Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties Via Toll-Like Receptor-4

Naftali‐Shani, Nili; Levin-Kotler, La-Paz; Palevski, Dahlia; Amit, Uri; Kain, David; Landa, Natalie; Hochhauser, Edith; Leor, Jonathan

doi:10.1161/circulationaha.116.023527

Cited by 59 publications

(45 citation statements)

References 45 publications

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“…Accumulating experimental and clinical data has shown that CSC transplantation can effectively treat MI [ 8 , 42 ]. However, after adoptive transfer, CSCs encounter various undesirable conditions including oxidative stress and inflammatory reactions [ 17 , 43 ]. Pathological stimulation causes functional mitochondrial disruption and consequently results in excessive ROS generation; ROS, in turn, deteriorate mitochondrial dysfunction and amplify mitochondrial apoptosis activation in a positive feedback loop [ 44 ], decreasing cell viability and thereby compromising therapeutic activities.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from miR‐214‐Enriched Bone Marrow‐Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Wang

Zhao

Liu³

et al. 2018

Oxidative Medicine and Cellular Longevity

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Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived from miR‐214‐Enriched Bone Marrow‐Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Wang

Zhao

Liu³

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…These differences could be explained by the fact that the MSC lifetime is dependent on the context they are put into because the environment where MSCs are implanted is decisive for their survival. 48,49 Likewise, different mouse models also present diverse grades of severity and disease progression. The Tg-ATXN3-69Q MJD model is extremely severe because it bears the truncated form of the human ataxin-3 protein, meaning that the achievements obtained in this model would probably represent the worst-case scenario.…”

Section: Discussionmentioning

confidence: 99%

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease

et al. 2018

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Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

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“…Mesenchymal stromal cells have been proven to possess immunomodulatory and antiinflammatory properties. 20 Currently, human MSCs hold great promise in regenerative medicine for the therapy of human diseases. [14][15][16] Human MCSs can be acquired from many tissues, such as umbilical cord, bone marrow, and chorionic membrane.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells ameliorate acute allergic rhinitis in rats

Wang

et al. 2017

Cell Biochemistry & Function

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Mesenchymal stromal cells (MSCs) have been extensively investigated as a potential antiinflammatory treatment in many inflammatory‐related diseases; however, it remains unclear whether MSCs could be used to treat acute allergic rhinitis. A rat model of allergic rhinitis was treated with MSCs. The effect of MSCs on the inflammation of allergic rhinitis was evaluated by sneezing, nose rubbing, the pathology of the nasal mucosa, and the expression of interleukin 4, tumour necrosis factor alpha, and immunoglobulin E in the serum of rats. Also, the population of MSCs isolated from umbilical cords of humans was evaluated to determine if they could inhibit the symptoms and inflammation of acute allergic rhinitis in a rat model. We observed that this population of cells inhibited sneezing, nose rubbing, and changes in the pathology of the nasal mucosa. Intriguingly, we observed that MSCs reduced the expression of interleukin 4, tumour necrosis factor alpha, and immunoglobulin E in the serum. Furthermore, MSCs reduced the expression of histamine and the recruitment of macrophages in the nasal mucosa of allergic rhinitis rats. We reasoned that the effect of MSCs on allergic rhinitis might be through its regulation of the secretion of related cytokines from macrophages during the process of acute allergic rhinitis. This work suggested that MSCs from the umbilical cords of humans could be used as a positive clinical therapy for the human disease.

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Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties Via Toll-Like Receptor-4

Abstract: The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by .

Cited by 59 publications

References 45 publications

Exosomes Derived from miR‐214‐Enriched Bone Marrow‐Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Exosomes Derived from miR‐214‐Enriched Bone Marrow‐Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease

Mesenchymal stromal cells ameliorate acute allergic rhinitis in rats

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