Circulating Cells Contribute to Cardiomyocyte Regeneration After Injury

Wu, Jang Yen; Hsueh, Ying Chang; Chang, Hui-Wen; Luo, Chwan Yau; Wu, Li-Wha; Nakauchi, Hiromitsu; Hsieh, Patrick C.

doi:10.1161/circresaha.116.304564

Cited by 50 publications

(66 citation statements)

References 38 publications

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“…Previous lineage studies concluded that most proliferation-labeled cardiomyocytes arise from preexisting cardiomyocytes 7,8 , which discounts the possibility that our observations can be explained by proliferation of a progenitor followed by cardiomyocyte differentiation. Fusion of cardiomyocytes with hematopoietic or other cell types can occur 27–29 , but this results in binuclear rather than mononuclear cells. Although we cannot formally exclude the possibility of DNA replication by preexisting binuclear or tetraploid cardiomyocytes with two subsequent rounds of division into MNDCMs, our observations are consistent with a proliferative response by MNDCMs that divide to generate more MNDCMs.…”

Section: Resultsmentioning

confidence: 99%

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Patterson¹,

Barske²,

Handel³

et al. 2017

Nat Genet

275

301

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Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

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Section: Resultsmentioning

confidence: 99%

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Patterson¹,

Barske²,

Handel³

et al. 2017

Nat Genet

275

301

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“…BMCs, the most common stem cell for cardiac therapy, apparently undergo engraftment through a combination of cell fusion and to a lesser degree by direct transdifferentiation events 25 . Membrane fusion is dependent upon signaling mechanisms involving paxillin induced focal adhesions and recycling of integrins as demonstrated between macrophages and myoblasts 26 .…”

Section: Discussionmentioning

confidence: 99%

Cardiac Stem Cell Hybrids Enhance Myocardial Repair

Quijada

Salunga

Hariharan

et al. 2015

Circulation Research

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Rationale Dual cell transplantation of cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction improves myocardial repair and performance in large animal models relative to delivery of either cell population. Objective To demonstrate that CardioChimeras (CCs) formed by fusion between CPCs and MSCs have enhanced reparative potential in a mouse model of myocardial infarction relative to individual stem cells or combined cell delivery. Methods and Results Two distinct and clonally derived CCs, CC1 and CC2 were utilized for this study. CCs improved left ventricular anterior wall thickness (AWT) at 4 weeks post injury, but only CC1 treatment preserved AWT at 18 weeks. Ejection fraction was enhanced at 6 weeks in CCs, and functional improvements were maintained in CCs and CPC + MSC groups at 18 weeks. Infarct size was decreased in CCs, whereas CPC + MSC and CPC parent groups remained unchanged at 12 weeks. CCs exhibited increased persistence, engraftment, and expression of early commitment markers within the border zone relative to combinatorial and individual cell population-injected groups. CCs increased capillary density and preserved cardiomyocyte size in the infarcted regions suggesting CCs role in protective paracrine secretion. Conclusions CCs merge the application of distinct cells into a single entity for cellular therapeutic intervention in the progression of heart failure. CCs are a novel cell therapy that improves upon combinatorial cell approaches to support myocardial regeneration.

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“…The second category includes adult, undifferentiated progenitor cells such as bone marrow mononuclear cells (BMCs) (147,260,318,396), MSCs (11,119,137), and resident adult cardiac progenitors (CPCs) (62,228). Although most of these cell types entered the clinical arena based on the hypothesis that they possessed myogenic differentiation capacity (191), further mechanistic studies revealed critical contributions of their anti-inflammatory and antifibrotic properties, as well as stimulation of endogenous cardiovascular progenitor and cardiomyocyte proliferation cell programs (144,219,229,291,349).…”

Section: Introductionmentioning

confidence: 99%

“…Although most of these cell types entered the clinical arena based on the hypothesis that they possessed myogenic differentiation capacity (191), further mechanistic studies revealed critical contributions of their anti-inflammatory and antifibrotic properties, as well as stimulation of endogenous cardiovascular progenitor and cardiomyocyte proliferation cell programs (144,219,229,291,349). Nonetheless, genetic lineage-fate mapping studies show that, under the proper conditions, endogenous CPCs (145,348,368), and to a smaller extent BMCs (289,396) and MSCs (60,144,290) produce new cardiomyocytes in the postnatal heart, albeit at a functionally insignificant level. Paradoxically, compared with ESC/iPSC-based strategies, engraftment of MSCs and CPCs is lower but leads to significant heart regeneration and recovery of heart function (62,97,119,137,143,144,147,174,175,228,229,284,290,321,322,385).…”

Section: Introductionmentioning

confidence: 99%

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

Golpanian

Wolf

Hatzistergos

et al. 2016

Physiological Reviews

274

211

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Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.

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Circulating Cells Contribute to Cardiomyocyte Regeneration After Injury

Cited by 50 publications

References 38 publications

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Cardiac Stem Cell Hybrids Enhance Myocardial Repair

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

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