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Date: 18 July 2023 (Tuesday)
Time: 11am - 12 pm (SGT) Format: Zoom Webinar (registration is required) Hosted by: Adrian TEO, IMCB, Singapore |
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Speaker's information
Benjamin Freedman University of Washington, USA "Human organoid models of genetic disease" |
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ABSTRACT
We have developed a simple, commercially available method to differentiate human pluripotent stem cells into intricately patterned, multi-segment organoids that resemble kidney tissues. These organoids form via a developmental pathway that induces the nephron progenitor cell, which gives rise to podocytes, parietal cells, proximal tubules, and distal tubules along a proximal-to-distal axis. Each of these cell types exhibits a unique morphology and gene expression profile. They also exhibit unique functional characteristics, which can be assessed in a growing list of physiology assays and mutant phenotypes. For instance, only proximal tubular cells, which express ACE2, can be infected with COVID-19, whereas only podocytes can recruit vascular cells after implantation to form glomerulus-like structures. The organoid developmental trajectory requires modulation of hedgehog signaling through primary cilia, thus cilia knockout stem cells fail to efficiently differentiate into organoids. Mutations associated with polycystic kidney disease or cilia knockout cause organoid tubules to swell thousands of times in size, producing large, fluid-filled cysts of centimeter diameters. Mutations in cystinosin, a lysosomal cystine transporter, result in cystine accumulation and nephron disintegration, similar to the human pediatric disorder, nephropathic cystinosis. These disease models are currently being used to test innovative therapeutics and disease-specific mechanisms. The combination of CRISPR gene editing with organoid differentiation enables new types of cell and developmental biology experiments, with high relevance for human kidney disease and regenerative medicine.
BIO
Benjamin Freedman is a professional scientist who has been continuously studying the cell biology of vertebrate stem cells for twenty years. Hallmarks of his career include 1) the application of stem cells for studying disease and regeneration, 2) quantitative comparison of gene mutants, 3) functional assays providing stoichiometric insight into protein dynamics and activity, and 4) reconstitution of complex physiological phenomena in defined component systems in vitro. Dr. Freedman's primary model system is the kidney, a beautiful, intricate, and essential organ responsible for cleaning and regulating the chemicals in our bodies. He has developed protocols directing differentiation of iPS cells into mini-kidney organoids that functionally model morphogenesis, physiology, and injury. Combining this with CRISPR/Cas9 genome-editing, he established kidney organoid models of polycystic kidney disease and glomerulosclerosis.
Dr. Freedman has received numerous honors, including being the recipient of the 2023 Donald A. Seldin Young Investigator Award from the American Society of Nephrology. He is currently an Associate Professor of Medicine at the University of Washington, where his group is combining stem cells, bioengineering and genome editing to model disease and, ultimately, regenerative therapy.
University Webpage PubMed link
We have developed a simple, commercially available method to differentiate human pluripotent stem cells into intricately patterned, multi-segment organoids that resemble kidney tissues. These organoids form via a developmental pathway that induces the nephron progenitor cell, which gives rise to podocytes, parietal cells, proximal tubules, and distal tubules along a proximal-to-distal axis. Each of these cell types exhibits a unique morphology and gene expression profile. They also exhibit unique functional characteristics, which can be assessed in a growing list of physiology assays and mutant phenotypes. For instance, only proximal tubular cells, which express ACE2, can be infected with COVID-19, whereas only podocytes can recruit vascular cells after implantation to form glomerulus-like structures. The organoid developmental trajectory requires modulation of hedgehog signaling through primary cilia, thus cilia knockout stem cells fail to efficiently differentiate into organoids. Mutations associated with polycystic kidney disease or cilia knockout cause organoid tubules to swell thousands of times in size, producing large, fluid-filled cysts of centimeter diameters. Mutations in cystinosin, a lysosomal cystine transporter, result in cystine accumulation and nephron disintegration, similar to the human pediatric disorder, nephropathic cystinosis. These disease models are currently being used to test innovative therapeutics and disease-specific mechanisms. The combination of CRISPR gene editing with organoid differentiation enables new types of cell and developmental biology experiments, with high relevance for human kidney disease and regenerative medicine.
BIO
Benjamin Freedman is a professional scientist who has been continuously studying the cell biology of vertebrate stem cells for twenty years. Hallmarks of his career include 1) the application of stem cells for studying disease and regeneration, 2) quantitative comparison of gene mutants, 3) functional assays providing stoichiometric insight into protein dynamics and activity, and 4) reconstitution of complex physiological phenomena in defined component systems in vitro. Dr. Freedman's primary model system is the kidney, a beautiful, intricate, and essential organ responsible for cleaning and regulating the chemicals in our bodies. He has developed protocols directing differentiation of iPS cells into mini-kidney organoids that functionally model morphogenesis, physiology, and injury. Combining this with CRISPR/Cas9 genome-editing, he established kidney organoid models of polycystic kidney disease and glomerulosclerosis.
Dr. Freedman has received numerous honors, including being the recipient of the 2023 Donald A. Seldin Young Investigator Award from the American Society of Nephrology. He is currently an Associate Professor of Medicine at the University of Washington, where his group is combining stem cells, bioengineering and genome editing to model disease and, ultimately, regenerative therapy.
University Webpage PubMed link