Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy

Molina, Ezequiel; Palma, Jon; Gupta, Dipin; Torres, Denise; Gaughan, John; Houser, Steven R.; Macha, Mahender

doi:10.1002/term.137

Cited by 38 publications

(25 citation statements)

References 33 publications

(35 reference statements)

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“…Matrix metalloproteinases (MMPs) are a group of essential molecules that maintain extracellular matrix (ECM) homeostasis and ECM remodeling plays a large role in regulating myocyte migration, differentiation, and regeneration (55). MSCs release a combination of various MMPs and tissue inhibitors that are involved in extracellular remodeling (245). Notably, the ratio of MMPs to tissue inhibitors can be modulated by overexpression of certain factors, which can reverse the process of cardiac remodeling (334,351).…”

Section: A Antifibrosis and Prosurvivalmentioning

confidence: 99%

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

Golpanian

Wolf

Hatzistergos

et al. 2016

Physiological Reviews

269

211

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Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.

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Section: A Antifibrosis and Prosurvivalmentioning

confidence: 99%

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

Golpanian

Wolf

Hatzistergos

et al. 2016

Physiological Reviews

269

211

View full text Add to dashboard Cite

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“…Three main mechanisms of action underlie the favorable actions of MSCs in disease: 1) reduction of fibrosis 69 , 2) Stimulation of angiogenesis 70 and 3) restoration of contractile function 66, 67 through engraftment 71 , differentiation and stimulation of endogenous cardiac stem cells to proliferate and differentiate 63 (Figure 3). These effects occur in concert and together lead to the replacement of scarred or dysfunctional myocardial tissue with contractile and perfused tissue 65, 66 .…”

Section: Introductionmentioning

confidence: 99%

“…Willems et al 90 showed that a 1,4-dihydropyridine inducer of type 2 TGF-β receptor (TGFBR2) degradation-1 (ITD-1) selectively enhanced the differentiation of uncommitted mesodermal cells to cardiomyocytes. Extensive studies in the field of bone and cartilage regeneration have shown us that mechanical forces and extracellular matrix components significantly influence MSCs 91 but also MSCs modulate the matrix by secreting metalloproteinases and their tissue inhibitors by shifting the balance towards domination of matrix-degrading effects 69 . This may require the secretion of hepatocyte growth factor 92 and heme oxygenase-1 93 by MSCs.…”

Section: Introductionmentioning

confidence: 99%

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Karantalis

Hare

2015

Circulation Research

367

332

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Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational interest in the use of stem and/or precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells (MSCs) are widely studied and in early stage clinical studies show promise for repair and regeneration of cardiac tissues. The ability of MSCs to differentiate into mesoderm and non-mesoderm derived tissues, their immunomodulatory effects, their availability and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. Here, we review the biology of MSCs, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting.

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“…It has been theorized that hMSCs reduce cardiac fibrosis 15 and enhance angiogenesis 16 largely through paracrine signaling (PS) mechanisms. 17,18 Moreover, recent studies have demonstrated that hMSC PS can modulate cardiomyocyte ion channel/pump activity.…”

Section: Introductionmentioning

confidence: 99%

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Mayourian

Cashman

Ceholski

et al. 2017

Circulation Research

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Rationale Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. Objective To better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. Methods and Results Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/SERCA activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased approximately 4-fold compared to non-hMSC-supplemented controls during physiologic 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential pro-arrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosomes-enriched, but not exosomes-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT developed force and expression of calcium handling genes (e.g., SERCA2a, L-type calcium channel). Conclusions Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.

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Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy

Cited by 38 publications

References 33 publications

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

Use of Mesenchymal Stem Cells for Therapy of Cardiac Disease

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

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