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Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence.

ABSTRACT: Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and anti-apoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.

SUBMITTER: Niu P

PROVIDER: S-EPMC4627227 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence.

Niu Ping P Smagul Aibek A Wang Lu L Sadvakas Aiman A Sha Ying Y Pérez Laura M LM Nussupbekova Aliya A Amirbekov Aday A Akanov Akan A AA Gálvez Beatriz G BG Jordan I King IK Lunyak Victoria V VV

Oncotarget 20150701 20

Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impe ...[more]

PMID: 26255627

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Project description:BACKGROUND: Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.METHODS: We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.RESULTS: Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. CONCLUSION: In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.

Dataset Information

Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence.

Publications

Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence.

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