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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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Upregulation of cell-cycle associated genes in resident cardiomyocytesA, B. Representative scatter plots of PCR microarray analysis of RNA isolated from GFP+ FACS-sorted cardiomyocytes for cell-cycle associated genes showing increased expression of positive cell-cycle regulators post-MI (red dots) compared to sham-operated animals (A), changes which are further upregulated after CDC therapy (B).C. Quantitative analysis of PCR microarray data. Results are presented as fold change compared to sham and were calculated using the ΔΔCt method. B-Actin was used as a control. (*p < 0.05 compared to sham; #p < 0.05 compared to MI, n = 3/group). All error bars represent SDs. One-way ANOVA followed by LSD post hoc test was used for statistical analysis (cyclin D1: MI vs sham p = 0.047, CDCs vs sham p = 0.001, CDCs vs MI p = 0.004; cyclin E1: CDCs vs sham p = 0.005, CDCs vs MI p = 0.02; cyclin A2: MI vs sham p = 0.009, CDCs vs sham p = 0.016, CDK4: MI vs sham p = 0.047, CDCs vs sham p = 0.019, Chek1: CDCs vs sham p = 0.014, PCNA: CDCs vs sham p = 0.009; all other p = ns).
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fig06: Upregulation of cell-cycle associated genes in resident cardiomyocytesA, B. Representative scatter plots of PCR microarray analysis of RNA isolated from GFP+ FACS-sorted cardiomyocytes for cell-cycle associated genes showing increased expression of positive cell-cycle regulators post-MI (red dots) compared to sham-operated animals (A), changes which are further upregulated after CDC therapy (B).C. Quantitative analysis of PCR microarray data. Results are presented as fold change compared to sham and were calculated using the ΔΔCt method. B-Actin was used as a control. (*p < 0.05 compared to sham; #p < 0.05 compared to MI, n = 3/group). All error bars represent SDs. One-way ANOVA followed by LSD post hoc test was used for statistical analysis (cyclin D1: MI vs sham p = 0.047, CDCs vs sham p = 0.001, CDCs vs MI p = 0.004; cyclin E1: CDCs vs sham p = 0.005, CDCs vs MI p = 0.02; cyclin A2: MI vs sham p = 0.009, CDCs vs sham p = 0.016, CDK4: MI vs sham p = 0.047, CDCs vs sham p = 0.019, Chek1: CDCs vs sham p = 0.014, PCNA: CDCs vs sham p = 0.009; all other p = ns).

Mentions: In order to detect changes in gene expression, we isolated RNA from FACS-sorted GFP+ cardiomyocytes and performed PCR microarray analysis for cell-cycle associated genes. We found that MI upregulated several genes associated with cell-cycle progression in resident cardiomyocytes, the expression of which was further amplified by therapy with CDCs (Fig 6). These genes include ones that orchestrate the G0/G1 transition (Cyclin D1, Cyclin-Dependent Kinase 4), the G1/S transition (Cyclin E, Cyclin-Dependent Kinase 2) and the G2/M transition (Cyclin A1-2, E2F1) (Li & Brooks, 1999; Pasumarthi & Field, 2002). Most of these genes have been shown to be upregulated in the embryonic and neonatal heart (Walsh et al, 2010), which are known to be capable of cardiomyocyte hyperplasia and robust regeneration post-injury (Porrello et al, 2011).


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)

Upregulation of cell-cycle associated genes in resident cardiomyocytesA, B. Representative scatter plots of PCR microarray analysis of RNA isolated from GFP+ FACS-sorted cardiomyocytes for cell-cycle associated genes showing increased expression of positive cell-cycle regulators post-MI (red dots) compared to sham-operated animals (A), changes which are further upregulated after CDC therapy (B).C. Quantitative analysis of PCR microarray data. Results are presented as fold change compared to sham and were calculated using the ΔΔCt method. B-Actin was used as a control. (*p < 0.05 compared to sham; #p < 0.05 compared to MI, n = 3/group). All error bars represent SDs. One-way ANOVA followed by LSD post hoc test was used for statistical analysis (cyclin D1: MI vs sham p = 0.047, CDCs vs sham p = 0.001, CDCs vs MI p = 0.004; cyclin E1: CDCs vs sham p = 0.005, CDCs vs MI p = 0.02; cyclin A2: MI vs sham p = 0.009, CDCs vs sham p = 0.016, CDK4: MI vs sham p = 0.047, CDCs vs sham p = 0.019, Chek1: CDCs vs sham p = 0.014, PCNA: CDCs vs sham p = 0.009; all other p = ns).
© Copyright Policy - open-access
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fig06: Upregulation of cell-cycle associated genes in resident cardiomyocytesA, B. Representative scatter plots of PCR microarray analysis of RNA isolated from GFP+ FACS-sorted cardiomyocytes for cell-cycle associated genes showing increased expression of positive cell-cycle regulators post-MI (red dots) compared to sham-operated animals (A), changes which are further upregulated after CDC therapy (B).C. Quantitative analysis of PCR microarray data. Results are presented as fold change compared to sham and were calculated using the ΔΔCt method. B-Actin was used as a control. (*p < 0.05 compared to sham; #p < 0.05 compared to MI, n = 3/group). All error bars represent SDs. One-way ANOVA followed by LSD post hoc test was used for statistical analysis (cyclin D1: MI vs sham p = 0.047, CDCs vs sham p = 0.001, CDCs vs MI p = 0.004; cyclin E1: CDCs vs sham p = 0.005, CDCs vs MI p = 0.02; cyclin A2: MI vs sham p = 0.009, CDCs vs sham p = 0.016, CDK4: MI vs sham p = 0.047, CDCs vs sham p = 0.019, Chek1: CDCs vs sham p = 0.014, PCNA: CDCs vs sham p = 0.009; all other p = ns).
Mentions: In order to detect changes in gene expression, we isolated RNA from FACS-sorted GFP+ cardiomyocytes and performed PCR microarray analysis for cell-cycle associated genes. We found that MI upregulated several genes associated with cell-cycle progression in resident cardiomyocytes, the expression of which was further amplified by therapy with CDCs (Fig 6). These genes include ones that orchestrate the G0/G1 transition (Cyclin D1, Cyclin-Dependent Kinase 4), the G1/S transition (Cyclin E, Cyclin-Dependent Kinase 2) and the G2/M transition (Cyclin A1-2, E2F1) (Li & Brooks, 1999; Pasumarthi & Field, 2002). Most of these genes have been shown to be upregulated in the embryonic and neonatal heart (Walsh et al, 2010), which are known to be capable of cardiomyocyte hyperplasia and robust regeneration post-injury (Porrello et al, 2011).

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