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  • br Introduction There are million

    2018-11-08


    Introduction There are 382million people with diabetes worldwide. All patients with Type I and approximately 25% of patients with Type II diabetes require exogenous insulin to survive (Koro et al., 2004). Unfortunately, insulin injections cannot match the minute-to minute precision that islets provide and this disparity leads to debilitating complications (e.g. blindness, heart disease, kidney failure). Islet transplantation has been tried with some success. However, the shortage of donor organ tissue and risks associated with lifelong immunosuppression limit islet transplantation to only the most severely impacted brittle diabetics (Ryan et al., 2006). Thus, successful development of a universal cell therapy to treat Lomefloxacin HCl diabetes requires a renewable, safe source of glucose responsive human islet cells and a means for their delivery without the use of chronic immunosuppression. Human embryonic stem cells (hESCs) represent an excellent starting material for the generation of numerous islet cells. Methods for the production of hESC-derived pancreatic epithelium (hESC-PE) have been described (D\'Amour et al., 2006; Kroon et al., 2008; Kelly et al., 2011; Schulz et al., 2012; Jiang et al., 2007; Shim et al., 2007; Rezania et al., 2012; Ku et al., 2004; Van Hoof et al., 2009; Bruin et al., 2013; Rezania et al., 2013; Aguayo-Mazzucato and Bonner-Weir, 2010; Mayhew and Wells, 2010; Zhang et al., 2009; Cho et al., 2012). Recently multi-step protocols were developed and optimized to differentiate the CyT49 hESC line from the naïve state through key stages of pancreatic development (D\'Amour et al., 2006; Kroon et al., 2008; Kelly et al., 2011; Schulz et al., 2012); definitive endoderm, foregut, and pancreatic epithelium, that efficiently generates functional β-cells in vivo. When transplanted under the kidney Lomefloxacin HCl of immunocompromised mice these cells develop into functional islets in vivo over the course of 7 to 16weeks. Notably, the CyT49 hESC line is amenable to the type of scalable processes ultimately needed for clinical use (Schulz et al., 2012). Cellular encapsulation has been investigated as a means of reducing and/or eliminating the need for chronic immunosuppression by protecting transplanted cells from direct contact with host immune effector cells. Previously, we and others have demonstrated that a planar pouch-like encapsulation device (TheraCyte, Inc.), featuring a bilaminar polytetrafluoroethylene (PTFE) membrane system, provides immunoprotection to transplanted cells in mice and in primates (Brauker et al., 1995; Carr-Brendel et al., 1997; Sweet et al., 2008; Loudovaris et al., 1999; Tatarkiewicz et al., 1999; Rafael et al., 2003; Tibell et al., 2001; Lee et al., 2009; Tarantal et al., 2009; Kumagai-Braesch et al., 2013). However, the clinical use of hESC-derived cell products may yet be hampered by safety concerns over the potential growth of teratomas developing from contaminating pluripotent hESCs, particularly in immunocompromised patients. Thus, a durable and retrievable encapsulation device might also serve as a platform for safely administering hESC-derived therapies. Importantly, we recently found that the TheraCyte device is extremely durable and maintains integrity after freezing (Yakhnenko et al., 2012). Thus, in addition to immunoprotection the device may provide full containment of grafts, but this has yet to be formally tested. Previously we showed that primary islet progenitor cells from the human fetal pancreas, encapsulated in the TheraCyte device, matured into fully functional islets in vivo over the course of 3 to 5months (Lee et al., 2009). This study was the first to demonstrate that direct contact between transplanted islet progenitors and host tissue is not required for β-cell maturation. The primary human cells exhibited a robust and sustained response in vivo capable of ameliorating alloxan induced diabetes, suggesting that encapsulated stem cell derived islet progenitors might similarly mature and function in vivo (Lee et al., 2009).