Article

Two Supporting Factors Greatly Improve the Efficiency of Human iPSC Generation

Cell stem cell (Impact Factor: 22.27). 12/2008; 3(5):475-9. DOI: 10.1016/j.stem.2008.10.002
Source: PubMed

ABSTRACT

Human fibroblasts can be induced into pluripotent stem cells (iPSCs), but the reprogramming efficiency is quite low. Here, we screened a panel of candidate factors in the presence of OCT4, SOX2, KLF4, and c-MYC in an effort to improve the reprogramming efficiency from human adult fibroblasts. We found that p53 siRNA and UTF1 enhanced the efficiency of iPSC generation up to 100-fold, even when the oncogene c-MYC was removed from the combinations.

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Available from: Chun Liu, Jul 15, 2014
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    • "As expected, using chemical compounds that inhibit the TGFβ and MEK-ERK pathways have increased reprogramming efficiency of human fibroblasts and decrease the time to cell line establishment (Lin et al., 2009). Other methods to enhance the reprogramming process include: adding SV40 large T antigen (which inactivates p53) to either set of 4 reprogramming genes enhances colony formation up to 70-fold higher with formation 1-2 weeks earlier (Mali et al., 2008); co-expressing RAR-γ and Lrh-1 with the Yamanaka factors (Wang et al., 2011 ); reprogramming cells under hypoxic conditions (Yoshida et al., 2009); using UTF1 forced transcription with p53 siRNA along with the Yamanaka factors (Zhao et al., 2008 ); and enrichment of the cell population for progenitor cells (Kleger et al., 2012).Table 14 different strategies to increase reprogramming efficiencies and iPSC colony formation. Researchers have confirmed, so far, iPSC induction in the following cell types: fetal lung fibroblasts, neonatal foreskin fibroblasts, mesenchymal stem cells and dermal fibroblasts taken from healthy patients (Park et al., 2008b), adult mouse liver and stomach cells (Aoi et al., 2008 ), primary human adult hepatocytes (Liu et al., 2010 ), fetal gut mesenteryderived cells (Li et al., 2010), human and mouse extra-embryonic cells (Nagata et al., 2009), human mesenchymal cells from the umbilical cord matrix and amniotic membrane (Cai et al., 2010), human amnion (Zhao et al., 2010), juvenile human primary keratinocytes (Aasen et al., 2008), mouse hematopoietic and myogenic cells (Polo et al., 2010 ), mouse fetal hepatocytes (Kleger et al., 2012; Lee et al., 2012), human fetal hepatocytes (Hansel et al., 2014), and human lymphoblastoid cells (Barrett et al., 2014).Table 14.13.3 summarizes some of the first successful reports in reprogramming different somatic cell types. "
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    ABSTRACT: Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end-stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell-based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc.
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    • "These studies define a new role for TRP53 in the embryo as a guardian of the entry of cells into the pluripotent ICM lineage. A similar conclusion arises from the observations that TRP53 expression compromises the capacity to reprogram somatic cells into an induced pluripotent state (Hong et al. 2009; Kawamura et al. 2009; Zhao et al. 2008). The integrity of the PI3K-mediated survival signalling pathway initiated by embryotrophins that maintains the latency of TRP53 in the early embryo seems to be a hallmark of normal development. "

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    • "Importantly, the somatic cell is not a tabula rasa and expresses genes that antagonize reprogramming, as has been shown for tumor suppressors (p53, INK4a/ARF, LATS2) (Kawamura et al., 2009; Qin et al., 2012; Zhao et al., 2008) and H3K9 methyltransferases (SETDB1, SUV39H, EHMT2) (Chen et al., 2013). In addition, focused RNAi screens have revealed other pathways that act as barriers to reprogramming, such as TGF-b signaling (Samavarchi-Tehrani et al., 2010), H3K79 methylation by DOT1L (Onder et al., 2012), or protein ubiquitination (Buckley et al., 2012). "
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