Heart regeneration for clinical application update 2016: from induced pluripotent stem cells to direct cardiac reprogramming

Yamakawa, Hiroyuki

doi:10.1186/s41232-016-0028-z

Cited by 12 publications

(13 citation statements)

References 43 publications

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“…24,25) Here we show that neonatal rat CMs possess high proliferative potential and response with active proliferation of CMs to increased afterload. Thus, ascending aorta constriction in neonatal rats may provide an attractive method to explore efficient CM generation therapy for endstage heart disease.…”

Section: Discussionmentioning

confidence: 99%

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

et al. 2017

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SummaryAdult heart suffering from increased workload will undergo myocardial hypertrophy, subsequent cardiomyocyte (CM) death, and eventually heart failure. However, the effect of increasing afterload on the neonatal heart remains unknown. We performed ascending aortic constriction (AAC) in neonatal rats 8-12 hours after birth (P0, P indicates postpartum). Seven days after surgery, in vivo heart function was evaluated using cardiac ultrasonography. Haematoxylineosin and Masson staining were used to assess CM diameter and collagen deposition. Moreover, expression of both EdU and Ki67 were evaluated to determine DNA synthesis levels, and pH3 and aurora B as markers for mitosis in CMs. CM isolation was performed by heart perfusion at P0, P3, P5, and P7, respectively. CM number on P0 was 1.01 ± 0.29 × 10 6 . We found that CM cell cycle activation was significantly increased among constricted hearts, as demonstrated by increased Ki67, EdU, pH3, and aurora B positive cells/1000 CMs. At day 7 (P7), constriction group hearts manifested increased wall thickness (0.55 ± 0.05 mm versus 0.85 ± 0.10 mm, P < 0.01, n = 6), and improved hemodynamics as well as left ventricular ejection fraction (65.5 ± 3.7% versus 77.7 ± 4.8%, P < 0.01, n = 6). Of note, the population of CMs was also markedly increased in the constriction group (2.92 ± 0.27 × 10 6 versus 3.41 ± 0.40 × 10 6 , P < 0.05, n = 6). In summary, we found that during the first week after birth significant numbers of neonatal CMs can reenter the cell cycle. Ascending aortic constriction promotes neonatal rat CM proliferation resulting in 16.7% more CMs in the heart. (Int Heart J 2017; 58: 264-270) Key words: Cell cycle reentry, Regeneration H eart failure is an increasing burden on health care systems around the world. 1) Many forms of heart diseases result in significant and permanent losses of functional cardiomyocytes (CMs), such as coronary artery disease and pressure-loading cardiomyopathies. Efforts to address this issue have led to the exploration of methods for CM regeneration even though the mammalian heart has long been considered a postmitotic organ. Recently, it was shown that individual CMs may be not as old as the person -almost 50% of CMs are replaced during a normal life span.2) By combining different genetic fate-mapping approaches, scientists have found that the genesis of CMs occurs by division of preexisting CMs.3,4) Although it happens at a very low rate, this evidence suggests that the heart is not terminally differentiated but instead an organ with regenerative potential. More lately, the discovery of an epimorphic regeneration potential in neonatal mammal hearts has contributed greatly to new insights in cardiac biology. In particular, neonatal mice can fully regenerate their heart after apex resection in a very short time.5) BrdU, pH3 labeling, and genetic fate-mapping have indicated that the majority of regenerated CMs originated from preexisting ones. A similar conclusion was obtained by another research group working on a different animal mode...

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Section: Discussionmentioning

confidence: 99%

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

et al. 2017

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“…However, directed differentiation is still a challenge faced by scientists and doctors. In addition, efficacy of ESC differentiated into cardiomyocytes is another barrier needed to break for clinical applications …”

Section: Introductionmentioning

confidence: 99%

Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes

Ding

Xian

et al. 2016

Cardiovascular Therapeutics

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SummaryAim: Embryonic stem cells (ESCs) are capable to differentiate into cardiomyocytes, with the potential to treat cardiovascular diseases. However, directed differentiation is still a challenge faced by scientists. As a natural substance in grapes, resveratrol (RV) is important for cardiovascular protection. The studies of RV and its effects on ESC differentiation have potential clinical applications. Methods:Using mouse embryonic stem cells (mESCs), we investigated the effects of different concentrations of RV (5,10,20, 50, and 100 μmol/L) exposure on mESCs viability, expression levels of cardiac marker genes in embryoid bodies (EBs) derived from mESCs, expression levels of maturity indicative cardiac markers in cardiomyocytes derived from mESCs, and the beating properties of EBs. Results:About 10 μmol/L of RV showed no toxicity on cell viability and was the optimal concentration to promote mESC differentiation, induce mESC differentiation to cardiomyocytes, and gain the beating properties of EBs. Conclusion:RV can successfully direct the differentiation of mESCs into cardiomyocytes, shedding light on its future applications to treat cardiovascular diseases. K E Y W O R D Scardiomyocytes, differentiation, embryonic stem cells, resveratrol Resveratrol (RV), a naturally occurring phytoalexin produced by some spermatophytes, is present in many fruits and plants, including grapes, raspberries, blueberries, Scots pine, and knotweed. As a natural substance, RV has been proven to be safe and is provided as an over-thecounter human nutritional supplement.4 RV has been known to contribute to the antioxidant function of red wine, which potentially prevents human cardiovascular diseases. 5,6 Many publications reported that RV has the functions of anti-inflammation and antioxidation, underscoring its importance for cardiovascular protection.

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“…14) miR-10a was shown to be involved in congenital heart disease by targeting T-box 5 (Tbx5), which is a factor participating in embryonic cardiac development. 15,16) However, the regulatory mechanisms of miRNA-10a in cardiac hypertrophy remain to be clarified.…”

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confidence: 99%

microRNA-10a Targets T-box 5 to Inhibit the Development of Cardiac Hypertrophy

Wang

Zhai

et al. 2017

Int. Heart J.

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SummaryThe mechanism of cardiac hypertrophy involving microRNAs (miRNAs) is attracting increasing attention. Our study aimed to investigate the role of miR-10a in cardiac hypertrophy development and the underlying regulatory mechanism.Transverse abdominal aortic constriction (TAAC) surgery was performed to establish a cardiac hypertrophy rat model, and angiotensin II (AngII) was used to induce cardiac hypertrophy in cultured neonatal rat cardiomyocytes. Expression of T-box 5 (TBX5) and miR-10a was altered by cell transfection of siRNA or miRNA mimic/inhibitor. Leucine incorporation assay, histological and cytological examination, quantitative real-time PCR (qRT-PCR), and Western blot were performed to detect the effects of miR-10a and TBX5 on cardiac hypertrophy. Dual-luciferase reporter assay was conducted to verify the regulation of TBX5 by miR-10a.miR-10a was down-regulated, and TBX5 was up-regulated in the rat model and AngII-stimulated cardiomyocytes. miR-10a inhibited TBX5 expression by directly targeting the binding site in Tbx5 3'UTR. Overexpression of miR-10a in AngII-treated cardiomyocytes decreased relative cell area, and significantly reduced the mRNA levels of natriuretic peptide A (Nppa), myosin heavy chain 7 cardiac muscle beta (Myh7), and leucine incorporation (P < 0.01 or P < 0.001). Knockdown of Tbx5 had similar effects on AngII-induced cardiomyocytes.Our findings indicate that miR-10a may inhibit cardiac hypertrophy via targeting Tbx5. Thus, miR-10a provides promising therapeutic strategies for the treatment of cardiac hypertrophy. (Int Heart J 2017; 58: 100-106)

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Heart regeneration for clinical application update 2016: from induced pluripotent stem cells to direct cardiac reprogramming

Cited by 12 publications

References 43 publications

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes

microRNA-10a Targets T-box 5 to Inhibit the Development of Cardiac Hypertrophy

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