Human Cardiac Progenitor Cells Engineered With Pim-I Kinase Enhance Myocardial Repair

Mohsin, Sadia; Khan, Mohsin; Toko, Haruhiro; Bailey, Brandi; Cottage, Christopher T.; Wallach, Kathleen; Nag, Divya; Lee, Andrew; Siddiqi, Sailay; Lan, Feng; Fischer, Kimberlee M.; Gude, Natalie; Quijada, Pearl; Avitabile, Daniele; Truffa, Silvia; Collins, Brett; Dembitsky, Walter P.; Wu, Joseph C.; Sussman, Mark A.

doi:10.1016/j.jacc.2012.04.047

Cited by 142 publications

(157 citation statements)

References 41 publications

(53 reference statements)

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“…2 Cells were fixed with 4% paraformaldehyde and immunostaining was performed as described earlier stained for paracrine factors, including fibroblast growth factor (bFGF; ABCAM, Cambridge MA), hepatocyte growth factor (HGF; ABCAM), insulin-like growth factor (IGF-1; ABCAM), vascular endothelial growth factor (VEGF; ABCAM), platelet-derived growth factor (ABCAM) before and after differentiation.…”

Section: Lineage Commitment and Immunostainingmentioning

confidence: 99%

“…Research from several laboratories, including ours, suggests that stem cells hold immense potential for cardiac repair and regeneration. [1][2][3][4] Clinical use of adult stem cells is a reality today and many stem cell types, including bone marrow-derived mesenchymal stem cells (MSCs), 5 bone marrow cells, 7,8 cardiac-derived cardiac progenitor, 6 and cardio-sphere derived cells 9 have been tested. The beneficial effects of tested cell therapies on cardiac structure and function have been modest and most studies to date have not been adequately powered to document efficacy.…”

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confidence: 99%

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Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mohsin

Troupes

Starosta

et al. 2015

Circulation Research

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Rationale: Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure. Objective: To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials. Methods and Results: CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca 2+ concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types. Conclusions: CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury.

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Section: Lineage Commitment and Immunostainingmentioning

confidence: 99%

mentioning

confidence: 99%

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mohsin

Troupes

Starosta

et al. 2015

Circulation Research

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“…[103][104][105][106][107] Genetic modification of aged human CPCs with Pim-1 kinase results in remarkable rejuvenation of the CPCs associated with enhanced proliferation, increased telomere lengths, and decreased susceptibility to replicative senescence. 104,105 Likewise, activation of NOTCH1 signaling pathway is implicated in rejuvenation of myogenic responses to satellite muscle cells. 108 Activation of telomere-telomerase axis is known to contribute to cell survival and proliferation, and to prevent cellular senescence.…”

Section: Rejuvenation Of Cardiac Stem Cellsmentioning

confidence: 99%

Recent Developments in Cardiovascular Stem Cells

Madonna

Ferdinándy

Caterina

et al. 2014

Circulation Research

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45Human embryonic stem cells have been shown to differentiate to beating cardiomyocytes, SA nodal-like cells and mesodermal Recent Developments in Cardiovascular Research:The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields. It is our hope and expectation that these "Recent Development" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research-The Editors. 50 Moreover, the use of induced pluripotent stem cell-derived cardiac myocytes for cardiac repair is hampered by their immature phenotype and the presence of epigenetic and genetic changes.24,51,52 Resident and bone marrow cells and cortical bone-derived cells are considered as potential sources for differentiation to cardiac myocytes but lacking compelling evidence for cardiac myogenesis and perhaps exerting their salutary biological effects through paracrine mechanisms. 19,29,[53][54][55][56][57][58] Equally exciting and challenging are the discovery and characterization of other CPCs that could give raise to various cardiac cells types, including smooth muscle cells, endothelial cells, and fibroblasts. [59][60][61][62][63] An important problem to overcome is the multiple comorbidities and their comedications of ischemic heart disease patients with heart failure that may affect cytoprotective signaling triggered by the different stem cell, as well as survival and differentiation properties of such stem cells in the injured tissue. [64][65][66] Clearly, the rapid face of discoveries is dazzling and a complete coverage of the recent developments in cardiovascular stem cells would be beyond the scope of this article. We regret that many valuable works were not covered in part or at all included in the present overview on Recent Developments. Clinical Trials In Human PatientsThe ClinicalTrials.gov lists >1000 clinical trials including >600 studies in the United States alone that tests effects of various stem cells in human patients (http://www.clinicaltrials. gov/). The list includes 71 including 38 active clinical trials in patients with heart failure using various stem cells, such as adipose-derived, mesenchymal, human embryonic, autologous CD133 + and CD34 + stem cells among the others.18,67-74Autologous skeletal myoblasts were probably the first cell type used to regenerate functional myocardium. It was tested initially in a rabbit model of myocardial cryoinjury, which showed incorporation of the injected myoblasts and improved myocardial performance. 75 Subsequent observational studies were followed by randomized clinical trials in human patients with heart failure injected with autologous skele...

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“…These factors include the age of the organ, the pathological state, and the severity of the cardiac disease. 16,17) Additionally, insufficient oxygen supply provided by the existing capillary network further complicates the extent of the therapeutic benefit provided by stem/progenitor cells. …”

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Mechanical Stress Regulates Endothelial Progenitor Cell Angiogenesis Through VEGF Receptor Endocytosis

et al. 2016

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SummaryThe clinical goal of cell-based treatment for chronic heart failure is to coordinately reconstitute the cardiomyocytes and associated circulation environment including coronary resistance arteries, arterioles, and capillary profiles.1) This goal can be possibly achieved by implementing multipotent adult stem cells. However, it remains a challenge to modify the capillary network in the decompensated heart. A mechanical stress model was used in this study to mimic the hemodynamic and hormonal states of the decompensated heart in vitro. The angiogenesis role of endothelial progenitor cells (EPCs) under stress has been well-recognized in vascular repair. We investigated the molecular mechanisms of EPCs in this model. We found that expression of vascular endothelial growth factor (VEGF) in EPCs was significantly decreased by mechanical stress, and this effect was accompanied by a decrease in angiogenesis in vitro. Interestingly, the defective angiogenesis can be reversed by upregulating the membrane VEGF receptor (VEGFR) endocytosis. An atypical protein kinase C (aPKC) inhibitor can promote the VEGFR internalization in EPCs and enhance the formation of vascular networks. Thus, the upregulation of VEGFR endocytosis in EPCs could be a potential therapy for the cell-based treatment of chronic heart failure by enhancing the cardiomyocytes. (Int Heart J 2016; 57: 356-362) Key words: Cell-based treatment, Capillary network I n the last decade, several types of cells have been utilized in cell-based therapies to treat acute myocardial infarction and chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are a useful cell type that has been tested experimentally in patients with encouraging results.2-6) Kocher, et al 7) infused freshly isolated human EPCs into a nude rat model of myocardial ischemia and observed preservation of left ventricular (LV) function and inhibition of cardiac apoptosis. More than 10 clinical trials [4][5][6][8][9][10][11][12][13][14] have been performed to elucidate the therapeutic effects of EPCs. These studies have provided information regarding the feasibility of using EPCsbased therapy to promote vasculogenesis. Despite these promising results, the search for a means to reverse the negative remodeling associated with CHF remains a concern. 15) This search is complicated by numerous factors that influence the growth and behavior of harvested cells. These factors include the age of the organ, the pathological state, and the severity of the cardiac disease. 16,17) Additionally, insufficient oxygen supply provided by the existing capillary network further complicates the extent of the therapeutic benefit provided by stem/progenitor cells. Editorial p.268Currently, the means of modifying the regeneration and integrity of the capillary network in the failing and hypertrophied decompensated heart are limited clinically, and the underlying mechanism remains unclear. The viability, proliferation, migration, and angiogenesis of EPCs are four critical determinants of revascularization in...

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Human Cardiac Progenitor Cells Engineered With Pim-I Kinase Enhance Myocardial Repair

Cited by 142 publications

References 41 publications

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Recent Developments in Cardiovascular Stem Cells

Mechanical Stress Regulates Endothelial Progenitor Cell Angiogenesis Through VEGF Receptor Endocytosis

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