Cardiomyocyte Proliferation

Yutzey, Katherine E.

doi:10.1161/circresaha.116.310058

Cited by 58 publications

(24 citation statements)

References 17 publications

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“…T-cell receptor-mediated signaling alone is adequate to induce Treg differentiation in neonates without the need of IL-2 and TGF-β that are both required for adult Treg differentiation 39 . Therefore, in addition to the binuclear feature of adult cardiomyocytes that exit the cell cycle irreversibly 40 , the more effective Th1 and Th17 responses and less effective Treg responses of the adult mice could partly explain that the adult heart is less amenable for repair compared to the neonates. Given the developmental differences in various immune cell types including CD4 + T-cells, CD8 + T-cells and macrophages, ablation of CD4 + T-cells alone was insufficient to promote adult heart repair.…”

Section: Discussionmentioning

confidence: 99%

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Li¹,

Cai²,

Yang³

et al. 2020

Theranostics

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Unlike adult cardiomyocytes, neonatal cardiomyocytes can readily proliferate that contributes to a transient regenerative potential after myocardial injury in mice. We have recently reported that CD4 + regulatory T-cells promote this process; however, the role of other CD4 + T-cell subsets as well as CD8 + T-cells in postnatal heart regeneration has been less studied. Methods: by comparing the regenerating postnatal day (P) 3 and the non-regenerating P8 heart after injury, we revealed the heterogeneity of CD4 + and CD8 + T-cells in the myocardium through single cell analysis. We also specifically ablated CD4 + and CD8 + T-cells using the lytic anti-CD4 and -CD8 monoclonal antibodies, respectively, in juvenile mice at P8 after myocardial injury. Results : we observe significantly more CD4 + FOXP3 - conventional T-cells in the P8 heart when compared to that of the P3 heart within a week after injury. Surprisingly, such a difference is not seen in CD8 + T-cells that appear to have no function as their depletion does not reactivate heart regeneration. On the other hand, specific ablation of CD4 + T-cells contributes to mitigated cardiac fibrosis and increased cardiomyocyte proliferation after injury in juvenile mice. Single-cell transcriptomic profiling reveals a pro-fibrotic CD4 + T-cell subset in the P8 but not P3 heart. Moreover, there are likely more Th1 and Th17 cells in the P8 than P3 heart. We further demonstrate that cytokines of Th1 and Th17 cells can directly reduce the proliferation and increase the apoptosis of neonatal cardiomyocytes. Moreover, ablation of CD4 + T-cells can directly or indirectly facilitate the polarization of macrophages away from the pro-fibrotic M2-like signature in the juvenile heart. Nevertheless, ablation of CD4 + T-cells alone does not offer the same protection in the adult heart after myocardial infarction, suggesting a developmental change of immune cells including CD4 + T-cells in the regulation of age-related mammalian heart repair. Conclusions : our results demonstrate that ablation of CD4 + but not CD8 + T-cells promotes heart regeneration in juvenile mice; and CD4 + T-cells play a distinct role in the regulation of heart regeneration and repair during development.

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Section: Discussionmentioning

confidence: 99%

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Li¹,

Cai²,

Yang³

et al. 2020

Theranostics

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“…Until recently, cardiomyocytes were thought to have largely limited proliferative ability due to their terminal differentiation. 5 The cardiomyocytes of neonatal mouse hearts display remarkable regenerative ability [6][7][8][9] ; however, this ability is quickly lost seven days after birth. 10 After this transitionary stage, the adult cardiomyocytes display limited proliferative ability after injury, a mechanism proposed to also occur in humans.…”

Section: Impact Statementmentioning

confidence: 99%

The cytoprotective impact of yes-associated protein 1 after ischemia-reperfusion injury in AC16 human cardiomyocytes

Khan

Makhoul

et al. 2019

Exp Biol Med (Maywood)

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The Hippo-signaling pathway is a mechanism implicated in cardiomyocyte cytoprotection and regeneration after a myocardial infarction. Yes-associated protein 1, the main effector protein of this pathway, acts as a co-transcriptional activator to promote cardiomyocyte proliferation and survival. However, the biological mechanisms by which yes-associated protein 1 protects the heart post-MI are currently unknown. Here, we propose that yes-associated protein 1 plays a critical role in cardiomyocyte cytoprotection after simulated ischemia-reperfusion injury. AC16 human cardiomyocytes were infected with lentiviral plasmids containing normal human yes-associated protein 1 and a constitutively active form of YAP, YAP1S127A. Cells were exposed to ischemia-reperfusion injury using a hypoxic chamber. Hippo-signaling characterization after ischemia-reperfusion injury was performed via Western blotting and reverse transcriptase polymerase chain reaction. Cell viability, apoptosis, and cellular hypertrophy were assessed as a measure of cytoprotection. The GSK3β inhibitor CHIR99021 was used to investigate cross-talk between Hippo and Wnt-signaling and their role in cytoprotection after ischemia-reperfusion-injury. Ischemia-reperfusion injury resulted in significant decreased expression of the non-phosphorylated Hippo signaling kinases MST1 and LATS1, along with decreased expression of YAP/TAZ. Overexpression of yes-associated protein 1 improved cellular viability, while reducing hypertrophy and apoptosis via the ATM/ATR DNA damage response pathway. Activation of β-catenin in YAP-infected cardiomyocytes synergistically reduced cellular hypertrophy after ischemia-reperfusion-injury. Our findings indicate that yes-associated protein 1 is cytoprotective in AC16 human cardiomyocytes after ischemia-reperfusion injury, which may be mediated by co-activation of the canonical Wnt/β-catenin pathway. Thus, activation of yes-associated protein 1 may be a novel therapeutic to repair the infarcted myocardium. Impact statement Genetically engineering the cells of the heart after myocardial infarction to display a more regenerative phenotype is a promising therapy for heart failure patients. Here, we support a regenerative role for yes-associated protein 1, the main effector protein of the Hippo signaling pathway, in AC16 human cardiomyocytes as a potential therapeutic gene target for cardiac repair after myocardial infarction.

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“…With a final concentration of cells in the bioinks was 300 million cells mL −1 , the total number of cells for constructing such a model is ≈15 million. Recently, some studies showed the possibilities of boosting the proliferation of adult CMs by removing the cell cycle blockers and/or adding drugs . With the turnover rate of CMs improved, the fabrication of large size cardiac muscle tissues, even whole heart, would be made possible.…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

“…Recently, some studies showed the possibilities of boosting the proliferation of adult CMs by removing the cell cycle blockers and/or adding drugs. [92][93][94] With the turnover rate of CMs improved, the fabrication of large size cardiac muscle tissues, even whole heart, would be made possible. Finally, the specific requirement of smooth muscle tissue engineering is the heterogeneous distribution of SMCs with their neighboring cells, e.g., ECs, instead of a simple mixing of all types of cells.…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

Nano‐ and Microfabrication for Engineering Native‐Like Muscle Tissues

et al. 2020

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Muscle tissues are characterized by highly organized 3D structures consisting of aligned myocytes and nonmyocytes. Several nano‐ and microfabrication technologies are used to engineer native‐like muscle tissues for muscle regeneration, the treatment of cardiovascular diseases, and in vitro disease modeling. In this paper, traditional tissue engineering methods and novel nano‐/microfabrication technologies for constructing muscle tissues are reviewed. Focus is given on the effects of nano‐/microfabricated architectures on the alignment of cells. In addition, issues of vascularization and cell–cell interaction in fabricating muscle tissues are discussed. Finally, common challenges of fabricating three types of muscle tissues and specific requirements for each type are reviewed, and perspectives are given for future studies.

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Cardiomyocyte Proliferation

Cited by 58 publications

References 17 publications

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

The cytoprotective impact of yes-associated protein 1 after ischemia-reperfusion injury in AC16 human cardiomyocytes

Nano‐ and Microfabrication for Engineering Native‐Like Muscle Tissues

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Cardiomyocyte Proliferation

Cited by 58 publications

References 17 publications

Specific ablation of CD4+ T-cells promotes heart regeneration in juvenile mice

Specific ablation of CD4+ T-cells promotes heart regeneration in juvenile mice

The cytoprotective impact of yes-associated protein 1 after ischemia-reperfusion injury in AC16 human cardiomyocytes

Nano‐ and Microfabrication for Engineering Native‐Like Muscle Tissues

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Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice

Specific ablation of CD4⁺ T-cells promotes heart regeneration in juvenile mice