CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu; Chen, SF; Zhang, Jianyi

doi:10.1161/circresaha.117.311504

Cited by 127 publications

(107 citation statements)

References 40 publications

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“…that are engrafted by the native-like tissues at the site of administration. When tested in a murine MI model, we and others have previously carried out several CM implantation studies using either CM patch (5,9) or CM suspension (20). It should be noted that in all previous studies performed both in our laboratory and by others, the engraftment rate was consistently and significantly lower than in the present study involving spheroids (less than~10% vs. more than~25%, respectively).…”

Section: Discussioncontrasting

confidence: 47%

“…It should be noted that in all previous studies performed both in our laboratory and by others, the engraftment rate was consistently and significantly lower than in the present study involving spheroids (less than~10% vs. more than~25%, respectively). Importantly, all of the studies performed in our laboratory (20) were performed under the same experimental conditions as the spheroid studies. These conditions included the same animal model, infarction procedure, surgical personnel, and source of CMs, CM differentiation and culturing methods, and engraftment rate assessment time point and methods.…”

Section: Discussionmentioning

confidence: 99%

“…The cardioprotective/regenerative capacity of hiPSC-CM spheroid fusions was evaluated in a murine model of MI. MI was surgically induced by permanently ligating the coronary artery, as previously described (20), and animals in the MI ϩ spheroid group were treated with a single five-spheroid fusion containing a total of 1 million hiPSC-CMs. The spheroids were suspended in a fibrin patch positioned over the site of infarction and held in place with a film of sodium hyaluronate carboxymethylcellulose that was sutured to the heart preventing adhesion to the serous pericardium (Fig.…”

Section: Generation and Characterization Of Hipsc-derived Cmsmentioning

confidence: 99%

See 2 more Smart Citations

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Mattapally

Zhu

Fast

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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The microenvironment of native heart tissue may be better replicated when cardiomyocytes are cultured in three-dimensional clusters (i.e., spheroids) than in monolayers or as individual cells. Thus, we differentiated human cardiac lineage-induced pluripotent stem cells in cardiomyocytes (hiPSC-CMs) and allowed them to form spheroids and spheroid fusions that were characterized in vitro and evaluated in mice after experimentally induced myocardial infarction (MI). Synchronized contractions were observed within 24 h of spheroid formation, and optical mapping experiments confirmed the presence of both Ca transients and propagating action potentials. In spheroid fusions, the intraspheroid conduction velocity was 7.0 ± 3.8 cm/s on days 1- 2 after formation, whereas the conduction velocity between spheroids increased significantly ( P = 0.003) from 0.8 ± 1.1 cm/s on days 1- 2 to 3.3 ± 1.4 cm/s on day 7. For the murine MI model, five-spheroid fusions (200,000 hiPSC-CMs/spheroid) were embedded in a fibrin patch and the patch was transplanted over the site of infarction. Later (4 wk), echocardiographic measurements of left ventricular ejection fraction and fractional shortening were significantly greater in patch-treated animals than in animals that recovered without the patch, and the engraftment rate was 25.6% or 30% when evaluated histologically or via bioluminescence imaging, respectively. The exosomes released from the spheroid patch seemed to increase cardiac function. In conclusion, our results established the feasibility of using hiPSC-CM spheroids and spheroid fusions for cardiac tissue engineering, and, when fibrin patches containing hiPSC-CM spheroid fusions were evaluated in a murine MI model, the engraftment rate was much higher than the rates we have achieved via the direct intramyocardial injection.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Section: Generation and Characterization Of Hipsc-derived Cmsmentioning

confidence: 99%

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Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Mattapally

Zhu

Fast

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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“…Since our TNNT2‐FUCCI reporter can accurately recapitulate the cell‐cycle behavior of human CMs, the cells can be easily adopted to identify novel chemicals or genes for heart regeneration in a high‐throughput manner. To test this function, we transfected Day 20 TNNT2‐FUCCI hPSC‐derived CMs with CCND2 expressing plasmid as CCND2 overexpression has been shown to increase CM cell‐cycle activity (W. Zhu, Zhao, Mattapally, Chen, & Zhang, 2018). As expected, CCND2 overexpression significantly increased the Clover expression in the TNNT2‐FUCCI hPSC‐CMs (Figure 5a,b).…”

Section: Resultsmentioning

confidence: 99%

Fluorescent indicators for continuous and lineage‐specific reporting of cell‐cycle phases in human pluripotent stem cells

Chang

Hellwarth

Randolph

et al. 2020

Biotech & Bioengineering

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Proper cell‐cycle progression is essential for the self‐renewal and differentiation of human pluripotent stem cells (hPSCs). The fluorescent ubiquitination‐based cell‐cycle indicator (FUCCI) has allowed the dual‐color visualization of the G1 and S/G2/M phases in various dynamic models, but its application in hPSCs is not widely reported. In addition, lineage‐specific FUCCI reporters have not yet been developed to analyze complex tissue‐specific cell‐cycle progression during hPSC differentiation. Desiring a robust tool for spatiotemporal reporting of cell‐cycle events in hPSCs, we employed the CRISPR/Cas9 genome editing tool and successfully knocked the FUCCI reporter into the AAVS1 safe harbor locus of hPSCs for stable and constitutive FUCCI expression, exhibiting reliable cell‐cycle‐dependent fluorescence in both hPSCs and their differentiated progeny. We also established a cardiac‐specific TNNT2‐FUCCI reporter for lineage‐specific cell‐cycle monitoring of cardiomyocyte differentiation from hPSCs. This powerful and modular FUCCI system should provide numerous opportunities for studying human cell‐cycle activity, and enable the identification and investigation of novel regulators for adult tissue regeneration.

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“…Combining cell and gene therapy offers the advantage that cells can be genetically engineered ex vivo prior to transplantation, offering a safer alternative and more precise control of gene expression compared to gene therapy alone. 27,38,[45][46][47] Another such approach involves the ex vivo engineering of cell grafts with mixtures of physiologically relevant cell types, such as cardiomyocytes; cardiac precursors; and vascular, neuronal, immune, and mesenchymal cell types, 35,41,[48][49][50][51][52][53][54] which may offer a more comprehensive regenerative strategy compared to each cell type alone, given that both cardiomyogenic and non-cardiomyogenic cells are necessary for heart function and regeneration.…”

mentioning

confidence: 99%

Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges

et al. 2018

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Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.

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CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Cited by 127 publications

References 40 publications

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice

Fluorescent indicators for continuous and lineage‐specific reporting of cell‐cycle phases in human pluripotent stem cells

Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges

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