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Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart.

Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marbán E - EMBO Mol Med (2013)

Bottom Line: After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes.Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium.The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair.

View Article: PubMed Central - PubMed

Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.

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Structural, functional and regenerative benefits of CDC therapyA–C. Representative images of Masson's Trichrome-stained infarcted mouse hearts at 5 weeks post MI. Viable heart muscle stains red, while scar stains blue. Four consecutive sections per heart (obtained at 500 µm intervals, starting from the level of LAD ligation towards the apex) are presented. Note that the level of first section is similar, as manifested by the similar structure of the papillary muscles. Images in (B,C) are higher power images of the insets in (A), showing increased viable myocardium at the edges (B) and at the center (C) of the infarct in CDC-treated hearts.D–F. Morphometric analysis of CDC-treated and control hearts. CDC transplantation led to significant reduction of scar mass (p = 0.027) (D), increase of viable myocardium (p = 0.038) (E) and increased infarcted wall thickness (p = 0.005) (F), compared to control animals (n = 5–6/group).G. Representative images of the border zone revealing no myocyte hypertrophy in CDC-treated hearts.H. Border zone cardiomyocyte cross-sectional area did not differ significantly between groups (n = 10/group).I. Quantitative analysis of cardiomyocyte nuclei per heart (n = 10/group; p = 0.029).J. Quantitative analysis of cardiomyocytes per heart section (n = 10/group; p = 0.047).K. Echocardiographic assessment of LV function reveals that CDC transplantation resulted in superior global function (p < 0.001) compared to controls (n = 9/group).L, M. CDC engraftment as determined by immunohistochemistry after administration of DiI-labelled cells. Long-term cell survival beyond 3 weeks post-MI is low (n = 2/timepoint). All error bars represent SDs (*p < 0.05 compared to infarcted controls). All error bars represent SDs. Independent samples t-test was used for statistical analysis. Scale bars: 3 mm (A), 1 mm (B,C), 20 µm (G,L).
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fig10: Structural, functional and regenerative benefits of CDC therapyA–C. Representative images of Masson's Trichrome-stained infarcted mouse hearts at 5 weeks post MI. Viable heart muscle stains red, while scar stains blue. Four consecutive sections per heart (obtained at 500 µm intervals, starting from the level of LAD ligation towards the apex) are presented. Note that the level of first section is similar, as manifested by the similar structure of the papillary muscles. Images in (B,C) are higher power images of the insets in (A), showing increased viable myocardium at the edges (B) and at the center (C) of the infarct in CDC-treated hearts.D–F. Morphometric analysis of CDC-treated and control hearts. CDC transplantation led to significant reduction of scar mass (p = 0.027) (D), increase of viable myocardium (p = 0.038) (E) and increased infarcted wall thickness (p = 0.005) (F), compared to control animals (n = 5–6/group).G. Representative images of the border zone revealing no myocyte hypertrophy in CDC-treated hearts.H. Border zone cardiomyocyte cross-sectional area did not differ significantly between groups (n = 10/group).I. Quantitative analysis of cardiomyocyte nuclei per heart (n = 10/group; p = 0.029).J. Quantitative analysis of cardiomyocytes per heart section (n = 10/group; p = 0.047).K. Echocardiographic assessment of LV function reveals that CDC transplantation resulted in superior global function (p < 0.001) compared to controls (n = 9/group).L, M. CDC engraftment as determined by immunohistochemistry after administration of DiI-labelled cells. Long-term cell survival beyond 3 weeks post-MI is low (n = 2/timepoint). All error bars represent SDs (*p < 0.05 compared to infarcted controls). All error bars represent SDs. Independent samples t-test was used for statistical analysis. Scale bars: 3 mm (A), 1 mm (B,C), 20 µm (G,L).

Mentions: The increased incidence of cycling resident cardiomyocytes, and the increased cardiomyogenic differentiation of recruited progenitors after cell therapy, were accompanied by structural and functional benefits in the infarcted heart. Five weeks post-MI, CDC-treated hearts exhibited smaller scar mass, increased infarcted wall thickness and increased viable myocardium compared to controls (Fig 10A–F). To rule out myocyte hypertrophy as a contributor to the increase in viable myocardium [a phenomenon that has been reported after therapy with endothelial progenitor cells (Doyle et al, 2008)], we measured cardiomyocyte cross-sectional area in the peri-infarct area and found that cardiomyocyte size was similar in the CDC + MI and MI groups (Fig 10G and H). The cross-sectional area of cardiomyocytes located in the peri-infarct area (of both CDC-treated animals and infarcted controls) was higher than that of cardiomyocytes in remote myocardium; in addition, cardiomyocytes from both the peri-infarct and remote myocardium had increased area compared to cardiomyocytes in non-infarcted hearts (Supporting Information Fig 9). These data confirm previous reports demonstrating cardiomyocyte hypertrophy post-MI, which is more pronounced in the peri-infarct area compared to remote myocardium (Angeli et al, 2010; Lee et al, 2007). The fact that cardiomyocyte size in the peri-infarct area did not differ significantly between the CDC + MI and MI groups [even though CDC-treated hearts contained more BrdU+ cardiomyocytes in the peri-infarct area (Fig 5D, Supporting Information Fig 7) and cycling cardiomyocytes were smaller compared to non-cycling myocytes (Fig 4E)] can be rationalized by the relatively small percentage (∼4.7%) of additional cycling myocytes induced by CDC therapy in the peri-infarct area [which comprised ∼25% of the viable myocardium in our study (Supporting Information Fig 5)].


Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart.

Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marbán E - EMBO Mol Med (2013)

Structural, functional and regenerative benefits of CDC therapyA–C. Representative images of Masson's Trichrome-stained infarcted mouse hearts at 5 weeks post MI. Viable heart muscle stains red, while scar stains blue. Four consecutive sections per heart (obtained at 500 µm intervals, starting from the level of LAD ligation towards the apex) are presented. Note that the level of first section is similar, as manifested by the similar structure of the papillary muscles. Images in (B,C) are higher power images of the insets in (A), showing increased viable myocardium at the edges (B) and at the center (C) of the infarct in CDC-treated hearts.D–F. Morphometric analysis of CDC-treated and control hearts. CDC transplantation led to significant reduction of scar mass (p = 0.027) (D), increase of viable myocardium (p = 0.038) (E) and increased infarcted wall thickness (p = 0.005) (F), compared to control animals (n = 5–6/group).G. Representative images of the border zone revealing no myocyte hypertrophy in CDC-treated hearts.H. Border zone cardiomyocyte cross-sectional area did not differ significantly between groups (n = 10/group).I. Quantitative analysis of cardiomyocyte nuclei per heart (n = 10/group; p = 0.029).J. Quantitative analysis of cardiomyocytes per heart section (n = 10/group; p = 0.047).K. Echocardiographic assessment of LV function reveals that CDC transplantation resulted in superior global function (p < 0.001) compared to controls (n = 9/group).L, M. CDC engraftment as determined by immunohistochemistry after administration of DiI-labelled cells. Long-term cell survival beyond 3 weeks post-MI is low (n = 2/timepoint). All error bars represent SDs (*p < 0.05 compared to infarcted controls). All error bars represent SDs. Independent samples t-test was used for statistical analysis. Scale bars: 3 mm (A), 1 mm (B,C), 20 µm (G,L).
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fig10: Structural, functional and regenerative benefits of CDC therapyA–C. Representative images of Masson's Trichrome-stained infarcted mouse hearts at 5 weeks post MI. Viable heart muscle stains red, while scar stains blue. Four consecutive sections per heart (obtained at 500 µm intervals, starting from the level of LAD ligation towards the apex) are presented. Note that the level of first section is similar, as manifested by the similar structure of the papillary muscles. Images in (B,C) are higher power images of the insets in (A), showing increased viable myocardium at the edges (B) and at the center (C) of the infarct in CDC-treated hearts.D–F. Morphometric analysis of CDC-treated and control hearts. CDC transplantation led to significant reduction of scar mass (p = 0.027) (D), increase of viable myocardium (p = 0.038) (E) and increased infarcted wall thickness (p = 0.005) (F), compared to control animals (n = 5–6/group).G. Representative images of the border zone revealing no myocyte hypertrophy in CDC-treated hearts.H. Border zone cardiomyocyte cross-sectional area did not differ significantly between groups (n = 10/group).I. Quantitative analysis of cardiomyocyte nuclei per heart (n = 10/group; p = 0.029).J. Quantitative analysis of cardiomyocytes per heart section (n = 10/group; p = 0.047).K. Echocardiographic assessment of LV function reveals that CDC transplantation resulted in superior global function (p < 0.001) compared to controls (n = 9/group).L, M. CDC engraftment as determined by immunohistochemistry after administration of DiI-labelled cells. Long-term cell survival beyond 3 weeks post-MI is low (n = 2/timepoint). All error bars represent SDs (*p < 0.05 compared to infarcted controls). All error bars represent SDs. Independent samples t-test was used for statistical analysis. Scale bars: 3 mm (A), 1 mm (B,C), 20 µm (G,L).
Mentions: The increased incidence of cycling resident cardiomyocytes, and the increased cardiomyogenic differentiation of recruited progenitors after cell therapy, were accompanied by structural and functional benefits in the infarcted heart. Five weeks post-MI, CDC-treated hearts exhibited smaller scar mass, increased infarcted wall thickness and increased viable myocardium compared to controls (Fig 10A–F). To rule out myocyte hypertrophy as a contributor to the increase in viable myocardium [a phenomenon that has been reported after therapy with endothelial progenitor cells (Doyle et al, 2008)], we measured cardiomyocyte cross-sectional area in the peri-infarct area and found that cardiomyocyte size was similar in the CDC + MI and MI groups (Fig 10G and H). The cross-sectional area of cardiomyocytes located in the peri-infarct area (of both CDC-treated animals and infarcted controls) was higher than that of cardiomyocytes in remote myocardium; in addition, cardiomyocytes from both the peri-infarct and remote myocardium had increased area compared to cardiomyocytes in non-infarcted hearts (Supporting Information Fig 9). These data confirm previous reports demonstrating cardiomyocyte hypertrophy post-MI, which is more pronounced in the peri-infarct area compared to remote myocardium (Angeli et al, 2010; Lee et al, 2007). The fact that cardiomyocyte size in the peri-infarct area did not differ significantly between the CDC + MI and MI groups [even though CDC-treated hearts contained more BrdU+ cardiomyocytes in the peri-infarct area (Fig 5D, Supporting Information Fig 7) and cycling cardiomyocytes were smaller compared to non-cycling myocytes (Fig 4E)] can be rationalized by the relatively small percentage (∼4.7%) of additional cycling myocytes induced by CDC therapy in the peri-infarct area [which comprised ∼25% of the viable myocardium in our study (Supporting Information Fig 5)].

Bottom Line: After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes.Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium.The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair.

View Article: PubMed Central - PubMed

Affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA, USA.

Show MeSH
Related in: MedlinePlus