Genotoxic damage of human adipose-tissue derived mesenchymal stem cells triggers their terminal differentiation

Altanerová, Veronika; Horváthová, Eva; Matúšková, Miroslava; Kučerová, Lucia; Altaner, Č

doi:10.4149/neo_2009_06_542

Cited by 25 publications

(22 citation statements)

References 44 publications

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“…However, same AT-MSC failed to support proliferation and growth of glioblastoma tumour cells. We have never observed tumour cell-triggered morphological changes, significant cell death or terminal differentiation in AT-MSC in contrast to response to genotoxic damage [44]. This study extends our observations to several breast cancer cell lines.…”

Section: Discussionsupporting

confidence: 74%

Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells

Kučerová¹,

Kovacovicova²,

Polák³

et al. 2011

neo

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Human adipose tissue was shown to be a very attractive source of mesenchymal stromal cells that have a wide scale of potential applications in reconstructive plastic surgery and regenerative medicine. However, these cells were described to have profound effects on biological behaviour of tumour cells. The aim of this study was to analyze the influence of adipose tissue-derived human mesenchymal stromal cells (AT-MSC) on the proliferation of breast cancer cells. We have tested proliferation of three different human breast cancer cell lines under the influence of AT-MSC derived soluble factors as well as in the direct cocultures. These data were supplemented with the expression analysis of cytokines and their cognate receptors on the target cells. We have observed stimulation of proliferation in breast cancer cells MDA-MB-361, T47D and EGFP-MCF7. AT-MSC were found to secrete wide scale of cytokines, chemokines and growth factors, thus we concluded that this pro-proliferative effect was a result of their synergistic action. These data bring out a need to evaluate whether primary breast tumour derived human cells would respond to these type of stimuli in a similar manner in order to exclude any potential clinical risk related to the application of human mesenchymal stromal cells under the context of patient with history of breast cancer malignancy.

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Section: Discussionsupporting

confidence: 74%

Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells

Kučerová¹,

Kovacovicova²,

Polák³

et al. 2011

neo

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“…A few data are available on the progeny of stem cells subjected to sublethal insults. Adipose-derived human MSCs recovered after genotoxic damage resumed proliferation but underwent parental cell-intrinsic replicative senescence (Altanerova et al 2009). MSC cultivation under improper conditions (serum deprivation, low oxygen, and especially long cell treatment with trypsin or collagenase) was exploited to enrich MSC populations by putative stem cells (Kuroda et al 2010;Heneidi et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Sublethal heat shock induces premature senescence rather than apoptosis in human mesenchymal stem cells

Алексеенко

Zemelko

Домнина

et al. 2014

Cell Stress and Chaperones

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Stem cells in adult organism are responsible for cell turnover and tissue regeneration. The study of stem cell stress response contributes to our knowledge on the mechanisms of damaged tissue repair. Previously, we demonstrated that sublethal heat shock (HS) induced apoptosis in human embryonic stem cells. This study aimed to investigate HS response of human adult stem cells. Human mesenchymal stem cells (MSCs) cultivated in vitro were challenged with sublethal HS. It was found that sublethal HS did not affect the cell viability assessed by annexin V/propidium staining. However, MSCs subjected to severe HS exhibited features of stress-induced premature senescence (SIPS): irreversible cell cycle arrest, altered morphology, increased expression of senescence-associated β-galactosidase (SA-β-gal) activity, and induction of cyclin-dependent kinase inhibitor p21 protein. High level of Hsp70 accumulation induced by sublethal HS did not return to the basal level, at least, after 72 h of the cell recovery when most cells exhibited SIPS hallmarks. MSCs survived sublethal HS, and resumed proliferation sustained the properties of parental MSCs: diploid karyotype, replicative senescence, expression of the cell surface markers, and capacity for multilineage differentiation. Our results showed for the first time that in human MSCs, sublethal HS induced premature senescence rather than apoptosis or necrosis. MSC progeny that survived sublethal HS manifested stem cell properties of the parental cells: limited replicative life span and multilineage capacity.

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“…Interestingly, both ATM and c-Abl were found to be activated not only by DNA damage induction but also by insulin treatment (20,34), suggesting a possible mechanism of c-Abl activation by adipogenic induction through ATM. It was also demonstrated that genotoxic drugs or reactive oxygen species can promote adipocyte differentiation of cultured mesenchymal progenitors of adipocytes (35,36). An intriguing possibility that should be further investigated is that controlled DNA damage is being used during normal adipogenesis to activate key regulators like c-Abl.…”

Section: Discussionmentioning

confidence: 99%

c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2

Keshet

Kraitshtein

Shanzer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Adipocyte differentiation, or adipogenesis, is a complex and highly regulated process. A recent proteomic analysis has predicted that the nonreceptor tyrosine kinase Abelson murine leukemia viral oncogene (c-Abl) is a putative key regulator of adipogenesis, but the underlying mechanism remained obscure. We found that c-Abl was activated during the early phase of mouse 3T3-L1 preadipocyte differentiation. Moreover, c-Abl activity was essential and its inhibition blocked differentiation to mature adipocytes. c-Abl directly controlled the expression and activity of the master adipogenic regulator peroxisome proliferator-activator receptor gamma 2 (PPARγ2). PPARγ2 physically associated with c-Abl and underwent phosphorylation on two tyrosine residues within its regulatory activation function 1 (AF1) domain. We demonstrated that this process positively regulates PPARγ2 stability and adipogenesis. Remarkably, c-Abl binding to PPARγ2 required the Pro12 residue that has a phenotypically wellstudied common human genetic proline 12 alanine substitution (Pro12Ala) polymorphism. Our findings establish a critical role for c-Abl in adipocyte differentiation and explain the behavior of the known Pro12Ala polymorphism.

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Genotoxic damage of human adipose-tissue derived mesenchymal stem cells triggers their terminal differentiation

Cited by 25 publications

References 44 publications

Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells

Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells

Sublethal heat shock induces premature senescence rather than apoptosis in human mesenchymal stem cells

c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2

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