Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies

Lee, Andrew S.; Tang, Chad; Rao, Mahendra S.; Weissman, Irving L.; Wu, Joseph C.

doi:10.1038/nm.3267

Cited by 580 publications

(437 citation statements)

References 70 publications

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“…40,41 The iPS cells and cancer stem cell share several properties. 40,41 In 2013, some research created mouse iPS cells were created using the combination of some specific small molecules 42 only without using of any such reprogramming viral factors. However, until now, there is no report about creation of human iPS cells using chemical alone.…”

Section: Discussionmentioning

confidence: 99%

Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support

Giri

Bader

2014

Journal of Clinical and Experimental Hepatology

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Background: Generation of genetically stable and non-tumoric immortalization cell line from primary cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. It is now universal acceptance that immortalization of human fetal hepatocytes based on recent advances of telomerase biology and oncogene, lead to unlimited population doubling could be the possible source for bioartificial liver device. Methods: Immortalization of human fetal hepatocytes cell line by ectopic expression of human telomerase reverse transcriptase (hTERT), human papilloma virus gene (E7) and simian virus 40 large T (SV40 T) antigens is main goal of present study. We used an inducible system containing human telomerase and E7, both of which are cloned into responder constructs controlled by doxycycline transactivator. We characterized the immortalized human fetal hepatocyte cells by analysis of green fluorescent cells (GFP) positive cells using flow cytometry (FACs) cell sorting and morphology, proliferative rate and antigen expression by immunohistochemical analysis. In addition to we analysized lactate formation, glucose consumption, albumin secretion and urea production of immortalized human fetal hepatocyte cells. Results: After 25 attempts for transfection of adult primary hepatocytes by human telomerase and E7 to immortalize them, none of the transfection systems resulted in the production of a stable, proliferating cell line. Although the transfection efficiency was more than 70% on the first day, the vast majority of the transfected hepatocytes lost their signal within the first 5-7 days. The remaining transfected hepatocytes persisted for 2-4 weeks and divided one or two times without forming a clone. After 10 attempts of transfection human fetal hepatocytes using the same transfection system, we obtained one stable human fetal hepatocytes cell line which was able albumin secretion urea production and glucose consumption. Conclusion: We established a conditional human fetal hepatocytes cell line with mesenchymal characteristics. Thus immortalization of human fetal hepatocytes cell line by telomerase biology offers a great challenge to examine basic biological mechanisms which are directly related to human and best cell source having unlimited population doubling for bioartificial support without any risk of replicative senescence and pathogenic risks. ( J CLIN EXP HEPATOL 2014;4:191-201)

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Section: Discussionmentioning

confidence: 99%

Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support

Giri

Bader

2014

Journal of Clinical and Experimental Hepatology

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“…It is not clear whether an in vitro culture of human ISCs may predispose these cells to develop tumors. Such a risk may be an important issue especially for transplantations using ES or iPS cell-derived cells [132]. In addition, we currently do not know much about what kind of pathogen may exist in the donor intestinal mucosa.…”

Section: Iecs As Target Cells For the Treatment Of Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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“…Pluripotent tumour forming potential can be divided into two categories: malignant transformation of differentiated PSCs, and benign teratoma formation from residual undifferentiated PSCs. 14,15 The former should be also investigated for safety. For example, CD30, which is a biomarker for transformed human ESCs, is correlated with karyotype abnormalities such as partial duplication of chromosome.…”

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confidence: 99%

Emerging innovation towards safety in the clinical application of ESCs and iPSCs

et al. 2014

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Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies

Cited by 580 publications

References 70 publications

Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support

Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Emerging innovation towards safety in the clinical application of ESCs and iPSCs

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