A Strong Regenerative Ability of Cardiac Stem Cells Derived From Neonatal Hearts

Simpson, David P.; Mishra, Rachana; Sharma, Sudhish; Goh, Saik Kia; Deshmukh, Savitha; Kaushal, Sunjay

doi:10.1161/circulationaha.111.084699

Cited by 122 publications

(121 citation statements)

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“…However, we did not investigate the activation of cardiac stem cell-like populations, such as c-kit + , Sca1 + cells.6, [19][20][21] Studies have indicated that neonatal-derived cardiac stem cells have a strong regenerative ability when compared with adult-derived cardiac stem cells. 22,23) In our results, we also noticed that there are large numbers of CMs generated in the normal development of neonatal rat. Since we did not investigate the occurrence and frequency of cardiac stem cells, it is extremely difficult for us to rule out cardiac stem cells as the source of new CM formation.…”

Section: Discussionsupporting

confidence: 69%

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: Discussionsupporting

confidence: 69%

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

et al. 2017

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“…Transcriptome analysis shows dysregulation of genes involved in various cellular processes, including pluripotent stem cell signaling, cell growth, and dedifferentiation. Interestingly, previous studies have shown an increase in cardiac progenitor cells in nondiseased infant hearts that are in an incomplete state of cardiac differentiation (16)(17)(18). As reported by Amir et al, these cells coexpress cardiac (SERCA) and stem cell markers and have the ability to differentiate into cardiomyocytes (16).…”

Section: Discussionmentioning

confidence: 83%

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

et al. 2017

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“…This has implications for the use of MSCs in pediatric patients, who are anticipated to have a robust response to MSC treatment. This expected response is based on our previous study, which demonstrated an increased number and enhanced regenerative capacity of resident CSCs in pediatric patients compared with adult patients (34). Should MSC therapy provide a similar benefit to RV performance, as has been observed for LV models of myocardial infarction, it would represent a breakthrough in the treatment of children with RV dysfunction.…”

Section: We Demonstrate For the First Time That Intramyocardial Injecmentioning

confidence: 75%

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Wehman

Sharma

Pietris

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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(MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n ϭ 5) or placebo (n ϭ 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P Ͻ 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P Ͻ 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P Ͻ 0.0001), superior recruitment of endogenous c-kitϩ cardiac stem cells to the RV (P Ͻ 0.0001) and increased proliferation of cardiomyocytes (P ϭ 0.0009) and endothelial cells (P Ͻ 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P ϭ 0.008), increased cardiomyocyte cross-sectional area (P ϭ 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ␤-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions. stem cell therapy; congenital heart disease; right ventricle; pressure overload CONGENITAL HEART DISEASE (CHD) is the leading cause of morbidity and mortality in children with birth defects. While surgical interventions have dramatically improved outcomes and longevity in patients with CHD, many patients still progress to heart failure, a population that has grown significantly over the last decade (30). In contrast to adult patients, in whom ischemic heart disease is the predominant etiology of heart failure, children with CHD are frequently exposed to acute or chronic ventricular pressure and volume overload, which if untreated can progress to ventricular dysfunction and ultimately to heart failure. Further, patients with CHD who develop right ventricular (RV) dysfunction have the poorest outcomes (23, 26), particularly in those patients with univentricular heart disease i...

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A Strong Regenerative Ability of Cardiac Stem Cells Derived From Neonatal Hearts

Cited by 122 publications

References 21 publications

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

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