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Skin cells to brain cells Simons VIP Family Meeting Orlando, Florida July 19th – 21st, 2013 Dr. Aditi Deshpande Postdoctoral fellow University of California San Francisco Background Human development Specialized cells Oocyte Sperm Organs Human Embryo • Genetic information to make a human is contained in a single cell • This cell divides to give rise to a multi-celled embryo • As development progresses, cells become specialized www.gandoza.com www.istockseller.com Pluripotent stem cells Background How do we study 16p11.2 deletions/duplications? • The mechanism is not determined • Limited treatment strategies and targets to test drugs • Classical approaches to study human neurodevelopmental disorders • Animal models • Post mortem studies in humans • Imaging studies in humans Background Clipart.com/78873 But to find out the precise disruption and design a treatment, we need to study the specialized cells that are malfunctioning Background • Cells are highly specialized • But every cell contains the same genetic information Hair Neurons?? Neurons?? Skin www.gandoza.com Can we convert one specialized cell type into another?? Induced pluripotent stem cells Yes!! Nobelprize.org iPSC technology Reprogramming Skin cells Induced pluripotent stem cells (iPSCs) Background iPSC technology • Allows cells to “go back in time” • Acquire a stem cell-like state Skin cells Pluripotent stem cells Neurons Organ What are iPSCs? Induced pluripotent stem cells (iPSCs) are • Generated in the lab • Made from specialized cells of the body by “forced” expression of certain proteins: induced • Able to be converted to many different cell types in the body: pluripotent • Able to multiply: self-renewing (stem cell) Why iPSCs? Non-invasive iPSCs are a potentially infinite resource They can be used to study human diseases and disorders affecting different organs Since they are derived from patients, they have the same genetic information that contributes to the pathophysiology of the disease Conversion of iPSCs to specialized cell type follows developmental principles They can be used to study the disease at different developmental stages The iPSCs technology Drug screening Disease models Developmental studies 16p11.2 CNV ASDs Down syndrome Alzheimer’s disease Parkinson’s disease Diabetes Adapted from http://www.bumc.bu.edu iPSC technology provides an excellent platform to study human diseases and disorders directly at the source, i.e. affected human cells Modeling 16p11.2 deletion/duplication in a dish Steps involved Skin cells 16p11.2 CNV carrier iPSCs Skin biopsy Adapted from Brennand KJ et al, 2012 Skin cells iPSC colony Modeling 16p11.2 deletion/duplication in a dish • 8-12 weeks iPSCs Day 3 Embryoid bodies Day 11 11 Day Day 20 3 42 Neural rosettes Neurospheres Day 20 Neurons Day 42 Modeling 16p11.2 deletion/duplication in a dish Neurite outgrowth assay 2 3 1 Summary • iPSCs are artificial, pluripotent, self-renewing resource for obtaining patient-derived specialized cells • The iPSC technology can be used to generate neurons from 16p11.2 deletion and duplication carriers Study the neurons with respect to their development, growth, migration and electrical properties; compare to controls Design therapeutic strategies Neurons Test drugs for treatment The goal is to better understand consequences of deletion or duplication of 16p11.2 in order to prevent or treat them Acknowledgements Dr. Lauren Weiss Zhi Yong Wu (Tony) Dr. Erika Yeh and other lab members Dr. Erik Ullian Dr. Gemma Rooney Simons Foundation