Transdifferentiation of Extra-Pancreatic Tissues for Cell Replacement Therapy for Diabetes

Abstract

Replenishment of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes mellitus (Cozar-Castellano and Stewart in Proc Natl Acad Sci USA 102:7781–7782, 2005; Efrat and Russ in Trends Endocrinol Metab TEM 23:278–285, 2012; Ricordi et al. in Regen Med 7:41–48, 2012). β cell replacement by pancreas transplantation or by islet cell implantation is both restricted by severe shortage of tissue supply from cadaver donors, and by the requirement for extensive, lifelong suppression of the immune system. Therefore, tissue replacement therapy will become widely available as a treatment for diabetic patients only when islets or insulin-producing cells will be available in unlimited amounts and preferentially will not be rejected by the diabetic recipients. Efforts have been put forth to generate transplantable islets in vitro from embryonic stem cells (D’Amour et al. in Nat Biotechnol 23:1534–1541, 2005, Nat Biotechnol 24:1392–1401, 2006; Rezania et al. in Stem Cells (Dayton, Ohio) 31:2432–2442, 2013; Schulz et al. in PloS One 7:e37004, 2012) or induced pluripotent cells (Alipio et al. in Proc Natl Acad Sci USA 107:13426–13431, 2010; Rezania et al. in Stem Cells (Dayton, Ohio) 31:2432–2442, 2014) as well as from self-renewing cell populations that reside outside or within the adult pancreas (Baeyens et al. in Diabetologia 48:49–57, 2005; Bonner-Weir et al. in Proc Natl Acad Sci USA 97:7999–8004, 2000; Courtney et al. in Diabetes Obes Metab 13:47–52, 2011; Zhou et al. in Nature 455:627–632, 2008). The present chapter will address the research in the field of generating functional insulin-producing cells by transdifferentiation of adult extra-pancreatic tissues. Adult cell reprogramming or transdifferentiation employs the instructive roles of pancreatic transcription factors in controlling pancreas organogenesis in the embryo to dictate the induction of pancreatic lineage and function in like manner in adult cells of differentiated tissues. The transient ectopic expression of pancreatic transcription factors in extra-pancreatic tissues induces the expression of otherwise silent genetic information that is characteristic to that of the pancreas. This in turn endows the adult extra-pancreatic tissues with pancreatic characteristics and function, thus promoting ex vivo differentiation into insulin-producing and secreting cells. The direct conversion of somatic cells into alternative committed lineages—transdifferentiation, has opened up tremendous opportunities for regenerative medicine. Our laboratory is the first to suggest the capacity of the pancreatic master regulator, Pdx-1 to induce functional liver to pancreas transdifferentiation in the year 2000 (Ferber et al. in Nat Med 6:568–572, 2000). The present chapter reviews 15 years of research in the field of generating insulin-producing cells by transdifferentiation from our and other laboratories. Transdifferentiation of adult extra-pancreatic tissues may result in the generation of custom made “self” surrogate β cells for the treatment of diabetes, overcoming both the shortage in tissue availability from cadaveric donors and the subsequent need for antirejection treatments.