Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: Improving the safety of iPS cell transplantation to myocardium

Zhang, Lan; Pan, Yaohua; Qin, Gangjian; Chen, Lijuan; Chatterjee, Tapan K.; Weintraub, Neal L.; Tang, Yaoliang

doi:10.4161/cc.27677

Cited by 31 publications

(25 citation statements)

References 54 publications

(58 reference statements)

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“…Recently, Ben-David et al (2013) have demonstrated that human embryonic stem cells are crucially dependent on SCD1 activity for their survival. The same findings were seen in undifferentiated mouse iPS derivates during cardiac differentiation (Zhang et al 2014). These data therefore suggest a pivotal role of SCD1 in promoting progenitor cell fate and function.…”

Section: Introductionsupporting

confidence: 73%

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Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl‐CoA desaturase 1 activity

et al. 2015

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Stearoyl-CoA desaturase 1 (SCD1) plays important roles in organ development, glucose tolerance, insulin sensitivity, and cancer. Here, we examined the role of SCD1 for the differentiation of human induced pluripotent stem (hiPS) cells to liver cells by using drug inhibition and biochemical experiments. hiPS cells cultured in a pro-hepatic medium were exposed to an SCD1 inhibitor at various stages throughout differentiation. Liver-specific markers, specifically a-fetoprotein, albumin and urea in conditioned medium, and hepatocyte nuclear factor 4a (HNF4a) and cytochrome P450 7A1 (CYP7A1) gene expressions and triglyceride in cellular extracts were analyzed at various development stages. Measures of hepatocyte-specific function and triglyceride accumulation in later stages were strongly inhibited a minimum of À29% (P < 0.05) by SCD1 inhibitor in the early stage of hepatic differentiation and effectively reversed (>30%, P < 0.01) by the addition of oleate. The results were also reproducible with human primary mononuclear cells (hPMN). SCD1 inhibitor had no significant effect on liverspecific markers when it was added in the hepatic maturation stage. However, it strikingly led to higher albumin (1.6-fold, P = 0.03) and urea (1.9-fold, P = 0.02) production, and HNF4a (1.9-fold, P = 0.02) and CYP7A1 (1.3-fold, P = 0.03) expression upon incubation during the lineage-commitment stage. Hepatic differentiation from cultured hiPS cells is sensitive to SCD1 inhibition and this sensitivity is affected by the stage of cellular differentiation. Notably, findings also indicate that this notion can be extended to hPMN. The requirement for SCD1 activity in functional differentiation of hepatocytes may have relevance for human liver disease and metabolic dysregulation.

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Section: Introductionsupporting

confidence: 73%

“…The same findings were seen in undifferentiated mouse iPS derivates during cardiac differentiation (Zhang et al . ). These data therefore suggest a pivotal role of SCD1 in promoting progenitor cell fate and function.…”

Section: Introductionmentioning

confidence: 97%

Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl‐CoA desaturase 1 activity

et al. 2015

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“…Studies have used iPSC-specific antiapoptotic factors, such as survivin or Bcl10, with smallmolecule inhibitors to eliminate pluripotent cells with teratoma potential [36]. Recent studies have investigated the inhibition of stearoyl-coA desaturase 1 (SCD1), which induces endoplasmic reticulum (ER) stress and generates reactive oxygen species, as a means to selectively eliminate undifferentiated iPSC derivatives [37]. However, the exact mechanism of SCD1 inhibitor remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA Topoisomerase II Selectively Reduces the Threat of Tumorigenicity Following Induced Pluripotent Stem Cell-Based Myocardial Therapy

Wyles

Yamada²,

Oommen

et al. 2014

Stem Cells and Development

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The advent of induced pluripotent stem cell (iPSC) technology creates new opportunities for transplant-based therapeutic strategies. The potential for clinical translation is currently hindered by the risk of dysregulated cell growth. Pluripotent stem cells reprogrammed by three-factor (Sox2, Klf, and Oct4) and four-factor (Sox2, Klf, Oct4, and c-Myc) strategies result in the capacity for teratogenic growth from residual pluripotent progeny upon in vivo transplantation. However, these pluripotent stem cells also have a stage-specific hypersensitivity to DNA-damaging agents that may allow separation of lineage-specific therapeutic subpopulation of cells. We aimed to demonstrate the selective effect of DNA topoisomerase II inhibitor, etoposide, in eliminating pluripotent cells in the early cardiac progenitor population thus decreasing the effect of teratoma formation. Immunodeficient murine hearts were infarcted and received implantation of a therapeutic dose of cardiac progenitors derived from partially differentiated iPSCs. Etoposide-treated cell implantation reduced mass formation in the intracardiac and extracardiac chest cavity compared with the same dose of iPSC-derived cardiac progenitors in the control untreated group. In vivo bioluminescence imaging confirmed the localization and engraftment of transplanted cells in the myocardium postinjection in both groups. Comparatively, the equivalent cell population without etoposide treatment demonstrated a greater incidence and size of teratoma formation. Hence, pretreatment with genotoxic etoposide significantly lowered the threat of teratogenicity by purging the contaminating pluripotent cells, establishing an adjunctive therapy to further harness the clinical value of iPSC-derived cardiac regeneration.

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“…The idea that some iPSC cells may be remaining following differentiation can be addressed by a purification step using flow cytometry, and then "spiking" experiments with as few as 10 to 100 iPSC are added back to the purified differentiated cells and tested their capacity to be tumorigenic in vivo. Recently this concern has been alternatively addressed by the selective elimination of these remaining Nanog-positives iPSCs by the inhibition of stearoyl-coA desaturase [24]. This method induced apoptosis in the undifferentiated residual iPSCs but not in the iPSC-derived cardiomyocytes they were differentiating to.…”

Section: Efficient Cell Differentiation Protocolsmentioning

confidence: 99%

The Future Challenges for the Clinical Application of Reprogrammed Cells

Palomo¹

2014

Human Genet Embryol

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Recent developments in the field of reprogramming somatic cells to induced pluripotent stem cells (iPSC) has brought the field closer to the exciting possibility of their future clinical application. A number of challenges remain to be addressed before clinical application of reprogrammed stem cells becomes a reality. The main issues are the threat of cancer, control of differentiation to tissue specific stem cells or body organs and the immune response of iPSC-derived cells. The future use of iPSC will require that they are cancer free, do not proliferate and can be contained to the specific injection site for tissue regeneration. This review discusses the recent advances that address these main challenges in the field of cellular reprogramming

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Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: Improving the safety of iPS cell transplantation to myocardium

Cited by 31 publications

References 54 publications

Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl‐CoA desaturase 1 activity

Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl‐CoA desaturase 1 activity

Inhibition of DNA Topoisomerase II Selectively Reduces the Threat of Tumorigenicity Following Induced Pluripotent Stem Cell-Based Myocardial Therapy

The Future Challenges for the Clinical Application of Reprogrammed Cells

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