Antiarrhythmic Potential of Mesenchymal Stem Cell Is Modulated by Hypoxic Environment

Hwang, Hye Jin; Chang, Won Hyuk; Song, Byeong‐Wook; Song, Heesang; Cha, Min‐Ji; Kim, Il-Kwon; Lim, Soyeon; Choi, Eun Ju; Ham, Ok Kyung; Lee, Seyeon; Shim, Jaemin; Joung, Boyoung; Pak, Hui-Nam; Kim, Sung Soon; Choi, Bum‐Rak; Jang, Yangsoo; Lee, Moon Hyoung; Hwang, Ki‐Chul

doi:10.1016/j.jacc.2012.04.056

Cited by 48 publications

(54 citation statements)

References 34 publications

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“…In support of our previous finding [14], this study was performed to determine whether proteomes from MSC-CMs that were affected by hypoxia contain therapeutic factors that could contribute to improving arrhythmogenicity in rats with MI.…”

Section: Introductionmentioning

confidence: 60%

“…Normoxic conditioned medium (NCM) and hypoxic conditioned medium (HCM) were obtained as previously reported [14]. rMSCs (1 × 10 6 cells) at 80% confluence were pre-washed twice with serumfree medium (SFM) and then incubated with new SFM under normoxic and hypoxic conditions for 12 h. To induce hypoxic conditions, the rMSCs were incubated at 37°C in 5% CO 2 , 5% H 2 and 0.5% O 2 in a chamber with an anaerobic atmosphere system (Technomart, Korea).…”

Section: Preparation Of Normoxic and Hypoxic Conditioned Mediummentioning

confidence: 99%

“…The use of these paracrine factors, which are secreted into the conditioned medium (CM) by MSCs, has emerged as an alternative approach for MSC-based therapies to treat various diseases, including myocardial infarction (MI) [10][11][12][13]. Our previous study showed that the factors that are released from MSCs under hypoxic conditions ameliorate the induction of ventricular arrhythmias after MI by preventing apoptosis and thereby accelerating functional recovery [14]. However, little is known about how environmental conditions affect the potential roles of stem cells, and it is necessary to identify proteins that might serve as novel indicators of cellular recovery [15].…”

Section: Introductionmentioning

confidence: 99%

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Proteomic Analysis and Identification of Paracrine Factors in Mesenchymal Stem Cell-Conditioned Media under Hypoxia

Song

Kim²,

Choi³

et al. 2016

Cell Physiol Biochem

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Background/Aims: We previously showed that a hypoxic environment modulates the antiarrhythmic potential of mesenchymal stem cells. Methods: To investigate the mechanism by which secreted proteins contribute to the pathogenesis of antiarrhythmic potential in mesenchymal stem cells, we used two-dimensional electrophoresis combined with MALDI-TOF-MS to perform a proteomic analysis to compare the paracrine media produced by normoxic and hypoxic cells. Results: The proteomic analysis revealed that 66 protein spots out of a total of 231 matched spots indicated differential expression between the normoxic and hypoxic conditioned media of mesenchymal stem cells. Interestingly, two tropomyosin isoforms were dramatically increased in the hypoxic conditioned medium of mesenchymal stem cells. An increase in tropomyosin was confirmed using Western blot to analyze the conditioned media between normoxic and hypoxic cells. In a network analysis based on gene ontology (GO) Molecular Function by GeneMANIA analysis, most of the identified proteins were found to be involved in the regulation of heart processes. Conclusion: Our results show that hypoxia up-regulates tropomyosin and other secreted proteins which suggests that tropomyosin may be involved in regulating proarrhythmic and antiarrhythmic functions.

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Section: Introductionmentioning

confidence: 60%

Section: Preparation Of Normoxic and Hypoxic Conditioned Mediummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteomic Analysis and Identification of Paracrine Factors in Mesenchymal Stem Cell-Conditioned Media under Hypoxia

Song

Kim²,

Choi³

et al. 2016

Cell Physiol Biochem

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“…On the contrary, the arrhythmic risk of implantation, homing, engraftment, and differentiation of regenerating cells within the damaged cardiac tissue has constantly been a reason for major concern in the clinical use (15,17,48,73,74). Nevertheless, a number of papers documented a direct prorhythmic (rather than arrhythmic) action of cell therapy (11,27,34,46,50,72,89,90,92,93).…”

Section: Repair Of Infarcted Heart By Local Injection Of C-kit Pos Camentioning

confidence: 99%

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Savi

Bocchi

Rossi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Kit pos cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF ϩ IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs ϩ GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs ϩ GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs ϩ GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs ϩ GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart. cardiac progenitor cells; growth factors and cytokines; myocardial infarction; arrhythmia; cardiac gap junction connexins NEW & NOTEWORTHY Repair of infarcted heart by local injection of c-kit pos cardiac progenitors supplemented with hepatocyte growth factor and IGF-1 has distinctive antiarrhythmic effects involving recovery of Connexin-43, Connexin-40, and Ca v1.2 expression levels differently than progenitors or cytokines alone. This new insight into the impact of regenerative therapies on cardiac electrogenesis has clinical relevance.HEART FAILURE (HF) very often proceeds as a consequence of myocardial infarction (MI) (59) and continues to be a major health problem (49). Over the past 15 yr, cell therapy has emerged as a new strategy aimed at revitalizing dead myocardium, thus circumventing the unfavorable outcome of degenerative heart diseases, including the vicious circle of MI/HF (67). However, results obtained so far in clinical trials with a large sample size using cells of different origin, mainly skeletal myoblasts (44) and bone marrow cells (78), have been contradictor...

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“…These secreted factors act in an auto-and paracrine manner regulating cell phenotype. The importance of paracrine actions in the host tissue have been studied extensively in repair and regeneration of the central nervous system (Drago et al, 2013), heart (Gnecchi et al, 2006;Hwang et al, 2012) and skin (Schlosser et al, 2012). The indirect action of progenitor cells implanted within the bone-healing environment is less understood; nevertheless, the importance of various factors secreted by cells present in fracture milieu is known to have great importance on bone regeneration.…”

Section: Introductionmentioning

confidence: 99%

Enhancing inflammatory and chemotactic signals to regulate bone regeneration

Czekanska¹,

Ralphs²,

Alini³

et al. 2014

eCM

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Stem cells have become the fundamental element in regenerative medicine due to their inherent potential to differentiate into various cell types, and the ability to produce various bioactive molecules, including growth factors, cytokines and extracellular matrix molecules. In vivo, the secretion of tropic factors is modulated by chemotactic and inflammatory factors. In this study, we analysed the influence of a 2 h stimulation of mesenchymal stem cells (MSCs) with interleukin-1β (IL1β), granulocytecolony stimulating factor (GCSF), stromal cell-derived factor 1 (SDF1) and stem cell factor (SCF). Our results demonstrated that this short stimulation exerts pronounced effects on the expression of multiple cytokine genes and proteins in MSC cells 48 and 72 h later. IL1β strongly promoted the secretion of a wide range of proteins with chemotactic, proinflammatory and angiogenic properties, whereas SCF regulated the expression of proteins involved in proliferation, chondrogenesis and ECM regulation. This demonstrates that the changes in secretome can be directed towards a desired final functional outcome by selection of the most appropriate cytokine. Moreover, the expression pattern of Wnt signalling pathway components suggested the differential regulation of this pathway by IL1β and SCF. Altogether, the robust paracrine action of MSCs can be achieved within a just 2 h treatment, which would be feasible within the operating theatre during a single surgical procedure. These results suggest that integrating inflammatory modulation in bone tissue engineering, by modifying the MSC secretome by way of a short stimulus, would provide a more targeted approach than administering unmodified MSCs alone.

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Antiarrhythmic Potential of Mesenchymal Stem Cell Is Modulated by Hypoxic Environment

Abstract: ObjectivesThe purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment.

Cited by 48 publications

References 34 publications

Proteomic Analysis and Identification of Paracrine Factors in Mesenchymal Stem Cell-Conditioned Media under Hypoxia

Proteomic Analysis and Identification of Paracrine Factors in Mesenchymal Stem Cell-Conditioned Media under Hypoxia

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Enhancing inflammatory and chemotactic signals to regulate bone regeneration

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