Dataset Information

Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation.

ABSTRACT:

Background

Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells.

Principal findings

Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs.

Significance

In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions.

SUBMITTER: Oliver L

PROVIDER: S-EPMC3093403 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation.

Oliver Lisa L Hue Erika E Rossignol Julien J Bougras Gwenola G Hulin Philippe P Naveilhan Philippe P Heymann Dominique D Lescaudron Laurent L Vallette François M FM

PloS one 20110512 5

<h4>Background</h4>Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells.<h4>Principal findings</h4>Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of und ...[more]

PMID: 21589877

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Project description:BackgroundApoptosis is a common and essential aspect of development. It is particularly prevalent in the central nervous system and during remodelling processes such as formation of the digits and in amphibian metamorphosis. Apoptosis, which is dependent upon a balance between pro- and anti-apoptotic factors, also enables the embryo to rid itself of cells damaged by gamma irradiation. In this study, the roles of the anti-apoptotic factor Bcl-xL in protecting cells from apoptosis were examined in Xenopus laevis embryos using transgenesis to overexpress the XR11 gene, which encodes Bcl-xL. The effects on developmental, thyroid hormone-induced and gamma-radiation-induced apoptosis in embryos were examined in these transgenic animals.ResultsApoptosis was abrogated in XR11 transgenic embryos. However, the transgene did not prevent the apoptotic response of tadpoles to thyroid hormone during metamorphosis. Post-metamorphic XR11 frogs were reared to sexual maturity, thus allowing us to produce second-generation embryos and enabling us to distinguish between the maternal and zygotic contributions of Bcl-xL to the gamma-radiation apoptotic response. Wild-type embryos irradiated before the mid-blastula transition (MBT) underwent normal cell division until reaching the MBT, after which they underwent massive, catastrophic apoptosis. Over-expression of Bcl-xL derived from XR11 females, but not males, provided partial protection from apoptosis. Maternal expression of XR11 was also sufficient to abrogate apoptosis triggered by post-MBT gamma-radiation. Tolerance to post-MBT gamma-radiation from zygotically-derived XR11 was acquired gradually after the MBT in spite of abundant XR11 protein synthesis.ConclusionOur data suggest that Bcl-xL is an effective counterbalance to proapoptotic factors during embryonic development but has no apparent effect on the thyroid hormone-induced apoptosis that occurs during metamorphosis. Furthermore, post-MBT apoptosis triggered by irradiation before the MBT could only be restrained by maternal expression of Bcl-xL. Although maternal expression of XR11 was sufficient to abrogate apoptosis triggered by post-MBT gamma-radiation, radiation tolerance from zygotically-derived XR11 was acquired gradually, indicating that synthesis of XR11 protein is not sufficient to prevent apoptosis. Thus, repression of radiation-induced apoptosis by overexpression of Bcl-xL during embryonic development depends upon the timing of its expression and post-translational events that enable the protein to become effective.

Project description:Mesenchymal stem cells (MSCs) affect diverse aspects of tumor progression, such as angiogenesis, tumor growth and metastasis. Bone marrow MSCs (BM?MSCs) are fibroblast?like cells with multipotent differentiation ability, that localize to areas of tissue damage, including wounds and solid tumors. The tumor suppressor gene, p53, is functionally involved in cell cycle control, apoptosis and genomic stability, and is mutated and inactivated in most human cancers. The present study aimed to investigate the role of p53 in the biology of BM?MSCs. In the present study, p53 wild?type (p53+/+), knockdown (p53+/?) and knockout (p53?/?) mouse BM?MSCs (mBM?MSCs) were observed to be similar in appearance and in the expression of cell surface biomarkers, but expressed differential p53 protein levels. The p53+/? and p53?/? mBM?MSCs demonstrated an increased proliferation rate compared with mBM?MSCs derived from p53+/+ mice. mBM?MSCs from all three groups, representing distinct p53 statuses, were unable to form tumors over a 3?month period in vivo. The adipogenic and osteogenic differentiation of mBM?MSCs was increased in the absence of p53. The colony formation and migratory abilities of p53+/? and p53?/? mBM?MSCs were markedly enhanced, and the expression levels of stem cell?associated proteins were significantly increased compared with p53+/+. The expression levels of microRNA (miR)?3152 and miR?337 were significantly increased in p53+/? and p53?/? mBM?MSCs, whereas the expression levels of miR?221, miR?155, miR?1288 and miR?4669 were significantly decreased. The expression levels of tumor necrosis factor?? and interferon???inducible protein?10 were significantly upregulated in the supernatant of p53+/? and p53?/? mBM?MSCs. Ubiquitin protein ligase E3 component n?recognin 2, RING?finger protein 31 and matrix metalloproteinase 19 were highly expressed in p53+/? and p53?/? mBM?MSCs. The results of the present study indicated that p53 may serve an important role in the biology of mBM?MSCs, and may provide novel insights into the role of cells with different p53 statuses in cancer progression.

Dataset Information

Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation.

Background

Principal findings

Significance

Publications

Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation.

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