p53 regulates the proliferation, differentiation and spontaneous transformation of mesenchymal stem cells

Armesilla-Diaz, Alejandro; Elvira, Gema; Silva, Augusto

doi:10.1016/j.yexcr.2009.08.004

Cited by 95 publications

(60 citation statements)

References 45 publications

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“…24 Additionally, it was reported that the proliferation rate of mesenchymal stem cells (MSCs) derived from p53 knockout mice was significantly increased, compared to the MSCs derived from wild-type animals. 25 In this study, our results demonstrated that p53 protein and its downstream target, p21, were decreased after vitamin C treatment, which was consistent with previous reports that suppression of p53-p21 pathway was beneficial to the proliferation of cells. 26,27 Additionally, we also evaluated the effect of vitamin C pretreatment on the H 2 O 2 -induced ROS production in the ADSCs.…”

Section: Discussionsupporting

confidence: 92%

Vitamin C promotes the proliferation of human adipose-derived stem cells via p53-p21 pathway

Zhang

et al. 2016

Organogenesis

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ABSTRACT. Although adipose-derived stem cells (ADSCs) have demonstrated a promising potential for the applications of cell-based therapy and regenerative medicine, excessive reactive oxygen species (ROS) are harmful to ADSCs cell survival and proliferation. Vitamin C is an important antioxidant, and is often added into culture media as an essential micronutrient. However, its roles on the proliferation of human ADSCs have not been studied. Therefore, in this study, human ADSCs were isolated, and detected by flow cytometry for the analysis of their cell surface antigens. Cell proliferation and cell cycle progression were measured with cell counting kit-8 assay and flow cytometry, respectively. Western blotting was used to detect the expression levels of cyclin E1, p53, p21, and CDK2 proteins. The effect of vitamin C pretreatment on the production of hydrogen peroxide (H 2 O 2 )-mediated ROS in the ADSCs was evaluated by flow cytometry. Our results indicated that vitamin C treatment significantly increased cell proliferation, and changed the cell cycle distribution of ADSCs by decreasing the percentage of G 1 phase, and concurrently increased the percentage of S and G 2 /M phase. Western blot analysis indicated that vitamin C treatment up-regulated the expression levels of cyclin E1 and CDK2, but down-regulated p53 and p21 proteins expression, which contributed to cell proliferation and cell cycle progression. Vitamin C pretreatment significantly reduced the production of H 2 O 2 -induced ROS in the ADSCs. These findings suggest that vitamin C can promote the proliferation and cell cycle progression in the ADSCs possibly through regulation of p53-p21 signal pathway.

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Section: Discussionsupporting

confidence: 92%

Vitamin C promotes the proliferation of human adipose-derived stem cells via p53-p21 pathway

Zhang

et al. 2016

Organogenesis

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“…We and others have demonstrated the relevant role that the deficiency of different cell cycle regulators, especially p53, has on the transformation of mMSCs [16][17][18][19][20]. In fact, p53 mutations and p53 deregulated expression are frequent in liposarcomas [21,22], supporting p53 as a potential secondary hit for hMSC transformation.…”

Section: Introductionmentioning

confidence: 92%

FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells

et al. 2011

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Human sarcomas have been modeled in mice by expression of specific fusion genes in mesenchymal stem cells (MSCs). However, sarcoma models based on human MSCs are still missing. We attempted to develop a model of liposarcoma by expressing FUS (FUsed in Sarcoma; also termed TLS, Translocated in LipoSarcoma)-CHOP (C/ EBP HOmologous Protein; also termed DDIT3, DNA Damage-Inducible Transcript 3), a hallmark mixoid liposarcoma-associated fusion oncogene, in wild-type and p53-deficient mouse and human adipose-derived mesenchymal stem/stromal cells (ASCs). FUS-CHOP induced liposarcoma-like tumors when expressed in p53 2/2 but not in wild-type (wt) mouse ASCs (mASCs). In the absence of FUS-CHOP, p53 2/2 mASCs forms leiomyosarcoma, indicating that the expression of FUS-CHOP redirects the tumor genesis/phenotype. FUS-CHOP expression in wt mASCs does not initiate sarcomagenesis, indicating that p53 deficiency is required to induce FUS-CHOP-mediated liposarcoma in fat-derived mASCs. In a human setting, p53-deficient human ASCs (hASCs) displayed a higher in vitro growth rate and a more extended lifespan than wt hASCs. However, FUS-CHOP expression did not induce further changes in culture homeostasis nor initiated liposarcoma in either wt or p53-depleted hASCs. These results indicate that FUS-CHOP expression in a p53-deficient background is sufficient to initiate liposarcoma in mouse but not in hASCs, suggesting the need of additional cooperating mutations in hASCs. A microarray gene expression profiling has shed light into the potential deregulated pathways in liposarcoma formation from p53-deficient mASCs expressing FUS-CHOP, which might also function as potential cooperating mutations in the transformation process from hASCs. STEM CELLS 2011; 29:179-192 Disclosure of potential conflicts of interest is found at the end of this article.

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“…mMSCs In the mouse setting, the use of genetically targeted mMSCs has demonstrated how the deficiency of different cell cycle regulators, especially p53, triggers a transformation process in mMSCs resulting in the generation of sarcoma [29][30][31] (Table 2). For instance, in contrast to wild-type (wt) ASCs, p53-depleted mASCs were capable of originating leiomyosarcoma-like tumors after injection into immunodeficient mice [31].…”

Section: Cell Cycle Control In Msc-based Sarcoma Modelingmentioning

confidence: 99%

Modeling sarcomagenesis using multipotent mesenchymal stem cells

2011

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Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

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p53 regulates the proliferation, differentiation and spontaneous transformation of mesenchymal stem cells

Cited by 95 publications

References 45 publications

Vitamin C promotes the proliferation of human adipose-derived stem cells via p53-p21 pathway

Vitamin C promotes the proliferation of human adipose-derived stem cells via p53-p21 pathway

FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells

Modeling sarcomagenesis using multipotent mesenchymal stem cells

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