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3. Adult human cardiac stem cell supplementation effectively increases contractile function and maturation in human engineered cardiac tissues

Author

Murphy, Jack F, Mayourian, Joshua, Stillitano, Francesca, Munawar, Sadek, Broughton, Kathleen M, Agullo-Pascual, Esperanza, Sussman, Mark A, Hajjar, Roger J, Costa, Kevin D, and Turnbull, Irene C

Subjects
Regenerative Medicine, Cardiovascular, Heart Disease, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, Cardiac Myosins, Cell Differentiation, Collagen, Drug Combinations, Electric Stimulation, Humans, Induced Pluripotent Stem Cells, Laminin, Myocardial Contraction, Myocardium, Myocytes, Cardiac, Myosin Heavy Chains, Proteoglycans, Transcriptome, Troponin I, Human cardiac stem cells, Human engineered cardiac tissue, Contractility, Myocardial function, Cardiomyocyte maturation, Biological Sciences, Technology, Medical and Health Sciences
Abstract

BACKGROUND:Delivery of stem cells to the failing heart is a promising therapeutic strategy. However, the improvement in cardiac function in animal studies has not fully translated to humans. To help bridge the gap between species, we investigated the effects of adult human cardiac stem cells (hCSCs) on contractile function of human engineered cardiac tissues (hECTs) as a species-specific model of the human myocardium. METHODS:Human induced pluripotent stem cell-derived cardiomyoctes (hCMs) were mixed with Collagen/Matrigel to fabricate control hECTs, with an experimental group of hCSC-supplemented hECT fabricated using a 9:1 ratio of hCM to hCSC. Functional testing was performed starting on culture day 6, under spontaneous conditions and also during electrical pacing from 0.25 to 1.0 Hz, measurements repeated at days 8 and 10. hECTs were then frozen and processed for gene analysis using a Nanostring assay with a cardiac targeted custom panel. RESULTS:The hCSC-supplemented hECTs displayed a twofold higher developed force vs. hCM-only controls by day 6, with approximately threefold higher developed stress and maximum rates of contraction and relaxation during pacing at 0.75 Hz. The spontaneous beat rate characteristics were similar between groups, and hCSC supplementation did not adversely impact beat rate variability. The increased contractility persisted through days 8 and 10, albeit with some decrease in the magnitude of the difference of the force by day 10, but with developed stress still significantly higher in hCSC-supplemented hECT; these findings were confirmed with multiple hCSC and hCM cell lines. The force-frequency relationship, while negative for both, control (- 0.687 Hz- 1; p = 0.013 vs. zero) and hCSC-supplemented (- 0.233 Hz- 1;p = 0.067 vs. zero) hECTs, showed a significant rectification in the regression slope in hCSC-supplemented hECT (p = 0.011 vs. control). Targeted gene exploration (59 genes) identified a total of 14 differentially expressed genes, with increases in the ratios of MYH7/MHY6, MYL2/MYL7, and TNNI3/TNNI1 in hCSC-supplemented hECT versus controls. CONCLUSIONS:For the first time, hCSC supplementation was shown to significantly improve human cardiac tissue contractility in vitro, without evidence of proarrhythmic effects, and was associated with increased expression of markers of cardiac maturation. These findings provide new insights about adult cardiac stem cells as contributors to functional improvement of human myocardium.

Published
2019

6. Extracellular Vesicle–Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart

Author

Li, Xisheng, La Salvia, Sabrina, Liang, Yaxuan, Adamiak, Marta, Kohlbrenner, Erik, Jeong, Dongtak, Chepurko, Elena, Ceholski, Delaine, Lopez-Gordo, Estrella, Yoon, Seonghun, Mathiyalagan, Prabhu, Agarwal, Neha, Jha, Divya, Lodha, Shweta, Daaboul, George, Phan, Anh, Raisinghani, Nikhil, Zhang, Shihong, Zangi, Lior, Gonzalez-Kozlova, Edgar, Dubois, Nicole, Dogra, Navneet, Hajjar, Roger J., and Sahoo, Susmita

Published
2023
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7. Adducin Regulates Sarcomere Disassembly During Cardiomyocyte Mitosis.

Author

Feng Xiao, Ngoc Uyen Nhi Nguyen, Ping Wang, Shujuan Li, Ching-Cheng Hsu, Suwannee Thet, Wataru Kimura, Xiang Luo, Lam, Nicholas T., Menendez-Montes, Ivan, Elhelaly, Waleed M., Campos Cardoso, Alisson, Macedo Pereira, Ana Helena, Singh, Rohit, Sadayappan, Sakthivel, Kanchwala, Mohammed, Chao Xing, Ladha, Feria A., Hinson, J. Travis, and Hajjar, Roger J.

Published
2024
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8. Direct reprogramming induces vascular regeneration post muscle ischemic injury

Author

Kaur, Keerat, Hadas, Yoav, Kurian, Ann Anu, Żak, Magdalena M., Yoo, Jimeen, Mahmood, Asharee, Girard, Hanna, Komargodski, Rinat, Io, Toshiro, Santini, Maria Paola, Sultana, Nishat, Sharkar, Mohammad Tofael Kabir, Magadum, Ajit, Fargnoli, Anthony, Yoon, Seonghun, Chepurko, Elena, Chepurko, Vadim, Eliyahu, Efrat, Pinto, Dalila, Lebeche, Djamel, Kovacic, Jason C., Hajjar, Roger J., Rafii, Shahin, and Zangi, Lior

Published
2021
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9. Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Author

Bartunek, Jozef, Terzic, Andre, Davison, Beth A, Filippatos, Gerasimos S, Radovanovic, Slavica, Beleslin, Branko, Merkely, Bela, Musialek, Piotr, Wojakowski, Wojciech, Andreka, Peter, Horvath, Ivan G, Katz, Amos, Dolatabadi, Dariouch, El Nakadi, Badih, Arandjelovic, Aleksandra, Edes, Istvan, Seferovic, Petar M, Obradovic, Slobodan, Vanderheyden, Marc, Jagic, Nikola, Petrov, Ivo, Atar, Shaul, Halabi, Majdi, Gelev, Valeri L, Shochat, Michael K, Kasprzak, Jaroslaw D, Sanz-Ruiz, Ricardo, Heyndrickx, Guy R, Nyolczas, Noémi, Legrand, Victor, Guédès, Antoine, Heyse, Alex, Moccetti, Tiziano, Fernandez-Aviles, Francisco, Jimenez-Quevedo, Pilar, Bayes-Genis, Antoni, Hernandez-Garcia, Jose Maria, Ribichini, Flavio, Gruchala, Marcin, Waldman, Scott A, Teerlink, John R, Gersh, Bernard J, Povsic, Thomas J, Henry, Timothy D, Metra, Marco, Hajjar, Roger J, Tendera, Michal, Behfar, Atta, Alexandre, Bertrand, Seron, Aymeric, Stough, Wendy Gattis, Sherman, Warren, Cotter, Gad, and Wijns, William

Subjects
Heart Disease, Clinical Research, Clinical Trials and Supportive Activities, Cardiovascular, Stem Cell Research, Adult, Aged, Double-Blind Method, Female, Heart Failure, Humans, Male, Mesenchymal Stem Cell Transplantation, Middle Aged, Myocardial Ischemia, Prospective Studies, Treatment Outcome, Young Adult, Regenerative medicine, Cardiopoiesis, Cardiovascular disease, Stem cell, Target population, Disease severity, Marker, Precision medicine, CHART Program, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

AimsCardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.Methods and resultsThis multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.ConclusionThe primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Published
2017

15. Child Health Promotion in Underserved Communities: The FAMILIA Trial

Author

Fernandez-Jimenez, Rodrigo, Jaslow, Risa, Bansilal, Sameer, Santana, Maribel, Diaz-Munoz, Raquel, Latina, Jacqueline, Soto, Ana V., Vedanthan, Rajesh, Al-Kazaz, Mohamed, Giannarelli, Chiara, Kovacic, Jason C., Bagiella, Emilia, Kasarskis, Andrew, Fayad, Zahi A., Hajjar, Roger J., and Fuster, Valentin

Published
2019
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21. Gene Therapy for Cardiomyopathy associated with Duchenne Muscular Dystrophy in a Pig Model

Author

Bähr, Andrea, primary, Hoppmann, Petra, additional, Bozoglu, Tarik, additional, Stirm, Michael, additional, Luksch, Ina, additional, Ziegler, Tilman, additional, Hornaschewitz, Nadja, additional, Shrestha, Samjhana, additional, Shashikadze, Bachuki, additional, Stöckl, Jan, additional, Raad, Nour, additional, Blum, Helmut, additional, Krebs, Stefan, additional, Fröhlich, Thomas, additional, Baumgartner, Christine, additional, Nowak-Imialek, Monika, additional, Walter, Maggie, additional, Weber, Christian, additional, Engelhardt, Stefan, additional, Moretti, Alessandra, additional, Klymiuk, Nik, additional, Wurst, Wolfgang, additional, Laugwitz, Karl-Ludwig, additional, Hajjar, Roger J., additional, Wolf, Eckhard, additional, and Kupatt, Christian, additional

Published
2023
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22. Selective regulation of cyclic nucleotide phosphodiesterase PDE3A isoforms

Author

Vandeput, Fabrice, Szabo-Fresnais, Nicolas, Ahmad, Faiyaz, Kho, Changwon, Lee, Ahyoung, Krall, Judith, Dunlop, Allan, Hazel, Mark W, Wohlschlegel, James A, Hajjar, Roger J, Houslay, Miles D, Manganiello, Vincent C, and Movsesian, Matthew A

Subjects
Biochemistry and Cell Biology, Medical Physiology, Biomedical and Clinical Sciences, Biological Sciences, Cardiovascular, 1.1 Normal biological development and functioning, 14-3-3 Proteins, Binding Sites, Chromatography, Gel, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 3, Electrophoresis, Gel, Two-Dimensional, Enzyme Activation, HEK293 Cells, Humans, Immunoprecipitation, Isoenzymes, Isoproterenol, Myocardial Contraction, Myocytes, Cardiac, Phosphodiesterase 3 Inhibitors, Phosphorylation, Protein Kinase C, cAMP, protein-protein interactions, protein–protein interactions
Abstract

Inhibitors of cyclic nucleotide phosphodiesterase (PDE) PDE3A have inotropic actions in human myocardium, but their long-term use increases mortality in patients with heart failure. Two isoforms in cardiac myocytes, PDE3A1 and PDE3A2, have identical amino acid sequences except for a unique N-terminal extension in PDE3A1. We expressed FLAG-tagged PDE3A1 and PDE3A2 in HEK293 cells and examined their regulation by PKA- and PKC-mediated phosphorylation. PDE3A1, which is localized to intracellular membranes, and PDE3A2, which is cytosolic, were phosphorylated at different sites within their common sequence. Exposure to isoproterenol led to phosphorylation of PDE3A1 at the 14-3-3-binding site S312, whereas exposure to PMA led to phosphorylation of PDE3A2 at an alternative 14-3-3-binding site, S428. PDE3A2 activity was stimulated by phosphorylation at S428, whereas PDE3A1 activity was not affected by phosphorylation at either site. Phosphorylation of PDE3A1 by PKA and of PDE3A2 by PKC led to shifts in elution on gel-filtration chromatography consistent with increased interactions with other proteins, and 2D electrophoresis of coimmunoprecipitated proteins revealed that the two isoforms have distinct protein interactomes. A similar pattern of differential phosphorylation of endogenous PDE3A1 and PDE3A2 at S312 and S428 is observed in human myocardium. The selective phosphorylation of PDE3A1 and PDE3A2 at alternative sites through different signaling pathways, along with the different functional consequences of phosphorylation for each isoform, suggest they are likely to have distinct roles in cyclic nucleotide-mediated signaling in human myocardium, and raise the possibility that isoform-selective inhibition may allow inotropic responses without an increase in mortality.

Published
2013

23. Contributors

Author

Agostoni, Pierfrancesco, primary, Landesberg, Amir, additional, Balkan, Wayne, additional, Banerjee, Monisha, additional, Banks, C. Adam, additional, Barac, Yaron, additional, Barker, Colin M., additional, Bejjanki, Harini, additional, Besola, Laura, additional, Bouten, C.V.C., additional, Bridges, Charles R, additional, Budassi, Simone, additional, Burkhoff, Daniel, additional, Burzotta, Francesco, additional, Cherian, Tharian S., additional, Chour, Tony, additional, Christman, Karen L., additional, Cleveland, David, additional, Colli, Andrea, additional, Cooper, David K.C., additional, Davis, Darryl R, additional, Ekser, Burcin, additional, Fargnoli, Anthony S, additional, Fiocco, Alessandro, additional, Folino, Giulio, additional, Gössl, Mario, additional, Garbutt, Tiffany A., additional, Gerosa, Gino, additional, Gheorghe, Livia, additional, Gubara, Sarah M, additional, Hahn, Rebecca T., additional, Hajjar, Roger J, additional, Hamid, Nadira, additional, Hara, Hidetaka, additional, Hare, Joshua M., additional, Hochman-Mendez, Camila, additional, Iwase, Hayato, additional, Jebran, Ahmad-Fawad, additional, Katz, Michael G, additional, Kazory, Amir, additional, Kliger, Chad, additional, Klouda, L., additional, Koratala, Abhilash, additional, Kutschka, Ingo, additional, Lee, Po-Feng, additional, Lenneman, Andrew J., additional, Lilly, Scott M., additional, Liu, Jiandong, additional, Lurier, E.B., additional, Marbán, Eduardo, additional, Nadali, Matteo, additional, Neofytou, Evgenios, additional, Nijenhuis, Vincent J, additional, Pagani, Francis D., additional, Pirelli, Luigi, additional, Prabhu, Sumanth D., additional, Pradegan, Nicola, additional, Qian, Li, additional, Rajapreyar, Indranee N., additional, Reardon, Michael J., additional, Russo, Giulio, additional, Sampaio, Luiz C., additional, Sorajja, Paul, additional, Tang, Liang, additional, Taylor, Doris A., additional, Topaz, Guy, additional, Trani, Carlo, additional, Trapana, Justin, additional, Tung, Roderick, additional, Nussinovitch, Udi, additional, Upadhyay, Gaurav A., additional, Uzendu, Anezi, additional, van der Heyden, Jan, additional, Vigliani, Marguerite B., additional, Wang, Raymond M., additional, Watt, Tessa M.F., additional, Wu, Joseph C., additional, Feld, Yair, additional, Zimmermann, Wolfram-Hubertus, additional, and Zivelonghi, Carlo, additional

Published
2020
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25. Gene Therapy in Heart Failure

Author

Fargnoli, Anthony S., Katz, Michael G., Bridges, Charles R., Hajjar, Roger J., Barrett, James E., Editor-in-chief, Flockerzi, Veit, Series editor, Frohman, Michael A., Series editor, Geppetti, Pierangelo, Series editor, Hofmann, Franz B., Series editor, Michel, Martin C., Series editor, Page, Clive P, Series editor, Rosenthal, Walter, Series editor, Wang, KeWei, Series editor, Bauersachs, Johann, editor, Butler, Javed, editor, and Sandner, Peter, editor

Published
2017
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28. Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes

Author

Ceholski, Delaine K., Turnbull, Irene C., Kong, Chi-Wing, Koplev, Simon, Mayourian, Joshua, Gorski, Przemek A., Stillitano, Francesca, Skodras, Angelos A., Nonnenmacher, Mathieu, Cohen, Ninette, Björkegren, Johan L.M., Stroik, Daniel R., Cornea, Razvan L., Thomas, David D., Li, Ronald A., Costa, Kevin D., and Hajjar, Roger J.

Published
2018
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29. HAX-1 regulates SERCA2a oxidation and degradation

Author

Bidwell, Philip A., Liu, Guan-Sheng, Nagarajan, Narayani, Lam, Chi Keung, Haghighi, Kobra, Gardner, George, Cai, Wen-Feng, Zhao, Wen, Mugge, Luke, Vafiadaki, Elizabeth, Sanoudou, Despina, Rubinstein, Jack, Lebeche, Djamel, Hajjar, Roger, Sadoshima, Junichi, and Kranias, Evangelia G.

Published
2018
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33. Shrink‐Film Configurable Multiscale Wrinkles for Functional Alignment of Human Embryonic Stem Cells and their Cardiac Derivatives

Author

Chen, Aaron, Lieu, Deborah K, Freschauf, Lauren, Lew, Valerie, Sharma, Himanshu, Wang, Jiaxian, Nguyen, Diep, Karakikes, Ioannis, Hajjar, Roger J, Gopinathan, Ajay, Botvinick, Elliot, Fowlkes, Charless C, Li, Ronald A, and Khine, Michelle

Subjects
Engineering, Chemical Sciences, Physical Sciences, Cardiovascular, Regenerative Medicine, Stem Cell Research, Stem Cell Research - Embryonic - Non-Human, Heart Disease, Action Potentials, Animals, Biomimetics, Cell Differentiation, Cells, Cultured, Embryonic Stem Cells, Equipment Design, Flow Cytometry, Humans, Materials Testing, Mice, Myocardium, Myocytes, Cardiac, Rats, Stem Cells, Surface Properties, biomimetics, human embryonic stem cell derived cardiomyocytes, contact guidance, action potential propagation, Nanoscience & Nanotechnology, Chemical sciences, Physical sciences
Abstract

A biomimetic substrate for cell-culture is fabricated by plasma treatment of a prestressed thermoplastic shrink film to create tunable multiscaled alignment "wrinkles". Using this substrate, the functional alignment of human embryonic stem cell derived cardiomyocytes is demonstrated.

Published
2011

34. Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes.

Author

Fu, Ji-Dong, Rushing, Stephanie N, Lieu, Deborah K, Chan, Camie W, Kong, Chi-Wing, Geng, Lin, Wilson, Kitchener D, Chiamvimonvat, Nipavan, Boheler, Kenneth R, Wu, Joseph C, Keller, Gordon, Hajjar, Roger J, and Li, Ronald A

Subjects
Heart Ventricles, Cell Line, Myocytes, Cardiac, Fetus, Animals, Humans, Mice, Calcium, MicroRNAs, Cell Differentiation, Ventricular Function, Adult, Embryonic Stem Cells, Electrophysiological Phenomena, Myocytes, Cardiac, General Science & Technology
Abstract

BackgroundMicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive.Methods and resultsWe hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p

Published
2011

46. Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration

Author

Magadum, Ajit, Singh, Neha, Kurian, Ann Anu, Munir, Irsa, Mehmood, Talha, Brown, Kemar, Sharkar, Mohammad Tofael Kabir, Chepurko, Elena, Sassi, Yassine, Oh, Jae Gyun, Lee, Philyoung, Santos, Celio X.C., Gaziel-Sovran, Avital, Zhang, Guoan, Cai, Chen-Leng, Kho, Changwon, Mayr, Manuel, Shah, Ajay M., Hajjar, Roger J., and Zangi, Lior

Published
2020
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47. Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction

Author

Hadas, Yoav, Vincek, Adam S., Youssef, Elias, Żak, Magdalena M., Chepurko, Elena, Sultana, Nishat, Sharkar, Mohammad Tofael Kabir, Guo, Ningning, Komargodski, Rinat, Kurian, Ann Anu, Kaur, Keerat, Magadum, Ajit, Fargnoli, Anthony, Katz, Michael G., Hossain, Nadia, Kenigsberg, Ephraim, Dubois, Nicole C., Schadt, Eric, Hajjar, Roger, Eliyahu, Efrat, and Zangi, Lior

Published
2020
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