scholarly journals Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Maaike te Lintel Hekkert ◽  
Gary Newton ◽  
Kathryn Chapman ◽  
Rehan Aqil ◽  
Robert Downham ◽  
...  
Keyword(s):  
Stem Cell ◽  
Infarct Size ◽  
Clinical Success ◽  
Heart Tissue ◽  
Balloon Occlusion ◽  
Large Mammals ◽  
Preclinical Trial ◽  
Large Mammal ◽  
Lv Mass ◽  
Technical Issues

AbstractReducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.

scholarly journals Stem Cells in the Path of Light, from Corneal to Retinal Reconstruction

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 873
Author(s):  
Ovidiu Samoila ◽  
Lacramioara Samoila
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Clinical Success ◽  
Corneal Stroma ◽  
Cell Transplant ◽  
Inclusion Criteria ◽  
Epithelial Stem Cells ◽  
Corneal Epithelial ◽  
Stem Cells Transplantation ◽  
Limbal Epithelial Stem Cells

The future of eye reconstruction invariably includes stem cells transplantation. Corneal limbus, corneal stroma, trabeculum, retinal cells, optic nerve, and all structures that are irreversibly damaged and have no means to be repaired or replaced, through conventional treatment or surgery, represent targets for stem cell reconstruction. This review tries to answer the question if there is any clinical validation for stem therapies, so far, starting from the cornea and, on the path of light, arriving to the retina. The investigation covers the last 10 years of publications. From 2385 published sources, we found 56 clinical studies matching inclusion criteria, 39 involving cornea, and 17 involving retina. So far, corneal epithelial reconstruction seems well validated clinically. Enough clinical data are collected to allow some form of standardization for the stem cell transplant procedures. Cultivated limbal epithelial stem cells (CLET), simple limbal epithelial transplant (SLET), and oral mucosa transplantation are implemented worldwide. In comparison, far less patients are investigated in retinal stem reconstructions, with lower anatomical and clinical success, so far. Intravitreal, subretinal, and suprachoroidal approach for retinal stem therapies face specific challenges.

Abstract 17313: Multiparametric Cardiac MRI Documents Reduced LV Remodeling and Improved Contractile Function in Regions Adjacent to the Infarct After Pharmacologic Immunomodulation via Adenosine 2a Receptor Stimulation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ya-Jian Cheng ◽  
Elie R Chemaly ◽  
Yikui Tian ◽  
Frederick H Epstein ◽  
Brent A French
Keyword(s):  
Infarct Size ◽  
Contractile Function ◽  
Black Blood ◽  
Inversion Recovery Imaging ◽  
Cardiac Strain ◽  
Lv Mass ◽  
Lv Remodeling ◽  
Acute Mi ◽  
Adenosine 2A Receptor ◽  
A2ar Agonist

Introduction: Agonists of the Adenosine 2a Receptor (A2aR) are used clinically as pharm-stress agents for perfusion imaging, but they are also potent immunomodulators that reduce the size of acute MI when administered at reperfusion in both large and small animal models of MI. Hypothesis: Sustained administration of an A2aR agonist can reduce post-MI LV remodeling and improve cardiac strain even when treatment is withheld until after infarct size has stabilized. Methods: Two groups of mice were studied: C57BL/6 mice treated with Vehicle or a highly selective A2aR agonist (ATL313). All mice received 1h coronary occlusion and 28d of reperfusion. ATL313 was administered for 28 days by subcutaneous micro-osmotic pumps implanted after MI. All mice underwent 7T CMR imaging at baseline and 2, 7 & 28 days post-MI. CMR included short-axis black-blood cines covering the entire heart, with mid-ventricular cine DENSE for circumferential strain (Ecc). Late Gd-enhanced (LGE) inversion recovery imaging was performed on Days 2&7 and molecular imaging with a collagen-targeted Gd contrast agent (EP3533) on Days 14&28. Mice with Day 2 LGE infarct sizes less than 22% or >42% LV mass were excluded from analysis. Results: Examples of LGE and DENSE analysis are shown in Panels A&B. Day 2 infarct size was similar between groups (ATL313 (n=9): 35±2 vs Vehicle (n=8): 34±2, mean±SEM, p=NS). In panel C, ATL313 significantly improved LV end-systolic volume as early as 2 days post-MI (mean±SEM, *p<0.05 vs Vehicle). In panel D, ATL313 improved Day 2 Ecc in adjacent zones vs. Vehicle (-10±2 vs -6±2%, *p<0.05). In panel E, ATL313 reduced LV mass at Day 28 vs Vehicle (121±7 vs 143±7mg, *p<0.05). Conclusions: Pharmacologic immunomodulation with an A2aR agonist inhibits LV remodeling, improves contractile function in infarct-adjacent regions at Day 2 post-MI and reduces LV mass at Day 28. Combined with previous work, these results suggest that A2aR stimulation may prove beneficial in both acute and sub-acute MI.

scholarly journals N-cadherin overexpression enhances the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes in infarcted mouse hearts

2019 ◽  
Vol 116 (3) ◽  
pp. 671-685 ◽  
Author(s):  
Xi Lou ◽  
Meng Zhao ◽  
Chengming Fan ◽  
Vladimir G Fast ◽  
Mani T Valarmathi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Infarct Size ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cell ◽  
Myogenic Differentiation ◽  
Functional Integration ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Cardiac Functions ◽  
Induced Pluripotent

Abstract Aims In regenerative medicine, cellular cardiomyoplasty is one of the promising options for treating myocardial infarction (MI); however, the efficacy of such treatment has shown to be limited due to poor survival and/or functional integration of implanted cells. Within the heart, the adhesion between cardiac myocytes (CMs) is mediated by N-cadherin (CDH2) and is critical for the heart to function as an electromechanical syncytium. In this study, we have investigated whether the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) can be enhanced through CDH2 overexpression. Methods and results CDH2-hiPSC-CMs and control wild-type (WT)-hiPSC-CMs were cultured in myogenic differentiation medium for 28 days. Using a mouse MI model, the cell survival/engraftment rate, infarct size, and cardiac functions were evaluated post-MI, at Day 7 or Day 28. In vitro, conduction velocities were significantly greater in CDH2-hiPSC-CMs than in WT-hiPSC-CMs. While, in vivo, measurements of cardiac functions: left ventricular (LV) ejection fraction, reduction in infarct size, and the cell engraftment rate were significantly higher in CDH2-hiPSC-CMs treated MI group than in WT-hiPSC-CMs treated MI group. Mechanistically, paracrine activation of ERK signal transduction pathway by CDH2-hiPSC-CMs, significantly induced neo-vasculogenesis, resulting in a higher survival of implanted cells. Conclusion Collectively, these data suggest that CDH2 overexpression enhances not only the survival/engraftment of cultured CDH2-hiPSC-CMs, but also the functional integration of these cells, consequently, the augmentation of the reparative properties of implanted CDH2-hiPSC-CMs in the failing hearts.

scholarly journals Stem cell-derived cell sheet transplantation for heart tissue repair in myocardial infarction

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rui Guo ◽  
Masatoshi Morimatsu ◽  
Tian Feng ◽  
Feng Lan ◽  
Dehua Chang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Tissue Repair ◽  
Cardiac Tissue ◽  
Cell Sheet ◽  
Clinical Manifestations ◽  
Induced Pluripotent Stem Cell ◽  
Heart Tissue ◽  
Therapeutic Effects ◽  
Cell Sheets

AbstractStem cell-derived sheet engineering has been developed as the next-generation treatment for myocardial infarction (MI) and offers attractive advantages in comparison with direct stem cell transplantation and scaffold tissue engineering. Furthermore, induced pluripotent stem cell-derived cell sheets have been indicated to possess higher potential for MI therapy than other stem cell-derived sheets because of their capacity to form vascularized networks for fabricating thickened human cardiac tissue and their long-term therapeutic effects after transplantation in MI. To date, stem cell sheet transplantation has exhibited a dramatic role in attenuating cardiac dysfunction and improving clinical manifestations of heart failure in MI. In this review, we retrospectively summarized the current applications and strategy of stem cell-derived cell sheet technology for heart tissue repair in MI.

scholarly journals Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

2020 ◽  
Vol 7 ◽  
Author(s):  
Christopher J. Charles ◽  
Renee R. Li ◽  
Teresa Yeung ◽  
Stephane M. Ibraham Mazlan ◽  
Ruenn Chai Lai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Infarct Size ◽  
Porcine Model ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Size Characterization

P5389Limited regenerative potential of the neonatal porcine heart after myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Malliaras ◽  
E Polychronopoulou ◽  
I Poulakida ◽  
D Sagris ◽  
K Makaritsis
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Infarct Size ◽  
Border Zone ◽  
Large Mammals ◽  
Infarct Transmurality ◽  
Neonatal Pigs ◽  
Regenerative Response ◽  
Systolic Thickening ◽  
Fractional Shortening

Abstract Background Neonatal murine hearts possess -for a brief period after birth- a robust capacity for spontaneous myocardial regeneration following cardiac injury. Whether hearts of neonatal large mammals possess similar regenerative potential is a matter of active investigation. Recently, two studies reported that 1-day-old and 2-day-old neonatal pigs exhibit a significant cardiac regenerative response post-myocardial infarction (MI), characterized by minimal cardiac fibrosis and spontaneous recovery of left ventricular (LV) function; this regenerative capacity is purportedly lost after the first two days of life. Purpose We sought to evaluate the regenerative potential of neonatal porcine hearts after MI. Methods Twenty-one neonatal farm pigs were randomly assigned to undergo MI by permanent ligation of the left anterior descending artery on postnatal day 1 (P1) or postnatal day 3 (P3). Infarcted P1 and P3 pigs were euthanized either at 1 week or at 7 weeks post-MI. Hearts explanted at 1 week post-MI underwent fluorescent immunohistochemistry for Ki67 and alpha-sarcomeric actinin to quantify myocyte cell cycle re-entry. Transthoracic echocardiography was performed at 7 weeks post-MI to quantify fractional shortening and systolic thickening of the anterior (infarcted) LV wall and the posterior (non-infarcted) LV wall. Hearts explanted at 7 weeks post-MI underwent staining with triphenyl-tetrazolium chloride and Masson's Trichrome to quantify infarct size, infarct circumference and infarct transmurality. Results Fourteen animals successfully completed the protocol. Infarct size (P1: 9.5±2.2% vs P3: 8.9±3.6% of LV, p=0.797), infarct circumference (P1: 33.8±7.1% vs P3: 29.8±10.6% of LV, p=0.566) and infarct transmurality (P1: 38.1±4.3% vs P3: 40.4±13.7% of anterior wall, p=0.764) were comparable in P1 and P3 animals at 7 weeks post-MI. LV fractional shortening (an index of global LV systolic function) was similar in P1 and P3 animals at 7 weeks post-MI (P1: 25.5±2.9% vs P3: 23.7±4.5%, p=0.662). Furthermore, systolic thickening in the anterior (infarcted) LV wall was depressed to a similar degree in P1 and P3 animals (P1: 31.8±5.3% vs P3: 32.3±8.5%, p=0.914) compared to systolic thickening in the posterior (non-infarcted) wall (P1: 72.5±9.0% vs P3: 69.0±11.4%, p=0.666) at 7 weeks post-MI. Myocyte cell cycle re-entry in the infarct border zone was increased in P1 animals compared to P3 animals (P1: 4.5±1.3 vs P3: 2.3±0.6 per field of view, p=0.045) at 1 week post-MI. Conclusions In contrast to recently-published reports, we did not observe a robust cardiac regenerative response in neonatal porcine hearts post-MI. Hearts of both 1-day-old and 3-day-old neonatal pigs exhibited substantial scarring and significant hypokinesia of the infarcted myocardium post-MI. Additional research is warranted to assess the cardiac regenerative potential of neonatal large mammals. Acknowledgement/Funding Co-financed by Greece and the European Union - European Social Fund

scholarly journals Adhesive Stem Cell Coatings for Enhanced Retention in the Heart Tissue

2020 ◽  
Vol 3 (5) ◽  
pp. 2930-2939
Author(s):  
Pei-Jung Wu ◽  
Hsuan Peng ◽  
Cong Li ◽  
Ahmed Abdel-Latif ◽  
Brad J. Berron
Keyword(s):  
Stem Cell ◽  
Heart Tissue

scholarly journals Gut microbiota regulates cardiac ischemic tolerance and aortic stiffness in obesity

2019 ◽  
Vol 317 (6) ◽  
pp. H1210-H1220 ◽  
Author(s):  
Micah L. Battson ◽  
Dustin M. Lee ◽  
Lance C. Li Puma ◽  
Kayl E. Ecton ◽  
Keely N. Thomas ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Infarct Size ◽  
Aortic Stiffness ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Obese Mice ◽  
Gut Permeability ◽  
Cardiovascular Pathology ◽  
Lv Mass

The gut microbiota has emerged as an important regulator of host physiology, with recent data suggesting a role in modulating cardiovascular health. The present study determined if gut microbial signatures could transfer cardiovascular risk phenotypes between lean and obese mice using cecal microbiota transplantation (CMT). Pooled cecal contents collected from obese leptin-deficient (Ob) mice or C57Bl/6j control (Con) mice were transplanted by oral gavage into cohorts of recipient Ob and Con mice maintained on identical low-fat diets for 8 wk ( n = 9–11/group). Cardiovascular pathology was assessed as the degree of arterial stiffness (aortic pulse wave velocity) and myocardial infarct size following a 45/120 min ex vivo global cardiac ischemia-reperfusion protocol. Gut microbiota was characterized by 16S rDNA sequencing, along with measures of intestinal barrier function and cecal short-chain fatty acid (SCFA) composition. Following CMT, the gut microbiota of recipient mice was altered to resemble that of the donors. Ob CMT to Con mice increased arterial stiffness, left ventricular (LV) mass, and myocardial infarct size, which were associated with greater gut permeability and reduced cecal SCFA concentrations. Conversely, Con CMT to Ob mice increased cecal SCFA, reduced LV mass, and attenuated myocardial infarct size, with no effects on gut permeability or arterial stiffness. Collectively, these data demonstrate that obesity-related changes in the gut microbiota, independent of dietary manipulation, regulate hallmark measures of cardiovascular pathology in mice and highlight the potential of microbiota-targeted therapeutics for reducing cardiovascular pathology and risk in obesity. NEW & NOTEWORTHY These data are the first to demonstrate that cecal microbiota transplantation (CMT) can alter cardiovascular pathology in lean and obese mice independent from alterations in dietary intake. Myocardial infarct size was reduced in obese mice receiving lean CMT and worsened in lean mice receiving obese CMT. Lean mice receiving obese CMT also displayed increased aortic stiffness. These changes were accompanied by alterations in short-chain fatty acids and gut permeability.

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