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Directed differentiation of human pluripotent stem cells to cardiac and pancreatic cells by modulation of Wnt signaling pathway

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Lance Lian The Pennsylvania State University
02 October 2018 from 4:00 PM to 5:00 PM
Berg Auditorium, 100 Life Sciences Building
Dept of Biology
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Abstract:  Because human pluripotent stem cells (hPSCs) can be propagated indefinitely while still retaining the capacity to differentiate into all somatic cell types, they are a potentially inexhaustible supply of human cells, including cardiomyocytes and pancreatic beta cells. 

 Cardiovascular disease, caused by the blockage of blood vessels, is the largest cause of mortality in the developed world.  Stem cell derived cardiac cells and grafts are used in treating this disease.  Here we show that temporal modulation of Wnt signaling is both essential and sufficient for efficient cardiac induction in hPSCs under defined, growth factor-free conditions. shRNA knockdown of β-catenin during the initial stage of hPSC differentiation fully blocked cardiomyocyte specification, whereas glycogen synthase kinase 3 inhibition at this point enhanced cardiomyocyte generation. Furthermore, sequential treatment of hPSCs with glycogen synthase kinase 3 inhibitors followed by inducible expression of β-catenin shRNA or chemical inhibitors of Wnt signaling produced a high yield of virtually (up to 98%) pure functional human cardiomyocytes from multiple hPSC lines. The robust ability to generate functional cardiomyocytes under defined, growth factor-free conditions solely by genetic or chemically mediated manipulation of a single developmental pathway should facilitate scalable production of cardiac cells suitable for research and regenerative applications.


Stem cell therapy is also useful for treating Type 1 diabetes (T1D), which is one of the most common endocrine disorders in children, resulting little or no insulin production by the pancreas.  The success of whole pancreas and especially islet transplantation has provided compelling evidence that beta cell-replacement therapy is a promising treatment option for T1D, however, the shortage of organ donors limits their widespread use.  It is well known that hPSCs could provide an unlimited supply of pancreatic progenitors (PPs) and insulin-producing beta cells.  Several multistep differentiation protocols designed to mimic in vivo pancreatic organogenesis have been successfully developed for pancreatic differentiation.  However, all of the previous protocols were growth factor dependent, which substantially increases the cost of cell biomanufacturing.  The large-scale and cost-effective production of quality-controlled PPs and beta cells from hPSCs for use in cell therapy and drug discovery would ideally require a chemically defined, growth-factor-free differentiation system.  Here we used a bio-inspired approach to optimize small molecules of developmental signaling pathways and developed a chemically defined and growth-factor-free differentiation protocol for generating PPs from hPSCs.  We achieved more than 95% Pdx1+ PPs in 10 days of differentiation without any growth factors from one human embryonic stem cell line (H1) and one human induced pluripotent stem cell line (IMR90C4).  Our findings should facilitate the ongoing development of beta cell-based therapies for treating diabetes.