Reprogramming of Pancreatic β Cells into Induced Pluripotent Stem Cells

Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA.
Current Biology (Impact Factor: 9.57). 07/2008; 18(12):890-4. DOI: 10.1016/j.cub.2008.05.010
Source: PubMed


Induced pluripotent stem (iPS) cells have been derived from fibroblast, stomach, and liver cultures at extremely low frequencies by ectopic expression of the transcription factors Oct4, Sox2, c-myc, and Klf4, a process coined direct or in vitro reprogramming [1-8]. iPS cells are molecularly and functionally highly similar to embryonic stem cells (ESCs), including their ability to contribute to all tissues as well as the germline in mice. The heterogeneity of the starting cell populations and the low efficiency of reprogramming suggested that a rare cell type, such as an adult stem cell, might be the cell of origin for iPS cells and that differentiated cells are refractory to reprogramming. Here, we used inducible lentiviruses [9] to express Oct4, Sox2, c-myc, and Klf4 in pancreatic beta cells to assess whether a defined terminally differentiated cell type remains amenable to reprogramming. Genetically marked beta cells gave rise to iPS cells that expressed pluripotency markers, formed teratomas, and contributed to cell types of all germ layers in chimeric animals. Our results provide genetic proof that terminally differentiated cells can be reprogrammed into pluripotent cells, suggesting that in vitro reprogramming is not restricted to certain cell types or differentiation stages.

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Available from: Kristen Brennand, Oct 07, 2014
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    • "Subsequently, the " reprogramming technology " needed to prove that iPSCs were the result of reprogrammed cells, and not the selection of novel uncharacterized tissuespecific pluripotent cells. This was achieved by reprogramming cells with specific traceable genetic characteristics, such as the albumin promoter in hepatocytes, insulin promoter in pancreatic beta cells or the recombined immunoglobulin locus of B lymphocytes (Aoi et al., 2008; Hanna et al., 2008; Stadtfeld et al., 2008a). Indeed, Hanna and colleagues demonstrated that iPSCs could emerge from daughter cells from any given cell of a starting population, provided that the cells were still viable and the four reprogramming factors could maintain expression for extended periods (Hanna et al., 2009). "
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    • "Tissues from different species such as mice (Takahashi and Yamanaka, 2006), rats (Liao et al., 2009), rhesus monkeys (Liu et al., 2008), and humans (Takahashi et al., 2007) have been used as source materials for iPS cell line generation. Successful reprogramming also quickly translated to a wide variety of other cell types, including pancreatic β-cells (Stadtfeld et al., 2008), neural stem cells (Eminli et al., 2008) mature B cells (Hanna et al., 2008), stomach and liver cells (Aoi et al., 2008), melanocytes (Utikal et al., 2009), adipose stem cells (Sun et al., 2009), and keratinocytes (Maherali and Hochedlinger, 2008), demonstrating a universal capacity to alter cellular identity . In dentistry, iPS cells have been generated from many types of dental tissues/cells, including SHEDs, SCAPs, DPSCs, tooth germ progenitor cells (TGPCs), buccal mucosa fibroblasts, gingival fibroblasts, and periodontal ligament fibroblasts (Egusa et al., 2010; Miyoshi et al., 2010; Oda et al., 2010; Tamaoki et al., 2010; Yan et al., 2010; Wada et al., 2011). "
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    • "Formation of teratomas which contain cell types from all three germ layers when injected into nude mice SSEA3, SSEA4, alkaline phosphatease, TRA-1-60, TRA-1- 81, GCTM2, GCT343, DPPA3 (STELLA), CD9, Thy1, KLF4 and REX1 Adewumi et al. (2007), Babaie et al. (2007), Chan et al. (2009), Clark et al. (2004), Perrett et al. (2008), Thomson et al. (1998) and Wobus (2001) Human pluripotent stem cells L. Gao et al. hESCs (Takahashi and Yamanaka, 2006; Takahashi et al., 2007a,b). Mouse iPSCs injected into murine blastocysts were able to contribute to all three germ layers in chimeric embryos (Stadtfeld et al., 2008; Kawamura et al., 2009). This evidence is consistent with iPSCs possessing very similar properties to ESCs. "
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