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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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Aortic ring sprouts.Representative phase contrast images from aortic rings embedded in collagen matrices 9 days post treatment with (A) CSp conditioned media, (B) 10% FBS culture media and (C) endothelial basal media. (D) Quantification of sprouts on day 9 under phase contrast microscopy. Arrows point at the new sprouts. (E) Immunofluorescence of the CSp conditioned media treated aortic ring reveals the phenotype of the de novo formed microvessels. Inserted photo is a high power field image of the immunostained microvessels for BS-lectin and smooth muscle actin. Three different experiments per group were evaluated (Scale bars 10 µm). Data are mean±SD. ¶ p<0.05 control vs. MI+CSp.
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pone-0088590-g004: Aortic ring sprouts.Representative phase contrast images from aortic rings embedded in collagen matrices 9 days post treatment with (A) CSp conditioned media, (B) 10% FBS culture media and (C) endothelial basal media. (D) Quantification of sprouts on day 9 under phase contrast microscopy. Arrows point at the new sprouts. (E) Immunofluorescence of the CSp conditioned media treated aortic ring reveals the phenotype of the de novo formed microvessels. Inserted photo is a high power field image of the immunostained microvessels for BS-lectin and smooth muscle actin. Three different experiments per group were evaluated (Scale bars 10 µm). Data are mean±SD. ¶ p<0.05 control vs. MI+CSp.

Mentions: To further verify a paracrine angiogenic effect of CSps, we performed an ex vivo angiogenesis assay [28] (Figure 4A–C). The number of de novo sprouts originating from the aortic ring was greatest in the CSp-conditioned media group 9 days post treatment compared to the other treated groups (p<0.05) (Figure 4D). In addition, fixed rings were further processed with immunohistochemistry to verify the endothelial and microvessel phenotype of the sprouts (Figure 4E). Since only CSp-conditioned media was used in this assay, the new vessel formation here arises purely from paracrine effects of CSps.


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)

Aortic ring sprouts.Representative phase contrast images from aortic rings embedded in collagen matrices 9 days post treatment with (A) CSp conditioned media, (B) 10% FBS culture media and (C) endothelial basal media. (D) Quantification of sprouts on day 9 under phase contrast microscopy. Arrows point at the new sprouts. (E) Immunofluorescence of the CSp conditioned media treated aortic ring reveals the phenotype of the de novo formed microvessels. Inserted photo is a high power field image of the immunostained microvessels for BS-lectin and smooth muscle actin. Three different experiments per group were evaluated (Scale bars 10 µm). Data are mean±SD. ¶ p<0.05 control vs. MI+CSp.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088590-g004: Aortic ring sprouts.Representative phase contrast images from aortic rings embedded in collagen matrices 9 days post treatment with (A) CSp conditioned media, (B) 10% FBS culture media and (C) endothelial basal media. (D) Quantification of sprouts on day 9 under phase contrast microscopy. Arrows point at the new sprouts. (E) Immunofluorescence of the CSp conditioned media treated aortic ring reveals the phenotype of the de novo formed microvessels. Inserted photo is a high power field image of the immunostained microvessels for BS-lectin and smooth muscle actin. Three different experiments per group were evaluated (Scale bars 10 µm). Data are mean±SD. ¶ p<0.05 control vs. MI+CSp.
Mentions: To further verify a paracrine angiogenic effect of CSps, we performed an ex vivo angiogenesis assay [28] (Figure 4A–C). The number of de novo sprouts originating from the aortic ring was greatest in the CSp-conditioned media group 9 days post treatment compared to the other treated groups (p<0.05) (Figure 4D). In addition, fixed rings were further processed with immunohistochemistry to verify the endothelial and microvessel phenotype of the sprouts (Figure 4E). Since only CSp-conditioned media was used in this assay, the new vessel formation here arises purely from paracrine effects of CSps.

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