Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik, Katarzyna A.; Trial, JoAnn; Entman, Mark L.

doi:10.1016/j.ajpath.2011.06.022

Cited by 51 publications

(94 citation statements)

References 71 publications

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“…On the other hand, we found no evidence that A 2B receptors promote cardiomyogenic differentiation of cardiac mesenchymal stem-like cells [10]. Recent evidence suggests that cardiac mesenchymal stemlike cells respond to stimulation with TGFβ in vitro, or to myocardial injury in vivo, by displaying myofibroblast characteristics that include an increased synthesis of extracellular matrix (ECM) components and the expression of the contractile protein α-smooth muscle actin (αSMA) [23][24][25]. The rapid accumulation and activity of cardiac myofibroblasts early after myocardial injury is thought to be critical for proper scar formation [26].…”

Section: Introductioncontrasting

confidence: 40%

Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Ryzhov

Sung

Zhang

et al. 2014

Purinergic Signalling

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Adenosine levels increase in ischemic hearts and contribute to the modulation of that pathological environment. We previously showed that A 2B adenosine receptors on mouse cardiac Sca1 + CD31− mesenchymal stromal cells upregulate secretion of paracrine factors that may contribute to the improvement in cardiac recovery seen when these cells are transplanted in infarcted hearts. In this study, we tested the hypothesis that A 2B receptor signaling regulates the transition of Sca1 + CD31 − cells, which occurs after myocardial injury, into a myofibroblast phenotype that promotes myocardial repair and remodeling. In vitro, TGFβ1 induced the expression of the myofibroblast marker α-smooth muscle actin (αSMA) and increased collagen I generation in Sca1 + CD31 − cells. Stimulation of A 2B receptors attenuated TGFβ1-induced collagen I secretion but had no effect on αSMA expression. In vivo, myocardial infarction resulted in a rapid increase in the numbers of αSMA-positive cardiac stromal cells by day 5 followed by a gradual decline. Genetic deletion of A 2B receptors had no effect on the initial accumulation of αSMA-expressing stromal cells but hastened their subsequent decline; the numbers of αSMA-positive cells including Sca1

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Section: Introductioncontrasting

confidence: 40%

Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Ryzhov

Sung

Zhang

et al. 2014

Purinergic Signalling

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“…30 TβRI and TβRII protein levels, as well as smad3 phosphorylation and α-SMA expression, are significantly reduced in fibroblasts of aged mice. 31 In addition, fibroblasts isolated from senescent hearts show a blunted response to TGF-ß stimulation. 32 Hence, it seems reasonable to assume that age-dependent impairment of wound healing is caused, at least in part, by impaired TGF-β signaling.…”

Section: Discussionmentioning

confidence: 99%

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway

et al. 2015

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Background— Sirt7, 1 of the 7 members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process. Methods and Results— In wild-type mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7 −/− ) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7 −/− mice. In vitro, Sirt7 −/− mouse–derived or Sirt7 siRNA–treated cardiac fibroblasts showed reduced transforming growth factor-β signal activation and low expression levels of fibrosis-related genes compared with wild-type mice–derived or control siRNA–treated cells. These changes were accompanied by reduction in transforming growth factor receptor I protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. Transforming growth factor-β receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-Cα was involved in this process. Conclusion— Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.

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“…Importantly pAMPK has been demonstrated to shift macrophages to the alternatively activated, type 2, anti-inflammatory phenotype [28]. pAMPK is also know to inhibit TGFβ1 signaling, which would further reduce pathologic inflammation and fibrosis [29]. Lastly, pAMPK also inhibits reactive oxygen species [30], reducing the pathologic consequences of an over active immune response even further.…”

Section: Discussionmentioning

confidence: 99%

The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia

Mull¹,

Berhanu²,

Roberts³

et al. 2014

Metabolism

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Objective Due to their previously identified naturally and chronically increased levels of skeletal muscle pAMPK we hypothesized and now investigated whether the MRL/MpJ (MRL) mice would be resistant to high fat diet (HFD)-induced metabolic changes. Materials/Methods Three-week old male MRL and control C57Bl/6 (B6) mice were randomly assigned to 12 weeks of high fat diets (HFD) or control diets (CD). Weekly animal masses and fasting blood glucose measurements were acquired. During the last week of diet intervention, fasted animals were subjected to glucose and insulin tolerance tests. At harvest, tissues were dissected for immunoblots and serum was collected for elisa assays. Results The MRL mouse strain is known for its ability to regenerate ear punch wounds, cardiac cryoinjury, and skeletal muscle disease. Despite gaining weight and increasing their fat deposits the MRL mice were resistant to all other indicators of HFD-induced metabolic alterations assayed. Only the HFD-B6 mice displayed fasting hyperglycemia, hyperinsulinemia and hypersensitivity to glucose challenge. HFD-MRL mice were indistinguishable from their CDMRL counterparts in these metrics. Skeletal muscles from the HFD-MRL contained heightened levels of pAMPK, even above their CD counterparts. Conclusions The MRL mouse strain is the first naturally occurring mouse strain that we are aware of that is resistant to HFD-induced metabolic changes. Furthermore, the increased pAMPK suggests a proximal mechanism for these beneficial metabolic differences. We further hypothesize that these metabolic differences and plasticity provide the basis for the MRL mouse strain’s super healing characteristics. This project’s ultimate aim is to identify novel therapeutic targets, which specifically increase pAMPK.

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Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cited by 51 publications

References 71 publications

Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway

The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia

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