scholarly journals Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

2017 ◽  
Vol 121 (6) ◽  
Author(s):  
Atsushi Tachibana ◽  
Michelle R. Santoso ◽  
Morteza Mahmoudi ◽  
Praveen Shukla ◽  
Lei Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Left Ventricular Ejection Fraction ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Paracrine Effects

Rationale: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. Objective: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model. Methods and Results: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. Conclusions: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.

scholarly journals Circular RNA Expression for Dilated Cardiomyopathy in Hearts and Pluripotent Stem Cell–Derived Cardiomyocytes

2021 ◽  
Vol 9 ◽  
Author(s):  
Yiyu Zhang ◽  
Guoqing Huang ◽  
Zhaohu Yuan ◽  
Yonggang Zhang ◽  
Rong Chang
Keyword(s):  
Heart Failure ◽  
Stem Cell ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Single Gene ◽  
Scientific Progress ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Circular Rnas ◽  
Ventricular Ejection Fraction

Dilated cardiomyopathy (DCM) is a type of heart disease delimited by enlargement and dilation of one or both of the ventricles along with damaged contractility, which is often accompanied by the left ventricular ejection fraction (LVEF) less than 40%. DCM is progressive and always leads to heart failure. Circular RNAs (circRNAs) are unique species of noncoding RNAs featuring high cell-type specificity and long-lasting conservation, which normally are involved in the regulation of heart failure and DCM recently. So far, a landscape of various single gene or polygene mutations, which can cause complex human cardiac disorders, has been investigated by human-induced pluripotent stem cell (hiPSC) technology. Furthermore, DCM has been modeled as well, providing new perspectives on the disease study at a cellular level. In addition, current genome editing methods can not only repair defects of some genes, but also rescue the disease phenotype in patient-derived iPSCs, even introduce pathological-related mutations into wild-type strains. In this review, we gather up the aspects of the circRNA expression and mechanism in the DCM disease scenario, facilitating understanding in DCM development and pathophysiology in the molecular level. Also, we offer an update on the most relevant scientific progress in iPSC modeling of gene mutation–induced DCM.

Abstract 355: Heart Failure Impairs Bone Marrow Mesenchymal Stem Cell Renewing Capacity and Migration

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Victoria Florea ◽  
Cristina Sanina ◽  
Darcy Difede ◽  
Krystalenia Valasaki ◽  
Aisha Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Bone Marrow ◽  
Growth Rate ◽  
Clinical Trials ◽  
Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Healthy Donors

Background: Clinical trials have shown a sustained beneficial effect of bone marrow mesenchymal stem cells (MSCs) as a therapy for acute and chronic heart failure (HF). Clinical grade cell manufacturing of autologous and allogeneic MSCs is becoming a standard procedure. This study investigates the differences of bone marrow MSC isolation and expansion in favorable in vitro conditions. We compared MSC production from both healthy young donors and chronic HF patients. Methods: We analyzed MSC manufacturing records from five clinical trials: TAC-HFT (Ischemic cardiomyopathy (CMP), patient and donors), POSEIDON (Ischemic CMP, donors), POSEIDON DCM (Dilated CMP, donors), TRIDENT (Ischemic CMP, donors), and CRATUS (Frailty, donors). Results: All cells expressed CD105, CD90 and lacked hematopoietic marker CD45. The age of healthy donors (25.5 ± 0.7 y.o., N=24) and HF patients (56.1 ± 2.5, y.o., N=23), was significantly different (P<0.0001). Collectively, the number of mononuclear cells (MNCs) isolated from bone marrow (volume range 58-125ml) didn’t differ between the groups. However, plated MNCs from healthy adults generated more MSCs than MNCs from HF patients (p0: 5.9x10^6±0.5x10^6, N=23 vs 3.8x10^6±0.4x10^6, N=24, respectively, P=0.003 and p1: 15.4x10^6±2.5x10^6, N=23 vs 10.8x10^6±1.1x10^6, N=24, respectively, P=0.036). No correlation was found between stem cell growth and age (35 to 78y.o.). Left ventricular ejection fraction (LVEF) in patients with HF had a direct correlation with MSC growth rate (P=0.03), particularly, in patients with severely depressed LVEF (<30%), which had a tendency to generate less MSCs overall. Moreover, MSCs from HF patients demonstrated less migration compared to MSCs from healthy donors at 6, 10 and 24 hours (h) relative to baseline (6 h: 9.5±3.0% vs 30.7±2.1%; 10 h: 19.9±13.7% vs 53.1±2.5% and 24 h: 41.5±15.8% vs 88.9±1.6%, N=4, respectively. P=0.03). Conclusions: Despite equivalent numbers of MNCs, healthy young donors generate significantly more MSCs than HF patients, due to increased growth rate and higher number of resident stromal bone marrow stem cells. MSC migration was impaired in HF patients compared to healthy donors. HF appears to be an independent factor for MSC renewal capacity and culture phenotype.

Cardiac Toxicity and Non-Relapse Mortality in Patients with Low Left Ventricular Ejection Fraction Undergoing Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3002-3002
Author(s):  
Diem T. Chu ◽  
Rima Saliba ◽  
Suhail Qureshi ◽  
Amin Alousi ◽  
Paolo Anderlini ◽  
...  
Keyword(s):  
Stem Cell ◽  
Left Ventricular Ejection Fraction ◽  
Myocardial Ischemia ◽  
Cardiac Toxicity ◽  
Hematologic Malignancies ◽  
Left Ventricular ◽  
Acute Myocardial Ischemia ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
History Of

Abstract BACKGROUND: Both autologous and allogeneic stem cell transplantation (SCT) are potentially curative treatment options for patients with hematologic malignancies. Due to a high risk of regimen-related toxicity, only patients with satisfactory organ-system function are considered eligible for this treatment. A low left ventricular ejection fraction (LVEF) of ≤ 45% is considered to be a major risk factor for post-transplant cardiac toxicity and non-relapse mortality (NRM). However, many patients with advanced hematologic malignancies and low LVEF can potentially benefit from this therapy. To address this issue, we studied the incidence of cardiac toxicity and NRM in 89 patients with low LVEF undergoing SCT. METHODS: We performed a retrospective analysis on 89 patients with impaired cardiac function, who underwent an autologous (33 patients) or allogeneic (56 patients) SCT between January 2000 and February 2006 at our institution. Pre-transplant evaluation included bidimensional echocardiogram and an electrocardiogram. Cardiac toxicity was defined as congestive heart failure (CHF), atrial/ventricular arrhythmia or acute myocardial ischemia. In the allogeneic group, 22 patients received a myeloablative (16 busulfan-based, 6 TBI-based), while 34 patients received a fludarabine-based reduced-intensity preparative regimen. Twenty-three patients (41%) received allo SCT from an unrelated donor. The majority of patients in the autologous group received BEAM (with rituximab or IL-2) based regimen (24 patients) and 6 patients received high dose melphalan. RESULTS: 57% of the allogeneic transplants were for acute leukemia. 76% of autologous transplant recipients had Hodgkin’s or non-Hodgkin’s lymphoma. Baseline LVEF, within 30 days prior to SCT, ranged from 20 to 45%. After a minimum of 6-month follow up, cardiac toxicity was seen in 6 patients in the auto SCT group and 6 patients in the allo SCT group (13%). In 9 of the 12 patients toxicity occurred within 60 days of SCT. Major causes of cardiac toxicity were CHF in 6 patients (7%) and atrial fibrillation in 5 patients (6%). Two patients had both CHF and AF. There were no documented episodes of acute myocardial ischemia. Median time to develop a cardiac event was 23 days from SCT (range, 9–200 days). Cumulative incidence of NRM at 100 days was 15% (95% CI 9–24). Only 1 death was directly attributable to a cardiac cause. These results are comparable to SCT performed in patients with normal LVEF. On univariate analysis age > 60 years at the time of SCT and history of smoking were significant predictors for development of cardiac toxicity after SCT. Prior history of smoking remained significant on multivariate analysis (HR 5.7, 95% CI 1.2–29, P=0.03). LVEF, type of transplant or the underlying disease did not emerge as significant predictors of post-transplant cardiac toxicity or NRM. Median survival was worse in patients who developed cardiac complications after SCT (median survival 108 days versus 889 days respectively). CONCLUSIONS: Both allogeneic and autologous SCT are feasible in patients with hematologic malignancies and low LVEF. A prospective study with stratification for cardiac risk factors is warranted in patients with low LVEF.

Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3960-3963 ◽  
Author(s):  
Angela Dispenzieri ◽  
Robert A. Kyle ◽  
Martha Q. Lacy ◽  
Terry M. Therneau ◽  
Dirk R. Larson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Peripheral Blood Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Control Study ◽  
Blood Stem Cell Transplantation

Abstract Primary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 μmol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

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