Can the life span of human marrow stromal cells be prolonged by bmi‐1, E6, E7, and/or telomerase without affecting cardiomyogenic differentiation?

Takeda, Yukiji; Mori, Taisuke; Imabayashi, Hideaki; Kiyono, Tohru; Gojo, Satoshi; Miyoshi, Shunichirou; Hida, Naoko; Ita, Makoto; Segawa, Kaoru; Ogawa, Satoshi; Sakamoto, Michiie; Nakamura, Shinobu; Umezawa, Akihiro

doi:10.1002/jgm.583

Cited by 86 publications

(125 citation statements)

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“…Overexpression of BMI1 can also transform and immortalize normal fibroblasts and mammary epithelial cells via reactivation of the human telomerase reverse transcriptase (hTERT) gene in these cells (Jacobs et al, 1999a;Dimri et al, 2002;Leung et al, 2004). Such oncogenic effects of BMI1 are consistent with other studies showing an extended life span in both rodent and human fibroblasts overexpressing BMI1 (Cohen et al, 1996;Itahana et al, 2003;Takeda et al, 2004;Mori et al, 2005;Terai et al, 2005). More recently, BMI1 activity has been proposed to be an important marker for predicting the progression of myelodysplastic syndrome and the prognosis of patients (Mihara et al, 2006).…”

Section: Introductionsupporting

confidence: 66%

“…This may be linked to the INK4A-ARF locus, which plays a major role in the regulation of cell proliferation via its p16 and p14 products (Jacobs et al, 1999a;Itahana et al, 2003;Bruggeman et al, 2005;Molofsky et al, 2005;Mihara et al, 2006). As BMI1 acts as a negative regulator of the INK4A-ARF locus, overexpression of BMI1 can repress p16 expression, and thus lead to an immortalization of murine fibroblasts and postpone cellular senescence in normal human cells (Jacobs et al, 1999a;Dimri et al, 2002;Takeda et al, 2004;Mori et al, 2005;Terai et al, 2005). To understand the cellular and molecular mechanisms underlying the growth retardation of cancer cells by RNAi of BMI1, we employed BrdU incorporation assays to detect the cell cycle positions of both BMI1 RNAi-treated and scrambled control-treated EC cells.…”

Section: Introductionmentioning

confidence: 99%

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Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

2006

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The polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function, but it is not known if BMI1 may also act as a cancer stem cell factor to promote cancer development. To determine the role of human BMI1 in cancer growth and survival, we performed a loss-of-function analysis of BMI1by RNA interference (RNAi) in both normal and malignant human cells. Our results indicate that BMI1 is crucial for the short-term survival of cancer cells but not of normal cells. We also demonstrated that loss of BMI1 was more effective in suppressing cancer cell growth than retinoid-treatment, and surviving cancer cells showed significantly reduced tumorigenicity. The cancer-specific growth retardation was mediated by an increased level of apoptosis and a delayed cell cycle progression due to the loss of BMI1. By comparison, BMI1 deficiency caused only a moderate inhibition of the cell cycle progression in normal lung cells. In both normal and cancer cells, the loss of BMI1 led to an upregulation of INK4A-ARF, but with no significant effect on the level of telomerase gene expression, suggesting that other BMI1-cooperative factors in addition to INK4A-ARF activation may be involved in the BMI1-dependent cancer-specific growth retardation. Thus, human BMI1 is critical for the short-term survival of cancer cells, and inhibition of BMI1 has minimal effect on the survival of normal cells. These findings provide a foundation for developing a cancer-specific therapy targeting BMI1.

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Section: Introductionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

2006

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“…Some groups reported expression and activity of telomerase in MSC [6,38], while others could not detect the enzyme [39]. Interestingly, stable transfection with the telomerase gene led to immortalization of MSC without any influence on their differentiation potential [40]. These findings are in agreement with the hypothesis that adult stem cells have a limited proliferation potential which may be an element of protection against malignant transformation.…”

Section: Characterization Of the Cellsmentioning

confidence: 52%

“…Most likely, additional factors are required for successful differentiation. In a recently published study, 24 h treatment of a single clone of hMSC with 10 µM 5-azacytidine did not stimulate differentiation, but the same cells differentiated when co-cultured with neonatal cardiac cardiomyocytes and that effect was strongly enhanced by 5-azacytidine [40].…”

Section: Evidence For Cardiac Differentiationmentioning

confidence: 91%

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5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

et al. 2006

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Previously, mouse bone marrow-derived stem cells (MSC) treated with the unspecific DNA methyltransferase inhibitor 5-azacytidine were reported to differentiate into cardiomyocytes. The aim of the present study was to investigate the efficiency of a similar differentiation strategy in human mononuclear cells obtained from healthy bone marrow donors. After 1-3 passages, cultures were exposed for 24 h to 5-azacytidine (3 µM) followed by 6 weeks of further culture. Drug treatment did not induce expression of myogenic marker MyoD or cardiac markers Nkx2.5 and GATA-4 and did not yield beating cells during follow-up. In patch clamp experiments, approximately 10-15% of treated and untreated cells exhibited L-type Ca 2+ currents. Almost all cells showed outwardly rectifying K + currents of rapid or slow activation kinetics. Mean current amplitude at +60 mV doubled after 6 weeks of treatment compared with time-matched controls. Membrane capacitance of treated cells was significantly larger than in controls 2 weeks after treatment and remained high after 6 weeks. Expression levels of mRNAs for the K + channels Kv1.1, Kv1.5, Kv2.1, Kv4.3 and KCNMA1 and for the Ca 2+ channel Ca v 1.2 were not affected by 5-azacytidine. Treatment with potassium channel blockers tetraethylammonium and clofilium at concentrations shown previously to inhibit rapid or slowly activating K + currents of hMSC inhibited proliferation of these cells. Our results suggest that despite the absence of differentiation of hMSC into cardiomyocytes, treatment with 5-azacytidine caused profound changes in current density.Cell Research (2006) 16:949-960.

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Strategies for immortalisation of amnion‐derived mesenchymal and epithelial cells

Ansari

Denton

Lim

2022

Cell Biology International

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Mesenchymal (human amniotic mesenchymal stem cell [HAMSC]) and epithelial cells (human amnion epithelial cell [HAEC]) derived from human amniotic membranes possess characteristics of pluripotency. However, the pluripotency of HAMSC and HAEC are sustained only for a finite period. This in vitro cell growth can be extended by cell immortalisation. Many well-defined immortalisation systems have been used for artificially overexpressing genes such as human telomerase reverse transcriptase in HAMSC and HAEC leading to controlled and prolonged cell proliferation. In recent years, much progress has been made in our understanding of the cellular machinery that regulates the cell cycle when immortalised. This review summarises the current understanding of molecular mechanisms that contribute to cell immortalisation, the strategies that have been employed to immortalise amnion-derived cell types, and their likely applications in regenerative medicine.

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Can the life span of human marrow stromal cells be prolonged by bmi‐1, E6, E7, and/or telomerase without affecting cardiomyogenic differentiation?

Abstract: The life span of hMSCs was prolonged without interfering with cardiomyogenic differentiation. hMSCs with an extended life span can be used to produce a good experimental model of cardiac cell transplantation and may serve as a highly useful cell source for cardiomyocytic transplantation.

Cited by 86 publications

References 49 publications

Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

Strategies for immortalisation of amnion‐derived mesenchymal and epithelial cells

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