Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

Arch. Immunol. Ther. Exp. (2013) 61:149–158 DOI 10.1007/s00005-012-0213-y REVIEW Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges Marta Pokrywczynska • Sandra Krzyzanowska • Arkadiusz Jundzill • Jan Adamowicz • Tomasz Drewa Received: 1 June 2012 / Accepted: 20 December 2012 / Published online: 3 January 2013 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012 Abstract Diabetes mellitus is one of the most serious public health challenges of the twenty-first century. Allogenic islet transplantation is an efficient therapy for type 1 diabetes. However, immune rejection, side effects of immunosuppressive treatment as well as lack of sufficient donor organs limits its potential. In recent years, several promising approaches for generation of new pancreatic b cells have been developed. This review provides an overview of current status of pancreatic and extra-pancreatic stem cells differentiation into insulin-producing cells and the possible application of these cells for diabetes treatment. The PubMed database was searched for English language articles published between 2001 and 2012, using the keyword combinations: diabetes mellitus, differentiation, insulin-producing cells, stem cells. Keywords Diabetes mellitus
Differentiation
Insulin-producing cells
Stem cells Introduction Diabetes mellitus (DM) is a chronic disease affecting nearly 350 million people worldwide. DM is classified into two major types (American Diabetes Association 2011). M. Pokrywczynska (&)
S. Krzyzanowska
A. Jundzill
J. Adamowicz
T. Drewa Department of Tissue Engineering, Ludwik Rydygier Medical College in Bydgoszcz, Nicolaus Copernicus University in Torun, Karlowicza 24, 85-092 Bydgoszcz, Poland e-mail: T. Drewa Department of Urology, Nicolaus Copernicus Hospital, Torun, Poland Type 1 diabetes mellitus (DM1) results from autoimmune destruction of insulin-producing b cells (Noguchi 2009). DM1 is responsible for approximately 10 % of all DM cases. Patients with DM1 require a long-life treatment with regular insulin injections. Type 2 diabetes mellitus (DM2) is a heterogenous metabolic disorder, characterized by both insulin resistance and relative insulin deficiency. This type is responsible for more than 80 % of DM cases (Raslova 2010). The first main treatment for DM2 includes proper diet and physical exercises. There are a lot of studies indicating new methods of treatment for patients with DM1. Currently, pancreas or islet transplantation is considered as the best therapeutic option for brittle type 1 diabetes. However, the low availability of organ donors limits the number of transplants which could be performed. Alternative source of insulinproducing cells could be zoonotic islets, but it creates a lot of problems, like increased risk of graft rejection or viruses transmission. Therefore, scientists are wondering whether stem cells could differentiate into insulin-producing ones. A number of studies indicated that it is possible. This opens up new possibilities for treating patients who can get their own autologous stem cells for therapy and avoid problems associated with allo or xenotransplants. Different types of stem cells were investigated to determine which of them would be most useful in the treatment of type 1 diabetes. Although stem cells were isolated from pancreatic ducts, islets and exocrine tissue the b-cell progenitors have not been identified (Baeyens et al. 2005; Carlotti et al. 2010; Gao et al. 2003; Soria et al. 2005). Interestingly, b cells mass increases in vivo significantly after injury and during metabolic demand for example pregnancy or obesity. Thus, it does seem that there is a regeneration of pancreatic b cells, but it is not clear whether it happens by self-replication or neogenesis 123 150 Arch. Immunol. Ther. Exp. (2013) 61:149–158 (Dor et al. 2004). However, it should be emphasized that progenitor cells isolated from diseased pancreas carry a high risk of dysfunction. Therefore, there is great need for a new sources of cells to generate insulin-producing cells (IPCs). Here, we review the strategies that have been applied to the generation of IPCs from stem cells. Pancreas Development Generation of IPCs in vitro requires understanding how b cells are formed in vivo. Pancreas development is a complex process guided by numerous cascades of signaling pathways and transcription factors that regulate cell differentiation. Diffusible factors secreted from surrounding tissues as well as cell–cell and cell–matrix interactions play a critical role in this process. During embryonic development, the pancreatic primordium is derived from definitive endoderm that subsequently gives rise to the primitive gut and posterior foregut. At this stage, formation of the pancreatic anlage is guided by retinoid signaling and depends on inhibition of hedgehog signaling (Lau et al. 2006; Stafford and Prince 2002; Stafford et al. 2004). The developing pancreas is consists of epithelial progenitors expressing: Pdx1 (Ipf1), Hnf6 (Onecut), Hlxb9, Ptf1a and Nkx6-1 that will give rise to endocrine, exocrine and ductal cells (Gu et al. 2002; Wilson et al. 2003). Further differentiation of pancreatic epithelium is regulated by signals from the adjacent mesenchyme, such as Fgf10 (Gittes 2009). Endocrine cell specification occurs by inhibition of Notch signaling and expression of the proendocrine gene Neurog3 (Ngn3) in some of the pancreatic epithelial cells (Wilson et al. 2003). Ngn3 triggers the expression of several transcription factors: Nkx2-2, Neurod1, Nkx6-1, Pax-4, Pax-6 and Isl1 that controls endocrine cell differentiation. Nascent endocrine cells migrate from the branched epithelium into surrounding mesenchyme and form the islets of Langerhans (Gittes 2009; Guo and Hebrok 2009). Main transcription factors involved in pancreas development are presented in Table 1. Differentiation of stem cells to b cells in vitro cannot be achieved in a single step, but requires a series of transition steps replicating pancreatic organogenesis. Stem cells can undergo differentiation through genetic manipulation as well as epigenetic influences from media containing the differentiating factors. Differentiating factors used to specific cell type differentiation are shown in Tables 2, 3. Differentiation of Embryonic Stem Cells Numerous studies have been performed to generate insulinproducing cells through differentiation of embryonic stem cells (ESCs). ESCs are cells derived from the inner cell Table 1 Main transcription factors involved in pancreas development Transcription factors Abbreviation Function References NK2 transcription factor related, locus 2 Nkx2.2 Pancreatic endocrine development and differentiation into pancreatic b cells Henseleit et al. (2005); Shiroi et al. (2005) NK6 transcription factor related, locus 6 Nkx6.1 Final differentiation of b cells Henseleit et al. (2005); Wang et al (...truncated)