scholarly journals PLURIPOTENT STEM CELL-DERIVED CARDIOVASCULAR PROGENITORS DIFFFERENTIATED ON LAMININ 221 REGENERATE AND IMPROVE FUNCTION OF INFARCTED SWINE HEARTS

2021 ◽  
Author(s):  
Lynn Yap ◽  
Li Yen Chong ◽  
Clarissa Tan ◽  
Swarnaseetha Adusumalli ◽  
Millie Seow ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Ventricular Arrhythmia ◽  
Heart Muscle ◽  
Host Tissue ◽  
Transcriptomic Analysis ◽  
Left Ventricular Ejection ◽  
List Type ◽  
Differentiation Method ◽  
Infarcted Region

AbstractBackgroundIschemic heart disease is a huge global burden where patients often have irreversibly damaged heart muscle. State-of-the-art technology using stem cell-derived products for cellular therapy could potentially replace damaged heart muscle for regenerative cardiology.Methods and ResultsPluripotent human embryonic stem cells (hESCs) were differentiated on a laminin LN521+221 matrix to cardiovascular progenitors (CVPs). Global transcriptome analyses at multiple time points by single-cell RNA-sequencing demonstrated high reproducibility (R2 > 0.95) between two hESCs lines. We identified several CVP signature genes as quality batch control parameters which are highly specific to our CVPs as compared to canonical cardiac progenitor genes. A total of 200 million CVPs were injected into the infarcted region caused by permanent ligation of the coronary arteries of 10 immunosuppressed pigs and maintained for 4- and 12-weeks post transplantation. The transplanted cells engrafted and proliferated in the infarcted area as indicated by IVIS imaging, histology staining and spatial transcriptomic analysis. Spatial transcriptomic analysis at 1 week following transplantation showed that the infarcted region expressed human genes in the same area as immunohistology sections. Heart function was analyzed by magnetic resonance imaging (MRI) and computerized tomography (CT). Functional studies revealed overall improvement in left ventricular ejection fraction by 21.35 ± 3.3 %, which was accompanied by significant improvements in ventricular wall thickness and wall motion, as well as a reduction in infarction size after CVP transplantation as compared to medium control pigs (P < 0.05). Immunohistology analysis revealed maturation of the CVPs to cardiomyocytes (CMs) where the human grafts aligned with host tissue forming end-to-end connections typical for heart muscle. Electrophysiology analyses revealed electric continuity between injected and host tissue CMs. Episodes of ventricular tachyarrhythmia (VT) over a period of 25 days developed in four pigs, one pig had persistent VT, while the rest remained in normal sinus rhythm. All ten pigs survived the experiment without any VT-related death.ConclusionsWe report a highly reproducible, chemically defined and fully humanized differentiation method of hESCs for the generation of potent CVPs. This method may pave the way for lasting stem cell therapy of myocardial infarction (MI) in humans.Clinical PerspectiveWhat is New?We present a highly reproducible, chemically defined and fully humanized laminin-based differentiation method for generation of large amounts of cardiovascular progenitors (CVP); 20 million cells in a 10 cm2 culture dish which were used for a preclinical study in pigs.Transplantation of the CVPs into the myocardial infarcted pig hearts yields maturation of the progenitor cells to cardiomyocytes (CMs) and improved cardiac function (21.35 ± 3.3 % LVEF improvement) using only 200 million CVPs.Temporary episodes of ventricular arrhythmia (50%) were observed after CVP transplantation. No fatal ventricular arrhythmia occurred.What are the clinical implications?Our laminin-based approach generated potent CVPs in vivo and largely restored function of the damaged heart.Cardiovascular progenitors may provide a new and safe therapeutic strategy for myocardial infarction.The results may have a significant impact on regenerative cardiology.

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.

scholarly journals Rational Route of Delivery Mesenchymal Stem Cell Therapy for Acute Myocardial Infarction (AMI) and Chronic Ischemic Cardiomyopathy (ICM): a Systematic Review and Meta-analysis

2021 ◽  
Author(s):  
Huang Yan ting ◽  
Lin Weizhao ◽  
Yang Xiangbin ◽  
Chen Shuqing ◽  
Gao Kai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Acute Myocardial Infarction ◽  
Stem Cell ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Secondary Outcome ◽  
Intracoronary Infusion ◽  
Route Of Delivery

Abstract Background: Recent studies suggest that mesenchymal stem cells (MSCs) may have therapeutic potential for both acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy (ICM). However, the rational route of delivery MSC therapy has not reached consensus. We performed a systematic review of clinical trials evaluating the rational route of delivery MSCs for AMI or ICM.Methods: Databases including Embase, PubMed, and Cochrane Central Register of Controlled Trials were searched from inception to February 2021. Studies that examined the use of MSCs in adults with AMI or ICM were eligible. Bias of included studies were assessed by the Cochrane risk of bias tool. The primary outcome was cardiac function assessed by left ventricular ejection fraction (LVEF) and the secondary outcome was cardiac remodeling which was assessed by left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), we also explored the safety between different routes. Results: 18 studies fulfilled eligibility criteria, which consist of 11 studies evaluated AMI and 7 studies evaluated ICM. In AMI group, only when patients received intracoronary infusion(IC) can improve LVEF (SMD 0.88, 95% CI 0.64-1.12), and there was a decrease in LVEDV&LVESV when administered IC or intravenous infusion (IV). While in ICM group, no significant difference in LVEF was noted no matter administered which route, and transendocardial stem cell injection(TESI) seems to be effective in decreasing LVEDV&LVESV. Safety appeared no difference between different routes. Conclusions: Results from our systematic review suggest that intracoronary infusion seems more effective for MSC’s delivery in AMI group, while in ICM group, TESI better.

Abstract 15413: Building New Arteriogenic Therapy for Ischemic Cardiomyopathyusing Notch-induced Mesenchymal Stem Cell Patch

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shusaku Maeda ◽  
Shigeru Miyagawa ◽  
Takuji Kawamura ◽  
Dai Chida ◽  
Takashi Shibuya ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Notch Signaling ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ischemic Lesion

Introduction: The induction of arteriogenesis is a promising approach for treatment of ischemic cardiomyopathy. Notch signaling has been reported to be a key regulator of arteriogenesis. Hypothesis: We hypothesized that Notch-induced human mesenchymal stem cell (SB623) sheet transplantation would induce arteriogenesis in ischemic lesion, leading to improvement of left ventricular function in ischemic cardiomyopathy model rats. Methods: Two weeks after the ischemic induction, SB623-patches were transplanted to myocardial infarction model rats (SB group, n=10) or shame operations were performed (Control group, n=10). We evaluated cardiac performance and histology six weeks after the treatment in vivo. In vitro, we performed RNA-sequencing of human umbilical vein endothelial cells (HUVECs) cocultured with SB623s. Results: Left ventricular ejection fraction was significantly improved 6 weeks after SB623-sheets transplantation (LVEF, 52±7% vs. 34±5%, p<0.001). Similarly, the attenuation of LV remodeling was observed at 6 weeks (LV diastolic dimension, 73±7 mm vs. 85±5 mm, p<0.001). Histological findings revealed that fibrosis was decreased in SB group (11±1% vs. 22±4%, p=0.02). Furthermore, vWF-positive capillary vessels (vessels, 516±110 /mm 2 vs. 248±26 /mm 2 , p<0.001) and αSMA- and vWF-positive arterioles with over 20μm diameter (arterioles, 25±8 /mm 2 vs. 6±3 /mm 2 , p=0.002) were significantly increased in SB group, suggesting the induction of angiogenesis and arteriogenesis. In vitro, whole transcriptome analysis showed that Notch signaling pathway was significantly upregulated (p<0.001) in HUVECs co-cultured with SB623s. Similarly, pathway analysis revealed upregulated “fluid shear stress and atherosclerosis” pathway (p<0.001) in vitro, suggesting an arteriogenic response of endothelial cell. In vivo study, upregulations of ephrin-B2 (p=0.03) and EphB4 (p=0.01) gene expressions in SB group were confirmed, indicating both arterial and venous remodeling induced by Notch signaling. Conclusions: SB623 patch transplantation induces arteriogenesis with functional recovery via Notch signaling in rat myocardial infarction model, proposing a new strategy for the treatment of ischemic cardiomyopathy.

scholarly journals Influence of intracoronary injections of bone-marrow-derived mononuclear cells on large myocardial infarction outcome: Quantum of initial necrosis is the key

2009 ◽  
Vol 66 (12) ◽  
pp. 998-1004 ◽  
Author(s):  
Slobodan Obradovic ◽  
Bela Balint ◽  
Radoslav Romanovic ◽  
Zoran Trifunovic ◽  
Sinisa Rusovic ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Autologous Bone Marrow ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Infarction Size ◽  
Autologous Bone

Background/Aim. Autologous bone-marrow-derived intracoronary injection of mononuclear cells (MNC) modestly improved left ventricular ejection fraction (LVEF) in the selected patients after acute ST elevation myocardial infarction (STEMI). Major determinants of stem cell therapy outcome in the subacute phase of STEMI still remain unknown. Therefore, the aim of this study was to determine modifying factors for the outcome of stem cell therapy after STEMI. Methods. Eighteen patients in the stem cell therapy group and 24 patients in the control group with the successfully reperfused first large STEMI (LVEF ? 40%) were enrolled in the study. The stem cell group was submitted to autologous bone-marrow-derived MNC injection between 7-12 days after MI. Left ventricular ejection fraction and infarction size at baseline and after 4 months were determined by echocardiography and scintigraphy examination. Age, pain onset to reperfusion time, admission glycemia, maximum lactate dehydrogenase (LDH) activity and C-reactive protein level, baseline LVEF and infarction size, and the number of MNC injected were compared between patients with and without significant improvement of LVEF and decrease of myocardial infarct size after 4 months. Results. In the stem cell group, patients with the improvement of LVEF for more than 5.1% had significantly lower levels of LDH than patients without such improvement (1689 ? 139 vs 2133 ? 215 IU/L, p < 0.001) and lower baseline infarction size on scintigraphy (26.7 ? 5.2 vs 34.9 ? 3.7%, p < 0.001). Such dependence was not found in the control group. Conclusion. In the patients with first large STEMI intracoronary injection of autologous bone-marrow-derived MNC leads to the significant decrease of myocardial infarction size but not the significant improvement of LVEF after four months. Higher serum LDH levels after STEMI and very large baseline infarction size are predictors of failure of stem cell therapy in our group of STEMI patients.

scholarly journals Is follow-up echocardiogram mandatory after a STEMI?

2020 ◽  
Vol 7 (3) ◽  
pp. K27-K30
Author(s):  
Sathish Kumar Parasuraman ◽  
Janaki Srinivasan ◽  
Paul Broadhurst
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Left Ventricular Ejection ◽  
List Type ◽  
Ventricular Ejection Fraction ◽  
Cardiac Symptoms ◽  
Pseudo Aneurysm ◽  
St Elevation

Summary Current guidelines do not advise follow-up echocardiograms after ST-segment elevation myocardial infarction (STEMI), unless the left ventricular ejection fraction is ≤40%. We present an interesting case of left ventricular pseudo-aneurysm – diagnosed 6 months after index STEMI presentation. Follow-up echocardiogram was performed in her case, due to jaw pain during routine haemodialysis. The patient was successfully treated with percutaneous closure device. This case raises the question of whether echo follow-up should be routinely advised after STEMI – even in those with minimal cardiac symptoms. Learning points: Patients with left ventricular pseudo-aneurysm can be haemodynamically stable and may not always be in extremis. Left ventricular pseudo-aneurysm can develop months after ST elevation myocardial infarction. In patients re-presenting with cardiac symptoms after ST elevation myocardial infarction, a repeat echocardiogram should be considered. In patients suffering ST elevation myocardial infarction, it is reasonable to consider repeat echocardiography even with mild LV dysfunction, especially with late presentation or disproportionately high biomarkers.

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