Abstract 15610: The Infusion of Mesenchymal Stromal Cells Post Myocardial Infarction Increases Myocardial S100A6, Attenuates Myocyte Hypertrophy, Reduces Myocyte Apoptosis and Improves Cardiac Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
James Tsoporis ◽  
Shehla Izhar ◽  
Jean-Francois Desjardins ◽  
Gerald Proteau ◽  
Gustavo Yannarelli ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Fold Increase ◽  
Coronary Artery Ligation ◽  
Myocyte Hypertrophy ◽  
Beneficial Effects ◽  
Infarcted Myocardium ◽  
Donor Cells

The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal stromal cells (BM-MSCs) to differentiate into cardiomyocytes have been questioned due to the transient presence of donor cells at injury site following myocardial infarction (MI) suggesting that the MSC-induced improvement in hemodynamic function may be attributable to paracrine effects. We showed that S100A6, a 20 kDa EF-hand calcium-binding dimer, is upregulated and secreted following MI and forced expression post-MI was beneficial to the preservation of cardiac function. The aim of this study was to determine whether the beneficial effects of infused BM-MSCs may be related to the autocrine secretion of S100A6. Balb/c murine cultured green fluorescence protein (GFP)-marked BM-MSCs express S100A6 at baseline and in response to hypoxia (5%C02/95% N2) for 1 hr increase S100A6 mRNA and protein (2-3 fold, and release S100A6 (1 nM) in the culture media, responses inhibited in BM-MSCs transfected with S100A6 siRNA. Treatment of neonatal Balb/c cardiac myocytes with human recombinant S100A6 (1nM) for 1-24 hrs attenuated baseline apoptosis (30 per cent decrease in BAX/BCL2 ratio), induced cyclin-dependent kinase 1(CDK1) mRNA 1.5 fold, miR199a 2 fold and myocyte proliferation 2.5 fold, the latter inhibited by anti-miR 199a. In 12 week old Balb/c mice, saline or GFP-marked BM-MSCs transfected with either a scrambled or S100A6 siRNA were infused intravenously 3-4 hrs post coronary artery ligation. After 3-4 days the GFP-marked cells were confined to ischemic areas and represented approximately 10% of total cellularity and co-expressed collagen type IV and myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Despite the absence of donor cells in the infarcted myocardium 21 days after infusion, mice that have received MSCs alone compared to MSCs transfected with an S100A6 siRNA or saline alone showed a 6-fold increase in S100A6 mRNA and protein, 3-fold increase in miR199a in peri-infarcted myocardium, attenuated myocyte hypertrophy, decreased fibrosis and apoptosis, and preservation of cardiac function. In conclusion, the secretion of S100A6 by infused BM-MSCs may contribute in limiting adverse LV remodeling post-MI.

Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction

Cytotherapy ◽  
2021 ◽  
Author(s):  
Sujitha Thavapalachandran ◽  
Thi Yen Loan Le ◽  
Sara Romanazzo ◽  
Fairooj N. Rashid ◽  
Masahito Ogawa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Cardiac Function ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Pluripotent Stem Cell

Abstract 492: Dual Stem Cell Therapy Improves the Cardiac Function After Experimental Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sinziana Popescu ◽  
Ana-Mihaela Lupan ◽  
Preda Bogdan Mihai ◽  
Maya Simionescu ◽  
Alexandrina Burlacu
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Cardiac Function ◽  
Protein Expression ◽  
Connexin 43 ◽  
Cell Contact ◽  
Coronary Artery Ligation ◽  
Cell Transplant ◽  
Infarcted Myocardium ◽  
Cell Based Therapy

As the mortality associated with cardiovascular diseases has accelerated in the past 10 years, advances in treatment options can have significant impact on the global population health. Mesenchymal Stromal Cells (MSC) have shown limited efficacy in clinical trials as sole contributors to tissue regeneration. Thus, we questioned whether the presence of Endothelial Colony Forming Cells (ECFC) could improve MSC-based cellular therapy of the infarcted myocardium. Acute myocardial infarction was induced in immunodeficient NSG mice by left coronary artery ligation and then MSCs or MSCs+ECFCs were immediately injected in the ventricular wall. Both healthy and sham-treated infarcted mice served as controls. At 7 days post-transplantation, echocardiography, qPCR and Western Blot (WB) were performed to assess cardiac function and protein expression. MSC - ECFC reciprocal modulation was studied in vitro by 24-hour co-culture in dual-chamber system or in direct contact, followed by qPCR and WB. The secretome collected from cultures was characterized by Matrigel angiogenesis assay, Proteome Profiler Arrays and ELISA. The results revealed that in dual-cell transplant compared to single transplant group the cardiac function (ejection fraction and stroke volume) was significantly improved. The protein expression of junctional molecules such as Connexin 43 and Integrin α-5 was increased by more than twofold in the MSC+ECFC vs. MSC-only group. Moreover, both MSC and ECFC secreted high levels of pro-angiogenic molecules, with only partially overlapping profiles, capable of inducing tube-like vascular structures on Matrigel. These observations suggest a putative complementary contribution of MSC and ECFC to the cardiac repair process. Significant increase in the Integrin α-5 expression was achieved in both culture settings, indicating a mechanism independent of cell to cell contact. However, a synergistic paracrine effect of the MSC-ECFC pair only occured after close cell interaction, especially for VEGF, SDF-1 and YKL-40, thus suggesting that both cell types are needed for sustained effects. In conclusion, we provide evidence that the complementary, dual stem cell-based therapy could positively modulate the function of infarcted myocardium.

Abstract P109: Spiny Mice Are Protected From Myocardial Infarction Induced Cardiac Pathophysiology

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
YanFei Qi ◽  
Juan Zhang ◽  
Lei Wang ◽  
Ashok Kumar ◽  
Avinash Mandloi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Tissue Injury ◽  
Fold Increase ◽  
Cardiac Cells ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Spiny Mice ◽  
Cd1 Mice

Background: Despite the advancement in drug and surgical interventions, myocardial damage and associated cardiac dysfunction lead to heart failure that remains common cause of death following myocardial infarction (MI). Spiny mice (Acomys cahirinus, SM) have been shown to possess regenerating capacity following deep tissue injury without scarring ( Nature 2013 ). This led us to investigate if this regenerative property would also be preserved in the heart. Methods and Results: Adult CD1 and SM were subject to left anterior descending coronary artery ligation or sham surgeries. Proliferative cells were identified by nuclear incorporation of 5-bromodeoxyuridine (BrdU, daily, i.p.) and injection was started from 3d post MI continued to 2wks post MI. Cardiac function was assessed using echocardiography and MRI. SM exhibited 3-fold smaller infarct size (SM-MI 18.6±3.4% vs CD1-MI 76.2±3.4%, p<0.05) and better contractility measured by ejection fraction (SM-MI 77.1±6.5 vs CD1-MI 24.6±4.6, %, p<0.05) than CD1 mice. SM showed 6-fold increase in BrdU + cells in left ventricle after MI while CD1 mice had 4-fold increase (CD1-sham 11±3.5 vs CD1-MI 44±9.1 and SM-sham 16±9.8 vs SM-MI 101.1±30.9, p<0.05). Though basal cardiac ACE2 activity was not different between CD1 and SM, MI resulted in a 16% decrease in cardiac ACE2 activity in CD1-MI mice but 20% elevation of cardiac ACE2 activity in myocardial tissue in SM-MI. Conclusions: SM are protected from ischemia induced cardiac damage and dysfunction. This involves increased proliferating cardiac cells and reduction in infarct size. Thus SM could be an ideal animal model for identification of molecular and genetic circuits involved in preservation/regeneration of cardiac function with translational implication to human MI.

scholarly journals Consistent Long-Term Therapeutic Efficacy of Human Umbilical Cord Matrix-Derived Mesenchymal Stromal Cells After Myocardial Infarction Despite Individual Differences and Transient Engraftment

2021 ◽  
Vol 9 ◽  
Author(s):  
Tiago L. Laundos ◽  
Francisco Vasques-Nóvoa ◽  
Rita N. Gomes ◽  
Vasco Sampaio-Pinto ◽  
Pedro Cruz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cardiac Remodeling ◽  
Human Umbilical Cord ◽  
Therapeutic Benefits ◽  
Umbilical Cord Matrix

Human mesenchymal stem cells gather special interest as a universal and feasible add-on therapy for myocardial infarction (MI). In particular, human umbilical cord matrix-derived mesenchymal stromal cells (UCM-MSC) are advantageous since can be easily obtained and display high expansion potential. Using isolation protocols compliant with cell therapy, we previously showed UCM-MSC preserved cardiac function and attenuated remodeling 2 weeks after MI. In this study, UCM-MSC from two umbilical cords, UC-A and UC-B, were transplanted in a murine MI model to investigate consistency and durability of the therapeutic benefits. Both cellular products improved cardiac function and limited adverse cardiac remodeling 12 weeks post-ischemic injury, supporting sustained and long-term beneficial therapeutic effect. Donor associated variability was found in the modulation of cardiac remodeling and activation of the Akt-mTOR-GSK3β survival pathway. In vitro, the two cell products displayed similar ability to induce the formation of vessel-like structures and comparable transcriptome in normoxia and hypoxia, apart from UCM-MSCs proliferation and expression differences in a small subset of genes associated with MHC Class I. These findings support that UCM-MSC are strong candidates to assist the treatment of MI whilst calling for the discussion on methodologies to characterize and select best performing UCM-MSC before clinical application.

Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

2004 ◽  
Vol 286 (1) ◽  
pp. H381-H387 ◽  
Author(s):  
Ling Chen ◽  
Chang Xun Chen ◽  
Xiaohong Tracey Gan ◽  
Norbert Beier ◽  
Wolfgang Scholz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Infarct Size ◽  
Treatment Delay ◽  
Left Ventricular ◽  
Heart Weight ◽  
Coronary Artery Ligation ◽  
Treatment Protocols ◽  
Beneficial Effects ◽  
All Treatment

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2–4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.

scholarly journals Quantitative and qualitative composition of the innate immune response are equally important in wound healing after myocardial infarction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Wrobel ◽  
J Rettkowski ◽  
H Seung ◽  
C Wadle ◽  
P Stachon ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Wound Healing ◽  
Innate Immunity ◽  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Myeloid Cells ◽  
Fold Increase ◽  
Remote Myocardium ◽  
Inflammatory Phenotype

Abstract Background Emergency hematopoiesis (EH) serves as the foundation of monocyte-derived and macrophage (Mφ) driven efferocytosis and ventricular remodeling after myocardial infarction (MI). Excessive myelopoiesis, however, can stipulate maladaptive wound healing and its therapeutic reduction may be a novel approach to preserve cardiac function. All-trans retinoic acid (ATRA) is a pleiotropic modulator of EH and innate immunity shielding hematopoietic stem cells from activation and driving survival and differentiation of myeloid cells. Purpose This study aimed to investigate this intriguing interplay of ATRA in wound healing after MI. Methods MI was induced by permanent coronary ligation in C57BL/6 mice and treated with daily injections of either ATRA (30mg/kg) or DMSO (vehicle) up to five days, starting 24h after ligation. Flow cytometry (FACS) was used for cell cycle analysis and immunophenotyping of leukocytes in bone marrow (BM), blood and heart. Immunohistochemistry (IH), masson trichrome (MT) staining and echocardiography evaluated inflammatory-fibrotic and functional development. Cytokine expression was analyzed by qPCR in bulk infarct and isolated, polarized Mφ-populations of BM-derived and cardiac resident origin. Results On day 2 after MI, EH was significantly reduced in ATRA-treated mice as compared to vehicle controls by means of cell cycle activity (n=6–13 per group; p&lt;0,01) and myeloid cells in BM, blood and infarct tissue (n=5–13; p&lt;0,05). Consequently, mRNA-expression of key inflammatory cytokines, IL-1β and TNFα, was diminished in the infarct tissue in this early phase (n=5–12; p&lt;0,05). These changes, however, failed to preserve cardiac function and ventricular remodeling, 21 days after MI (n=10–11; not significant). By qPCR, non-canonical activation of recruited ATRA-primed monocyte-derived Mφ, was found to propagate a pro-inflammatory phenotype with higher expression of MMP2 and MMP9 in sorted cardiac Mφ (n=4–5; p&lt;0,001). Furthermore, prominent IL-1β-expression in M2-polarized BM-derived Mφ indicated an impaired anti-inflammatory phenotype after ATRA treatment (n=4–6; p&lt;0,05). Strikingly, these changes also occurred in remote myocardium where IH revealed a 2-fold increase of CD11b - positive myeloid cells accompanied by increased expression of TNFα and TGFβ (n=9; p&lt;0,001). MT-staining, performed 21 days after MI, demonstrated an almost 3-fold increase in collagen deposition in remote myocardium of ATRA treated mice in contrast to vehicle controls (n=4–6; p&lt;0,0001). Conclusion Despite a beneficial reduction of EH after MI, short-term treatment with ATRA induced profound and persisting changes in the cytokine expression of monocyte-derived Mφ, which significantly altered their function and thus prevented improvements in cardiac function. Our data provide evidence that quantitative and qualitative changes in innate immunity are equally important for cardiac remodeling after MI. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

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