scholarly journals Loss of Endogenously Cycling Adult Cardiomyocytes Worsens Myocardial Function

2020 ◽  
Author(s):  
Leigh A Bradley ◽  
Alexander Young ◽  
Hongbin Li ◽  
Helen O Billcheck ◽  
Matthew J Wolf
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Myocardial Function ◽  
Cultured Cells ◽  
Left Ventricular ◽  
Left Ventricular Chamber ◽  
Adult Cardiomyocytes ◽  
Border Zones ◽  
And Function ◽  
Chamber Size

Rationale: Endogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle. Objective: We created and validated a new transgenic mouse, αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted αDKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), αDKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI. Methods and Results: A tandem αDKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The αDKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, αDKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre-treated αDKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 {plus minus} 0.5 vs. 3.3 {plus minus} 0.3 CMs per ten-micron section, N = 8-9 mice per group, n = 16-24 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was ~9 to 1 (5.2 {plus minus} 0.4 single vs. 0.6 {plus minus} 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in αDKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls. Conclusions: Although scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

scholarly journals Ablation of endogenously cycling adult cardiomyocytes worsens myocardial function after injury

2020 ◽  
Author(s):  
Leigh A. Bradley ◽  
Alexander Young ◽  
Helen O. Billcheck ◽  
Matthew J. Wolf
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Myocardial Function ◽  
Cultured Cells ◽  
Left Ventricular ◽  
Left Ventricular Chamber ◽  
Adult Cardiomyocytes ◽  
Border Zones ◽  
And Function ◽  
Chamber Size

AbstractRationaleEndogenously cycling adult cardiomyocytes (CMs) increase after myocardial infarction (MI) but remain scare, and are generally thought not to contribute to myocardial function. However, this broadly held assumption has not been tested, mainly because of the lack of transgenic reporters that restrict Cre expression to adult CMs that reenter the cell cycle.ObjectiveWe created and validated a new transgenic mouse, αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (denoted αDKRC) that restricts Cre expression to cycling adult CMs and uniquely integrates spatial and temporal adult CM cycling events based on the DNA specificities of orthologous Dre- and Cre recombinases. We then created mice that expressed an inducible Diphtheria toxin (DTA), αDKRC::DTA mice, in adult cycling CMs and examined the effects of ablating these endogenously cycling CMs on myocardial function after Ischemic-Reperfusion (I/R) MI.Methods and ResultsA tandem αDKRC transgene was designed, validated in cultured cells, and used to make transgenic mice. The αDKRC transgene integrated between MYH6 and MYH7 and did not disrupt expression of the surrounding genes. Compared to controls, αDKRC::RLTG mice treated with Tamoxifen expressed tdTomato+ in CMs with rare Bromodeoxyuridine (BrdU)+, eGFP+ CMs, consistent with reentry of the cell cycle. We then pre- treated αDKRC::RLTG mice with Tamoxifen to activate the reporter before sham or reperfusion (I/R) myocardial infarction (MI) surgeries. Compared to Sham surgery, the I/R MI group had increased single and paired eGFP+ CMs predominantly in the border zones (5.8 ± 0.5 vs. 3.3 ± 0.3 CMs per ten-micron section, N = 8 mice, n = 16 sections per mouse), indicative of cycled CMs. The single to paired eGFP+ CM ratio was ∼9 to 1 (5.2 ± 0.4 single vs. 0.6 ± 0.2 paired CMs) in the I/R MI group after MI, suggesting that cycling CMs were more likely to undergo polyploidy than replication. The ablation of endogenously cycling adult CMs in αDKRC::DTA mice caused progressive worsening left ventricular chamber size and function after I/R MI, compared to controls.ConclusionsAlthough scarce, endogenously cycling adult CMs contribute to myocardial function after injury, suggesting that these cells may be physiologically relevant.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

Abstract 587: A Randomized Study Evaluating Outcomes of Cardiopulmonary Resuscitation in Rats with Myocardial Infarction Treated with Three Delivery Methods of Mesenchymal Stem Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tong Wang ◽  
Zhi Wan ◽  
Wanchun Tang ◽  
Shijie Sun ◽  
Zitong Huang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiopulmonary Resuscitation ◽  
Survival Time ◽  
Myocardial Function ◽  
Left Ventricular ◽  
Left Ventricular Cavity ◽  
Intramyocardial Injection ◽  
Administration Routes

We investigated the effect of allogeneic mesenchymal stem cells (MSCs) on myoardial function following cardiopulmonary resuscitation (CPR) in a rat model of myocardial infarction. We further investigated the efficacy of three routes of MSCs administration including intravenous, intraventricular and intramyocardial injection. Regardless of administration routes, MSCs would improve myocardial function after CPR in myocardial infarction animals. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in 54 rats (6 groups, 9 rats for each). One month later, animals were randomized to receive injection of 5×10 6 MSCs labeled with PKH26 or PBS alone as a placebo into right femoral vein or left ventricular cavity or the infarction zone in the anterior ventricular free wall. Four weeks after injection, 6 minutes of untreated ventricular fibrillation (VF) followed by 6 minutes of CPR were performed prior to defibrillation. Hemodynamics, including cardiac index (CI), dp/dt40, −dp/dt and left ventricular diastolic pressure(LVDP) were measured before induction of VF (baseline) and hourly following resuscitation. There were siginificant improvements in CI, dp/dt40(Figure 1 ), −dp/dt, LVDP after CPR in MSCs treated animals, regardless of the sites of injection. Survival time after CPR was siginificantly increased in MSCs trearted groups comparing with the corresponding PBS treated groups. Independent of administration routes, myocardial function and survival time after CPR were comparably improved in all groups treated with MSCs in constrast to the PBS groups. Figure 1

Abstract 1111: Embryoinc Stem Cell Derived Cardiovascular Progenitor Cells Improve Function More Than Hemangioblasts in a Mouse Model of Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Eric Adler ◽  
Vincient Chen ◽  
Anne Bystrup ◽  
Wilson Young ◽  
Steve Giovannone ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Myocardial Function ◽  
Es Cells ◽  
Fluorescent Microscopy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

BACKGROUND: Intramyocardial transplantation of stem cells improves left ventricular ejection fraction (EF) in animal studies and preliminary clinical trials. The mechanism may involve either replacement of myocytes or improved vascular supply to existing myocytes. We recently identified an Embyronic Stem cell derived cardiovascular progenitor cell (ES-CPC) that is the common precursor of cardiomyocyte and vascular cell lineages. To determine whether myocyte transplantation improves myocardial function more than angiogenesis alone does, we compared the effect of ES-CPCs to hemangioblasts (vascular/hematopoetic progenitor cells) on EF in a mouse model of myocardial infarction. METHODS: ES-CPC and hemangioblasts were isolated from a doxycycline-responsive, Notch-inducible ES cell line containing Notch 4 cDNA under the control of a tetracycline-inducible promoter. Notch induction of mesoderm-derived ES cells resulted in a CPC phenotype, whereas non-induced cells developed into hemangioblasts. Mice underwent transplantation of 500,000 ES-CPC (n=20), hemangioblasts (n=16), or an equal volume of serum-free media (n=12) 30 minutes after surgically-induced myocardial infarction. All cell lines constitutively expressed green fluorescent protein (GFP). EF was assessed two weeks post-transplantation using 9.4 Tesla MRI. Mice were then euthanized and frozen heart sections were examined using fluorescent microscopy. RESULTS: The mean EF was 59Â ± 15, 46Â ± 17, and 39Â ± 13% in the ES-CPC, hemangioblast, and control groups, respectively (p<0.05 for the differences among all 3 groups; ANOVA). GFP + cells were detected in frozen sections of both the ES-CPC and hemangioblast groups. GFP + cells in ES-CPC treated hearts expressed markers associated with both cardiomyocyte and vascular phenotypes, whereas the GFP + cells in the hemangioblast group expressed markers associated with vascular phenotypes. CONCLUSIONS: Both hemangioblast and ES-CPC transplantation improves EF in a mouse model of myocardial infarction, but ES-CPC transplantation was more effective. This suggests that enhancement of myocardial function by transplantation of both cardiomyocyte and vascular phenotypes exceeds that with vascular phenotypes alone.

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