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Angiogenesis, cardiomyocyte proliferation and anti-fibrotic effects underlie structural preservation post-infarction by intramyocardially-injected cardiospheres.

Tseliou E, de Couto G, Terrovitis J, Sun B, Weixin L, Marbán L, Marbán E - PLoS ONE (2014)

Bottom Line: Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated.The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection.These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.

View Article: PubMed Central - PubMed

Affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

ABSTRACT

Objective: We sought to understand the cellular and tissue-level changes underlying the attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial infarction (MI).

Background: Cardiospheres (CSps) are heart-derived multicellular clusters rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation improves left ventricular (LV) function and attenuates remodeling in both small and large animal studies. However, the mechanisms of benefit have not yet been fully elucidated.

Methods: Four groups were studied: 1) "Sham" (Wistar Kyoto rats with thoracotomy and ligature without infarction); 2) "MI" (proximal LAD ligation with peri-infarct injection of vehicle); 3) "MI+CSp" (MI with cardiospheres injected in the peri-infarct area); 4) "Small MI" (mid-LAD ligation only).

Results: In vivo 1 week after CSp transplantation, LV functional improvement was associated with an increase in cardiomyocyte proliferation. By 3 weeks, microvessel formation was enhanced, while cardiomyocyte hypertrophy and regional fibrosis were attenuated. Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated. The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection. In vitro, CSp-conditioned media reduced collagen production in coculture with fibroblasts and triggered neoangiogenesis in an ex vivo aortic ring assay.

Conclusion: Cardiospheres enhance cardiomyocyte proliferation and angiogenesis, and attenuate hypertrophy and fibrosis, in the ischemic myocardium. These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.

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Related in: MedlinePlus

Tissue morphology and cardiac function.(A) Representative photomicrographs of myocardial sections stained with Masson's trichrome. Sections are from CSp treated (n = 5) and placebo treated (n = 5) animals at 7 and 21 days post MI and treatment. (B–F) Quantitative data for infarct mass, viable mass, infarct size, infarct thickness and septum thickness. Five different hearts were processed and 5–6 different sections from the apex to the base from each heart were used for the analysis. (G–I) EF ejection fraction, LVEDD left ventricular end diastolic diameter, LVPWT left ventricular posterior wall thickness in diastole. Baseline represents measurements 18–24 hours after coronary ligation and treatment. n = 6 for each animal group studied. Bars are presented as mean±SD. ¶ p<0.05 control vs MI +CSp.
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pone-0088590-g001: Tissue morphology and cardiac function.(A) Representative photomicrographs of myocardial sections stained with Masson's trichrome. Sections are from CSp treated (n = 5) and placebo treated (n = 5) animals at 7 and 21 days post MI and treatment. (B–F) Quantitative data for infarct mass, viable mass, infarct size, infarct thickness and septum thickness. Five different hearts were processed and 5–6 different sections from the apex to the base from each heart were used for the analysis. (G–I) EF ejection fraction, LVEDD left ventricular end diastolic diameter, LVPWT left ventricular posterior wall thickness in diastole. Baseline represents measurements 18–24 hours after coronary ligation and treatment. n = 6 for each animal group studied. Bars are presented as mean±SD. ¶ p<0.05 control vs MI +CSp.

Mentions: We performed Masson's trichrome staining to evaluate infarct size one week and three weeks post-MI (Figure 1A). Five different hearts were processed and 5–10 different sections from the apex to the base from each heart were analyzed. Infarct size was defined as infarct mass divided by total LV mass. By three weeks post-MI, we found a scar mass reduction of 35%, while viable mass was increased by 13%, in the CSp-treated group (Figure 1B, 1C). Scar size in the MI+CSp group was significantly reduced relative to the MI group one week post treatment (Figure 1D). We also evaluated septal and infarct wall thickness in the same sections. At three weeks, CSp-treated hearts had a 20% lower septal thickness and a 35% higher infarcted wall thickness (Figure 1E, 1F). The increase in infarct wall thickness and the attenuated septal wall thickness, indicate relatively preserved cardiac tissue structure with cardiospheres evident as soon as 1 week post-MI.


Angiogenesis, cardiomyocyte proliferation and anti-fibrotic effects underlie structural preservation post-infarction by intramyocardially-injected cardiospheres.

Tseliou E, de Couto G, Terrovitis J, Sun B, Weixin L, Marbán L, Marbán E - PLoS ONE (2014)

Tissue morphology and cardiac function.(A) Representative photomicrographs of myocardial sections stained with Masson's trichrome. Sections are from CSp treated (n = 5) and placebo treated (n = 5) animals at 7 and 21 days post MI and treatment. (B–F) Quantitative data for infarct mass, viable mass, infarct size, infarct thickness and septum thickness. Five different hearts were processed and 5–6 different sections from the apex to the base from each heart were used for the analysis. (G–I) EF ejection fraction, LVEDD left ventricular end diastolic diameter, LVPWT left ventricular posterior wall thickness in diastole. Baseline represents measurements 18–24 hours after coronary ligation and treatment. n = 6 for each animal group studied. Bars are presented as mean±SD. ¶ p<0.05 control vs MI +CSp.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3928273&req=5

pone-0088590-g001: Tissue morphology and cardiac function.(A) Representative photomicrographs of myocardial sections stained with Masson's trichrome. Sections are from CSp treated (n = 5) and placebo treated (n = 5) animals at 7 and 21 days post MI and treatment. (B–F) Quantitative data for infarct mass, viable mass, infarct size, infarct thickness and septum thickness. Five different hearts were processed and 5–6 different sections from the apex to the base from each heart were used for the analysis. (G–I) EF ejection fraction, LVEDD left ventricular end diastolic diameter, LVPWT left ventricular posterior wall thickness in diastole. Baseline represents measurements 18–24 hours after coronary ligation and treatment. n = 6 for each animal group studied. Bars are presented as mean±SD. ¶ p<0.05 control vs MI +CSp.
Mentions: We performed Masson's trichrome staining to evaluate infarct size one week and three weeks post-MI (Figure 1A). Five different hearts were processed and 5–10 different sections from the apex to the base from each heart were analyzed. Infarct size was defined as infarct mass divided by total LV mass. By three weeks post-MI, we found a scar mass reduction of 35%, while viable mass was increased by 13%, in the CSp-treated group (Figure 1B, 1C). Scar size in the MI+CSp group was significantly reduced relative to the MI group one week post treatment (Figure 1D). We also evaluated septal and infarct wall thickness in the same sections. At three weeks, CSp-treated hearts had a 20% lower septal thickness and a 35% higher infarcted wall thickness (Figure 1E, 1F). The increase in infarct wall thickness and the attenuated septal wall thickness, indicate relatively preserved cardiac tissue structure with cardiospheres evident as soon as 1 week post-MI.

Bottom Line: Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated.The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection.These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.

View Article: PubMed Central - PubMed

Affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

ABSTRACT

Objective: We sought to understand the cellular and tissue-level changes underlying the attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial infarction (MI).

Background: Cardiospheres (CSps) are heart-derived multicellular clusters rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation improves left ventricular (LV) function and attenuates remodeling in both small and large animal studies. However, the mechanisms of benefit have not yet been fully elucidated.

Methods: Four groups were studied: 1) "Sham" (Wistar Kyoto rats with thoracotomy and ligature without infarction); 2) "MI" (proximal LAD ligation with peri-infarct injection of vehicle); 3) "MI+CSp" (MI with cardiospheres injected in the peri-infarct area); 4) "Small MI" (mid-LAD ligation only).

Results: In vivo 1 week after CSp transplantation, LV functional improvement was associated with an increase in cardiomyocyte proliferation. By 3 weeks, microvessel formation was enhanced, while cardiomyocyte hypertrophy and regional fibrosis were attenuated. Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated. The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection. In vitro, CSp-conditioned media reduced collagen production in coculture with fibroblasts and triggered neoangiogenesis in an ex vivo aortic ring assay.

Conclusion: Cardiospheres enhance cardiomyocyte proliferation and angiogenesis, and attenuate hypertrophy and fibrosis, in the ischemic myocardium. These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.

Show MeSH
Related in: MedlinePlus