Abstract 15555: Administration of c-Kit+ Cardiac Stem Cells (CSCs) Results in Increased Proliferation and Cardiac Content of CSCs 1 Year Later

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Qianhong Li ◽  
Ning Chen ◽  
Li Luo ◽  
Qinghui Ou ◽  
Wei Xie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Border Zone ◽  
Functional Improvement ◽  
Vehicle Group ◽  
Lv Function ◽  
Female Rat ◽  
Infarct Zone ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Rat Hearts

Background: We have previously shown in rats that the beneficial effects of c-kit + CSCs on LV function and remodeling post-myocardial infarction persist for at least 1 year after CSC administration. However, in that study the retention of transplanted Y-chromosome + cells in the risk region (RR) of female rat hearts at 1 year was low (<10% of total nuclei) and not sufficient to account for the functional improvement, suggesting that other mechanisms must be at work. Methods and Results: To address this issue, rats received intracoronary vehicle or 1x10 6 syngeneic CSCs 4 h after a 90-min coronary occlusion; 11 months later, BrdU treatment was given for 1 month. CSCs, which are c-kit + /CD45 − , were distinguished from c-kit + hematopoietic stem cells/mast cells, which are CD45 + . At 1 year after CSC administration, the total number of c-kit + or c-kit + /BrdU + cells in the heart (the sum of c-kit + /CD45 − and c-kit + /CD45 + cells) did not differ between CSC and control groups (Figs. H and I). However, CSC transplantation resulted in increased numbers of CSCs (c-kit + /CD45 − cells) in the RR (i.e., the infarct zone plus border zone)(47.6±7.0% of total c-kit + cells vs. 27.9±4.1% in vehicle group; n=5, P <0.05; Fig. J). Among CSCs (c-kit + /CD45 − cells), the fraction that was newly formed (c-kit + /CD45 − /BrdU + ) was dramatically increased in the RR of the CSC group (+ 2.6-fold vs. vehicle group; n=4, P <0.05; Fig. M), indicating increased CSC proliferation and turnover. Conclusions: These data reveal, for the first time, that a single intracoronary infusion of CSCs is followed by an increase in both the proliferation and the total number of c-kit + CSCs in the myocardium that persists, surprisingly, for at least 1 year after cell delivery. Since transplanted cells do not differentiate into adult myocytes, these data suggest that the long-term salubrious effects of CSCs on cardiac function are mediated by sustained activation of the CSC pool in the heart.

scholarly journals Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy

2021 ◽  
Vol 22 (6) ◽  
pp. 3145
Author(s):  
Qianhong Li ◽  
Yiru Guo ◽  
Yibing Nong ◽  
Alex Tomlin ◽  
Anna Gumpert ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Ischemic Cardiomyopathy ◽  
Dose Group ◽  
Weight Ratio ◽  
Cardiac Cells ◽  
Vehicle Group ◽  
Lv Function ◽  
Body Weight Ratio ◽  
Beneficial Effects ◽  
The Difference

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (−32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and −28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.

Abstract 427: Tissue Inhibitor of Matrix Metalloproteinase-3 (TIMP3) Provides Beneficial Effects Post-MI by Promoting Angiogenesis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Abhijit R Takawale ◽  
Pu Zhang ◽  
Ratnadeep Basu ◽  
Abul Azad ◽  
Maikel Farhan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Lv Function ◽  
Vascular Density ◽  
Tissue Inhibitor ◽  
Infarct Zone ◽  
Fibrin Gel ◽  
Beneficial Effects

Introduction: Myocardial infarction (MI) results in loss of cardiomyocytes, adverse extracellular matrix (ECM) remodelling, leading to left ventricular (LV) dilation and dysfunction. Tissue inhibitor of metalloproteinase (TIMPs) are MMP inhibitors, main regulators of ECM integrity. TIMPs can also regulate other aspects of myocardial remodeling such as hypertrophy, fibrosis and inflammation. TIMP3 levels are reduced in the peri-infarct zone within 24 hours post-MI in mice. Hypothesis: Replenishment of TIMP3 post-MI limit infarct expansion, and attenuate LV dilation and dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad- hTIMP3) or no-TIMP (Ad-Null, control) were injected in the peri-infarct zone (5.4x10 7 pfu, 5 injections/heart). Cardiac function was assessed by echocardiography. Cardiomyocyte density (WGA/DAPI staining), vascular density (Fluo-lectin injection, CD31 IHC), ECM composition (PSR staining) were assessed at 3 and 7 days post-MI. In vitro, angiogenic potency of TIMP3 (rTIMP3) was assessed using the 3D fibrin gel-based angiogenesis assay using primary human vascular (HUVECs) and coronary artery endothelial cells (HCAECs), and co-IP between TIMP3 and VEGFR2. Results: Ad-TIMP3 injections significantly improved LV function and reduced LV dilation as compared to Ad-Null group post-MI. Infarct size was markedly reduced with TIMP3 injections and more viable myocytes were preserved in the infarct zone at 1wk post-MI. Ad-TIMP3-MI group showed a higher density of endothelial cells and increased coronary density in the infarct and peri-infarct regions compared to the Ad-null group. This suggested that Ad-TIMP3 promotes angiogenesis in the infarcted myocardium. In vitro studies confirmed that rTIMP3 promoted angiogenesis/sprouting in human endothelial cells up to100ng/ml. However at higher concentrations (>1ug/ml), rTIMP3 exerted anti-angiogenic effects by binding to VEGFR2. This function of rTIMP3 appears to be through an MMP-inhibitory mechanism. Conclusion: The novel pro-angiogenic function of TIMP3 post-MI could provide additional beneficial effects in post-MI treatment.

scholarly journals Functional recovery after the systemic administration of mesenchymal stem cells in a rat model of neonatal hypoxia-ischemia

2018 ◽  
Vol 22 (5) ◽  
pp. 513-522 ◽  
Author(s):  
Takuro Sakai ◽  
Masanori Sasaki ◽  
Yuko Kataoka-Sasaki ◽  
Shinichi Oka ◽  
Masahito Nakazaki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Volume ◽  
Treated Group ◽  
Brain Regions ◽  
Functional Improvement ◽  
Vehicle Group ◽  
Walk Test ◽  
Hypoxia Ischemia

OBJECTIVEChildren who have experienced neonatal hypoxic-ischemic encephalopathy often develop cerebral palsy. Although many treatments have been performed, few effective therapies are available. In this study, the authors tested in rats with hypoxia-ischemia (HI) injuries the hypothesis that the systemic infusion of mesenchymal stem cells (MSCs) would result in functional improvement by facilitating neural compensation in the contralesional cortex.METHODSPostnatal day (P) 7 (P7) rats that had undergone unilateral hemisphere hypoxia-ischemia (modified Rice-Vannucci model) were randomly assigned to MSC-infused or vehicle-infused groups. MSCs (1.0 × 106/200 μL) or vehicle were intravenously infused on P10. Brain volume was measured using in vivo MRI on P8 and P35. On P35, the rats were sacrificed after their behavior was evaluated using a beam walk test, and their brains were then prepared for histological analyses.RESULTSThe MSC-treated group had fewer slips on the beam walk test compared to those in the vehicle group (p = 0.041). MRI was used to measure the volumes of the whole brain, contralesional brain (hemisphere), and residual brain regions of interest, and the results indicated increased brain volume after the intravenous MSC infusions. The histological analyses revealed increased thicknesses of the contralesional cortex and corpus callosum in the MSC group compared with those in the vehicle group (p = 0.021, p = 0.019), which confirmed the volume increases. In the contralesional cortex, the MSC-treated group exhibited significant increases in the numbers of NeuN-positive cells (p = 0.004) and synaptic puncta (p = 0.000) compared with the numbers observed in the vehicle group.CONCLUSIONSThe intravenous infusion of MSCs resulted in improvements in functional outcome, increased brain volume, and enhanced synaptogenesis in HI rats.

Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts

2009 ◽  
Vol 297 (3) ◽  
pp. H1020-H1031 ◽  
Author(s):  
Lei Wang ◽  
Jixian Deng ◽  
Weichen Tian ◽  
Bo Xiang ◽  
Tonghua Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Cardiac Function ◽  
Recovery Period ◽  
Capillary Density ◽  
Left Ventricular ◽  
Border Zone ◽  
Wall Thickening ◽  
Adipose Derived Stem Cells ◽  
Rat Hearts

This study assessed the potential therapeutic efficacy of adipose-derived stem cells (ASCs) on infarcted hearts. Myocardial infarction was induced in rat hearts by occlusion of the left anterior descending artery (LAD). One week after LAD occlusion, the rats were divided into three groups and subjected to transplantation of ASCs or transplantation of cell culture medium (CCM) or remained untreated. During a 1-mo recovery period, magnetic resonance imaging showed that the ASC-treated hearts had a significantly greater left ventricular (LV) ejection fraction and LV wall thickening than did the CCM-treated and untreated hearts. The capillary density in infarct border zone was significantly higher in the ASC-treated hearts than in the CCM-treated and untreated hearts. However, only 0.5% of the ASCs recovered from the ASC-treated hearts were stained positive for cardiac-specific fibril proteins. It was also found that ASCs under a normal culture condition secreted three cardiac protective growth factors: vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1. Results of this study suggest that ASCs were able to improve cardiac function of infarcted rat hearts. Paracrine effect may be the mechanism underlying the improved cardiac function and increased capillary density.

Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation

2007 ◽  
Vol 293 (3) ◽  
pp. H1772-H1780 ◽  
Author(s):  
Julia Feygin ◽  
Abdul Mansoor ◽  
Peter Eckman ◽  
Cory Swingen ◽  
Jianyi Zhang
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Stem Cell Transplantation ◽  
Wall Stress ◽  
Border Zone ◽  
Infarct Zone ◽  
Beneficial Effects ◽  
Myocardial Contractile ◽  
Contractile Performance

Preclinical and clinical studies have demonstrated that stem cell transplantation can improve the left ventricular (LV) contractile performance, yet the underlying mechanisms remain unknown. We examined whether mesenchymal stem cell (MSC) transplantation-induced beneficial effects are secondary to paracrine-associated improvements in LV contractile performance, wall stress, and myocardial bioenergetics in hearts with postinfarction LV remodeling. Myocardial contractile function and bioenergetics were compared 4 wk after acute myocardial infarction in normal pigs ( n = 6), untreated pigs with myocardial infarction (MI group; n = 6), and pigs receiving autologous MSC transplantation (MI + MSC group; n = 5). A distal occlusion of the left anterior descending coronary artery instigated significant myocardial hypertrophy. Ejection fraction decreased from 55.3 ± 3.1% (normal) to 30.4 ± 2.3% (MI group; P < 0.01) and to 45.4 ± 3.1% (MI + MSC group; P < 0.01 vs. MI). Hearts in the MI group developed severe contractile dyskinesis in the infarct zone and border zone (BZ). MSC transplantation significantly improved contractile performance from dyskinesis to active contraction ( P < 0.01 vs. MI). BZ systolic wall stress was severely increased in MI hearts but significantly improved after MSC transplantation ( P < 0.01 vs. MI). The BZ demonstrated profound bioenergetic abnormalities in MI pigs; this was significantly improved after MSC transplantation ( P < 0.01 vs. MI). Patchy spared myocytes were found in the infarct zone of hearts receiving MSC transplantation but not in control hearts. These data demonstrate that MSC transplantation into the BZ causes significant improvements in myocardial contractile performance and reduction in wall stress, which ultimately results in significant bioenergetic improvements. Low cell engraftment indicates that MSCs did not provide a structural contribution to the damaged heart and that the observed beneficial effects likely resulted from paracrine repair mechanisms.

scholarly journals Cellular therapy promotes endogenous stem cell repair

2012 ◽  
Vol 90 (10) ◽  
pp. 1335-1344 ◽  
Author(s):  
Forum Kamdar ◽  
Mohammad Nurulqadr Jameel ◽  
Paul Score ◽  
Jianyi Zhang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cellular Therapy ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Lv Function ◽  
Beneficial Effects ◽  
Cellular Transplantation

Cellular transplantation for cardiac repair has emerged as an exciting treatment option for patients with myocardial infarction (MI) and heart failure. Animal models of post-infarction left ventricular remodeling have demonstrated an improvement in left ventricular (LV) function, decrease in scar size, and amelioration of adverse cardiac remodeling after stem cell transplantation. These beneficial effects occur despite minimal engraftment and negligible differentiation of transplanted cells. Evidence of the heart capability to self-renew continues to mount; however, the extent to which this occurs is still unclear. Although there is a specific population of cardiac stem cells capable of differentiating into cardiomyocytes, they alone are not capable of fully regenerating tissue damaged by MI. Therefore, paracrine mechanisms may be responsible for activating endogenous stem cells to promote regeneration and prevent apoptosis. These structural beneficial effects may reduce regional wall stresses, consequently leading to long-term host myocardium gene/protein expression changes, which may subsequently result in improvement in LV function.

Abstract P021: Adipose-Derived Stromal Cell Therapy Stabilizes Cardiac Function and Improves Border Zone Remodeling After Coronary Occlusion in Rats

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Antonio C Campos de Carvalho ◽  
Luiza Bagno ◽  
João Pedro Werneck de Castro ◽  
Patricia Oliveira ◽  
Marcia Abreu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Coronary Artery ◽  
Cardiac Function ◽  
Left Coronary Artery ◽  
Enzymatic Digestion ◽  
Left Ventricular ◽  
Female Rats ◽  
Border Zone ◽  
Functional Improvement ◽  
Vehicle Group

Recent studies have identified adipose tissue as a new source of mesenchymal stem cells for therapy. The purpose of this study was to investigate the therapy with rat adipose derived stromal cells (ASC) in a rat model of healed myocardial infarction (MI). ASC from inguinal subcutaneous adipose tissue of male Wistar rats were isolated by enzymatic digestion and filtration. Cells were then cultured until passage 3. Four weeks after ligation of the left coronary artery of female rats, a suspension of either 100µl with PBS + Matrigel + 2 x 106 ASC labeled with Hoechst (n=11) or 100µ;l of PBS + Matrigel (n=10) was injected along the borders of the ventricular wall scar tissue. A sham operated group (n=5) was submitted to the same surgical procedure except permanent ligation of left coronary artery. Cardiac performance was assessed by electro and echocardiogram. Echo was performed prior to injections (baseline-BL) and six weeks after injections (follow-up - FU), and values after treatment were normalized by values obtained before treatment. Hemodynamic measurements were performed 6 weeks after injections. All data are expressed as mean ± SEM. Student's paired or unpaired T test was used to compare the same group in two different times or two distinct groups, while two way ANOVA was used to compare more than two groups along different times and p was set at <0.05. All infarcted animals exhibited cardiac function impairment. Ejection fraction (EF), shortening fractional area (SFA) and left ventricular akynesia (LVA) were similar between infarcted groups before treatment. Six weeks after therapy, ASC group showed significant improvement in all three Echo indexes in comparison to vehicle group. In non-anesthetized animals dp/dt+ was also significantly higher in ASC when compared to vehicle. In agreement with functional improvement scar area was diminished in the ASC group. We conclude that ASC stabilize cardiac function in infarcted rats when administered directly to the myocardium.

scholarly journals Endurance Exercise Mobilizes Developmentally Early Stem Cells into Peripheral Blood and Increases Their Number in Bone Marrow: Implications for Tissue Regeneration

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Krzysztof Marycz ◽  
Katarzyna Mierzejewska ◽  
Agnieszka Śmieszek ◽  
Ewa Suszynska ◽  
Iwona Malicka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endurance Exercise ◽  
Peripheral Blood ◽  
Long Distance ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Long Distance Running ◽  
Human Volunteers ◽  
One Year

Endurance exercise has been reported to increase the number of circulating hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) as well as in bone marrow (BM). We therefore became interested in whether endurance exercise has the same effect on very small embryonic-like stem cells (VSELs), which have been described as a population of developmentally early stem cells residing in BM. Mice were run daily for 1 hour on a treadmill for periods of 5 days or 5 weeks. Human volunteers had trained in long-distance running for one year, six times per week. FACS-based analyses and RT-PCR of murine and human VSELs and HSPCs from collected bone marrow and peripheral blood were performed. We observed that endurance exercise increased the number of VSELs circulating in PB and residing in BM. In parallel, we observed an increase in the number of HSPCs. These observations were subsequently confirmed in young athletes, who showed an increase in circulating VSELs and HSPCs after intensive running exercise. We provide for the first time evidence that endurance exercise may have beneficial effects on the expansion of developmentally early stem cells. We hypothesize that these circulating stem cells are involved in repairing minor exercise-related tissue and organ injuries.

Sign in / Sign up

Export Citation Format

Share Document