mini kidneys’ from human stem cells, known as kidney organoids, to model TSC kidney disease. This provides a more advanced model compared to traditional cells grown in a dish. We have shown that ‘mini kidneys’ can also be transplanted into mouse kidneys, creating human TSC tumors and cysts in mice with improved cellular maturation to study a complex disease like TSC.

Purpose: Presently, our ‘mini kidneys’ cannot form some important kidney structures and have limitations in how the developing kidney structures organise themselves, limiting their applications. Recently, scientists have made more mature and improved ‘mini kidneys’ named human kidney progenitor assembloids (KPAs). By transplanting them into mouse kidneys, scientists demonstrated kidney-like functions of KPAs including blood filtration, the uptake of proteins by kidney tubular cells, kidney hormone production, and early signs of urine production. Consequently, the purpose of this project is to develop and apply a human KPA model to the study of TSC kidney disease. We predict that the advantages of human KPAs offers us the potential to study the ways in which TSC affects the kidneys, including cyst development ogenesis, R-AML development, and progressive CKD.

Method: We propose to generate these new mini kidneys (KPAs) from human stem cells and use them in mouse transplant experiments to study how TSC kidney disease develops as well as the spectrum of TSC disease manifestations. We will use a novel technology called ‘spatial transcriptomics’ to identify molecular mechanisms that drive TSC kidney disease. This powerful technique allows us to map gene expression activity within the kidney environment. It can be thought of like a city street map: the city and buildings represent the kidney and cells, respectively. The map provides information on which cell types are present, what they are doing, and how they are organized and interacting with one-another.

Anticipated Outcomes: Leveraging human stem cells for making next generation mini kidneys (KPAs) will not only offer new insights into the development mechanisms of TSC lesions, but, will also serve to advance human stem cell research for kidney disease.

Patient engagement: We are well connected with the TSC research and patient advocacy communities (TSC Alliance and LAM Foundation Scientific Advisory Board) as well as local patients. We will present our research at the international research conferences, which include patient discussions, sponsored by these foundations.

Relevance to Patients/Community: The development of robust, physiologically relevant models is critical for novel biomarker and therapeutic development.

Conclusion: As leaders in human stem cell and TSC research, we have the necessary expertise, infrastructure, and tools to advance stem cell-derived models of TSC and KPAs for regenerative medicine applications for a variety of kidney diseases.