121 results on '"Kannappan R"'
Search Results
2. Magnetic, catalytic, EPR and electrochemical studies on binuclear copper(II) complexes derived from 3,4-disubstituted phenol
- Author
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Kannappan, R., Mahalakshmy, R., Rajendiran, T. M., Venkatesan, R., and Rao, P. Sambasiva
- Published
- 2003
- Full Text
- View/download PDF
3. Synthesis and physiochemical studies on binuclear Cu(II) complexes derived from 2,6-[(N-phenylpiperazin-1-yl)methyl]-4-substituted phenols
- Author
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Karthikeyan, S., Rajendiran, T. M., Kannappan, R., Mahalakshmy, R., Venkatesan, R., and Rao, P. Sambasiva
- Published
- 2001
- Full Text
- View/download PDF
4. Exogenous bridging and nonbridging in Cu(II) complexes of Mannich base ligands: Synthesis and physical properties
- Author
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Sujatha, S, Rajendiran, T M, Kannappan, R, Venkatesan, R, and Rao, P Sambasiva
- Published
- 2000
- Full Text
- View/download PDF
5. Abstract
- Author
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Balakrishnarajan, M. M., Jemmis, Eluvathingal D, Gupta, Sayan, Mazumdar, Shyamalava, Mukherjee, Pulakesh, Machonkin, Tim, Dubois, Jennifer L, Cole, Adam P, Hedman, Britt, Hodgson, Keith O, Solomon, Edward I, Stack, T. D. P., Roesky, Herbert W, Manoharan, P. T., Baitalik, Sujoy, Nag, Kamalaksha, Sarkar, Sabyasachi, Seshadri, Ram, Felser, Claudia, Nixon, John F, Katti, Kattesh V, Pillarsetty, Nagavarakishore, Kamei, Hideo, Bora, Upasana, Chaudhuri, Mihir K., Dhar, Sidhartha S., Kalita, Dipak, Anand, B. N., Ramanan, A., Roy, Prasun, Duraisamy, T., Sharma, Sanjeev, Ayyappan, P., Gupta, B. D., Kanth, V. Vijai, Singh, Veena, Suresh, Eringathodi, Boopalan, Kamla, Jasra, Raksh Vir, Bhadbhade, Mohan Madhav, Naganagowda, G. A., Ramanathan, K. V., Gayathri, V., Nanjegowda, N. M., Sengupta, P., Ghosh, S., Bhattacharjee, Manish, Gupta, Shamayita Sen, Datta, Riya, Sastri, C. V., Easwaramoorthy, D., Lakshmi, Athi, Giribabu, L., Maiya, B. G., Reddy, P. Rabindra, Radhika, M., Nightingale, K. Florence, Srinivasan, R., Venkatesan, R., Rajendiran, T. M., Sambasiva Rao, P., Bhavana, P., Bhyrappa, P., Ravikanth, M., Kumaraswamy, Sudha, Kommana, Praveen, Padmaja, G., Kumara Swamy, K. C., Mondal, B., Chakraborty, S., Lahiri, G. K., Ray, Manabendra, Que, Lawrence, Saxena, Anubhav, Sampriya, N., Brar, A. S., Shankar, Ravi, Sahoo, B. B., Panday, G., Wasthi, A. A., Chauhan, S. M. S., Wadhwani, Parvesh, Bandyopadhyay, Deb Kumar, Bandyopadhyay, Ratna, Biswas, Sudeb, Bhattacharyya, Ramgopal, Johis, Vishwas, Kotkar, Dilip, Pathak, Vinit S., Swayambhunathan, V., Kamat, Prashant, Das, Amitava, Ghosh, Pushpito K., Gupta, Rajeev, Mukherjee, Rabindranath, Walawalkar, M. G., Pal, Sushanta K., Krishnan, Anu, Samuelson, A. G., Das, Puspendu K., Anantharaman, G., Baheti, Kanhayalal, Murugavel, R., Garg, Gunjan, Ganguli, Ashok K., Suresh, M., Prasadarao, A. V., Neeraj, S., Natarajan, Srinivasan, Rao, C. N. R., Vanitha, P. V., Santhosh, P. N., Rao, C. N. R., Kumar, G. Girish, Munichandraiah, N., Ramakrishna, T. V. V., Elias, Anil J., Vij, Ashwani, Rajak, Kajal Krishna, Rath, Sankar Prasad, Dutta, Sujit, Bhattacharya, P. K., Natarajan, P., Paul, P., Dhanasekaran, T., Prakash, H., Mangayarkarasi, N., Zacharias, P. S., Srinivasan, A., Pushpan, Simi K, Anand, V. G., Chandrashekar, T. K., Tripathi, Punam, Som, Abhigyan, Bharadwaj, Parimal K., Mathew, Nisha, Jagirdar, Balaji R., Mandal, Swadhin K., Naganagowda, G. A., Krishnamurthy, Setharampattu S., Singh, Udai P., Singh, R., Hikichi, S., Moro-Oka, Y., Sevagapandian, S., Nehru, K., Athappan, P. R., Murali, Mariappan, Palaniandavar, Mallayan, Singh, Rajkumar Bhubon, Mitra, Samiran, Reddy, Pattubala A. N., Datta, Riya, Chakravarty, Akhil R., Sunkari, Sailaja, Rajasekharan, M. V., Shukla, Atindra D., Bajaj, H. C., Das, Amitava, Krishnamurthy, Divya, Sathiyendiran, M., Murugavel, R., Rao, K. Mohan, Boag, N. M., Neogi, D. N., Bhawmick, R., Bandyopadhyay, P., Thomas, A. M., Mandal, G. C., Tiwary, S. K., Chakravarty, A. R., Sah, Ajay Kumar, Das, T. Mohan, Wegelius, E. K., Kolehmainen, E., Saarenketo, P. K., Rissanen, K., Rao, Chebrolu P., Warad, D. U., Satish, C. D., Bajgur, Chandrasekhar S., Manonmani, J., Narayanan, V., Kandaswamy, M., Kingston, J. Vijeyakumar, Sundaram, G. S. M., Rao, M. N. Sudheendra, Rajendiran, T. M., Kannappan, R., Venkatesan, R., Rao, P. Sambasiva, Bilakhiya, Anvarhusen K., Tyagi, Beena, Paul, Parimal, Dhar, Siddhartha D., Chaudhuri, Mihir K., Ghosh, Tamal, Banerjee, Rupendranath, Kureshy, R. I., Khan, N. H., Abdi, S. H. R., Patel, S. T., Iyer, P., Jasra, R. V., Chatterjee, Debabrata, Mitra, Anannya, Mukherjee, Sanghamitra, Ganesan, V., Ramaraj, R., Shunmugasundari, T., Thanasekaran, P., Rajagopal, S., Bohra, R., Sharma, Nikita, Nagar, S., Panda, Rashmishree, Balakrishna, M. S., Vaidhyanathan, R., Natarajan, S., Rao, C. N. R., Choudhury, Amitava, Natarajan, Srinivasan, Rao, C. N. R., Chakrabarty, Debojit, Mahapatra, Samiran, Devi, M. Suseela, Vidyasagar, K., Mody, Haresh M., Pandya, Priti, Bhatt, Prashant, Jasra, Raksh Vir, Padmanabhan, M., Mathew, Tessymol, Shukla, Atindra D., Dave, Paresh C., Suresh, Eringathodi, Pathak, Gopal, Das, Amitava, Dastidar, Parthasarathi, Mahalakshmi, L., Krishnamurthy, S. S., Nethaji, M., Rath, Nibedita, Mathew, Nisha, Jagirdhar, Balajir, Gopalan, R. Srinivasa, Kulkarni, G. U., Sridevi, S., Narayanan, Jeyaprakash, Chandrashekar, T. K., Saha, Amrita, Ghosh, Amit K., Majumdar, Partha, Goswami, Sreebrata, Abhyankar, Rita M., Balakrishna, M. S., Basuli, Falguni, Bhattacharya, Samaresh, Mondal, N., Saha, M. K., Bag, B., Mitra, S., Pal, Satyanarayan, Sangeetha, Nimma Rajaiah, Pal, Samudranil, Dey, Mishtu, Saarenketo, P. K., Kolehmainen, E., Rissanen, K., Rao, Chebrolu P., Suresh, E., Bhadbhade, Mohan M., Padmakumar, K., Manoharan, P. T., Vernekar, Beena, Srinivasan, B. R., Ramesh, K., Bharathi, D. Saravana, Samuelson, Ashoka G., Lokanath, N. K., Shridhar, M. A., Prasad, Sashidara, Venkatraman, N. V., Vasudevan, S., Mimani, T., Patil, K. C., Tiwari, A. P., Mukkada, B. J., Arunan, E., Mathias, P. C., Abraham, B., Karthikeyan, B., Pal, Sushanta K., Samuelson, A. G., Umapathy, S., Panda, Pradeepta K., and Krishnan, V.
- Published
- 2000
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6. Response to letter regarding article, 'growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery'
- Author
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D'Amario, Domenico, Leone, Antonio Maria, Iaconielli, Antonio, Luciani, Nicola, Gaudino, Mario Fulvio Luigi, Kannappan, R, Manchi, Melissa, Severino, Anna, Shin, Sh, Graziani, Francesca, Biasillo, Gina, Macchione, Andrea, Smaldone, Costantino, Cellini, Carlo, Siracusano, Andrea, Ottaviani, L, Massetti, Massimo, Goichberg, P, Leri, Annarosa, Anversa, Piero, Crea, Filippo, Leone, Antonio Maria (ORCID:0000-0002-1276-9883), Luciani, Nicola (ORCID:0000-0002-9407-0303), Gaudino, Mario Fulvio Luigi (ORCID:0000-0001-7529-438X), Graziani, Francesca (ORCID:0000-0002-4520-5689), Massetti, Massimo (ORCID:0000-0002-7100-8478), Crea, Filippo (ORCID:0000-0001-9404-8846), D'Amario, Domenico, Leone, Antonio Maria, Iaconielli, Antonio, Luciani, Nicola, Gaudino, Mario Fulvio Luigi, Kannappan, R, Manchi, Melissa, Severino, Anna, Shin, Sh, Graziani, Francesca, Biasillo, Gina, Macchione, Andrea, Smaldone, Costantino, Cellini, Carlo, Siracusano, Andrea, Ottaviani, L, Massetti, Massimo, Goichberg, P, Leri, Annarosa, Anversa, Piero, Crea, Filippo, Leone, Antonio Maria (ORCID:0000-0002-1276-9883), Luciani, Nicola (ORCID:0000-0002-9407-0303), Gaudino, Mario Fulvio Luigi (ORCID:0000-0001-7529-438X), Graziani, Francesca (ORCID:0000-0002-4520-5689), Massetti, Massimo (ORCID:0000-0002-7100-8478), and Crea, Filippo (ORCID:0000-0001-9404-8846)
- Abstract
N/A
- Published
- 2014
7. Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery
- Author
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D'Amario, Domenico, Leone, Am, Iaconelli, Amerigo, Luciani, Nicola, Gaudino, Mario Fulvio Luigi, Kannappan, R, Manchi, Melissa, Severino, Anna, Shin, Sh, Graziani, Francesca, Biasillo, Gina, Macchione, Andrea, Smaldone, Costantino, De Maria, Gl, Cellini, Carlo, Siracusano, A, Ottaviani, L, Massetti, Massimo, Goichberg, P, Leri, A, Anversa, P, Crea, Filippo, Luciani, Nicola (ORCID:0000-0002-9407-0303), Gaudino, Mario Fulvio Luigi (ORCID:0000-0001-7529-438X), Graziani, Francesca (ORCID:0000-0002-4520-5689), Massetti, Massimo (ORCID:0000-0002-7100-8478), Crea, Filippo (ORCID:0000-0001-9404-8846), D'Amario, Domenico, Leone, Am, Iaconelli, Amerigo, Luciani, Nicola, Gaudino, Mario Fulvio Luigi, Kannappan, R, Manchi, Melissa, Severino, Anna, Shin, Sh, Graziani, Francesca, Biasillo, Gina, Macchione, Andrea, Smaldone, Costantino, De Maria, Gl, Cellini, Carlo, Siracusano, A, Ottaviani, L, Massetti, Massimo, Goichberg, P, Leri, A, Anversa, P, Crea, Filippo, Luciani, Nicola (ORCID:0000-0002-9407-0303), Gaudino, Mario Fulvio Luigi (ORCID:0000-0001-7529-438X), Graziani, Francesca (ORCID:0000-0002-4520-5689), Massetti, Massimo (ORCID:0000-0002-7100-8478), and Crea, Filippo (ORCID:0000-0001-9404-8846)
- Abstract
BACKGROUND: The efficacy of bypass surgery in patients with ischemic cardiomyopathy is not easily predictable; preoperative clinical conditions may be similar, but the outcome may differ significantly. We hypothesized that the growth reserve of cardiac stem cells (CSCs) and circulating cytokines promoting CSC activation are critical determinants of ventricular remodeling in this patient population. METHODS AND RESULTS: To document the growth kinetics of CSCs, population-doubling time, telomere length, telomerase activity, and insulin-like growth factor-1 receptor expression were measured in CSCs isolated from 38 patients undergoing bypass surgery. Additionally, the blood levels of insulin-like growth factor-1, hepatocyte growth factor, and vascular endothelial growth factor were evaluated. The variables of CSC growth were expressed as a function of the changes in wall thickness, chamber diameter and volume, ventricular mass-to-chamber volume ratio, and ejection fraction, before and 12 months after surgery. A high correlation was found between indices of CSC function and cardiac anatomy. Negative ventricular remodeling was not observed if CSCs retained a significant growth reserve. The high concentration of insulin-like growth factor-1 systemically pointed to the insulin-like growth factor-1-insulin-like growth factor-1 receptor system as a major player in the adaptive response of the myocardium. hepatocyte growth factor, a mediator of CSC migration, was also high in these patients preoperatively, as was vascular endothelial growth factor, possibly reflecting the vascular growth needed before bypass surgery. Conversely, a decline in CSC growth was coupled with wall thinning, chamber dilation, and depressed ejection fraction. CONCLUSIONS: The telomere-telomerase axis, population-doubling time, and insulin-like growth factor-1 receptor expression in CSCs, together with a high circulating level of insulin-like growth factor-1, represent a novel biomarker able to predict
- Published
- 2014
8. Separation of actinides and lanthanides: Synthesis and molecular structure of a new di-μ-phenoxo-bridged dinuclear bis(dioxouranium(VI)) complex
- Author
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Kannappan, R, Tooke, D.M., Spek, A.L., Reedijk, J., R¿ntgenparticipatieprogramma, and Dep Scheikunde
- Subjects
International (English) - Published
- 2006
9. An alternating chain of spider-like tris(peptides) stabilized by stacking and by N-H...N and N-H...O=C hydrogen bonding
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Kannappan, R, Tooke, D.M., Spek, A.L., Reedijk, J., R¿ntgenparticipatieprogramma, Universiteit Utrecht, and Dep Scheikunde
- Subjects
International - Published
- 2005
10. (2-Pyridylmethyl)ammonium nitrate
- Author
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Tooke, D.M., Spek, A.L., Reedijk, J., Kannappan, R, R¿ntgenparticipatieprogramma, Universiteit Utrecht, and Dep Scheikunde
- Subjects
International - Published
- 2004
11. Separation of actinides and lanthanides: crystal and molecular structures of N,N'-bis(3,5-di-t-butylsalicylidene)-4,5-dimethyl-1,2-phenylenediamine and its uranium complex
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Kannappan, R, Tanase, S., Tooke, D.M., Spek, A.L., Mutikainen, I., Turpeinen, U., Reedijk, J., R¿ntgenparticipatieprogramma, Universiteit Utrecht, and Dep Scheikunde
- Subjects
International - Published
- 2004
12. Selection of Chiral Zinc Catalysts for the Kinetic Resolution of Esters via Dynamic Templating
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Kannappan, R., primary and Nicholas, K. M., additional
- Published
- 2013
- Full Text
- View/download PDF
13. An alternating chain of spider-like tris(peptides) stabilized by stacking and by N-H...N and N-H...O=C hydrogen bonding
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R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Kannappan, R, Tooke, D.M., Spek, A.L., Reedijk, J., R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Kannappan, R, Tooke, D.M., Spek, A.L., and Reedijk, J.
- Published
- 2005
14. Separation of actinides and lanthanides: crystal and molecular structures of N,N'-bis(3,5-di-t-butylsalicylidene)-4,5-dimethyl-1,2-phenylenediamine and its uranium complex
- Author
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R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Kannappan, R, Tanase, S., Tooke, D.M., Spek, A.L., Mutikainen, I., Turpeinen, U., Reedijk, J., R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Kannappan, R, Tanase, S., Tooke, D.M., Spek, A.L., Mutikainen, I., Turpeinen, U., and Reedijk, J.
- Published
- 2004
15. (2-Pyridylmethyl)ammonium nitrate
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R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Tooke, D.M., Spek, A.L., Reedijk, J., Kannappan, R, R¿ntgenparticipatieprogramma, Universiteit Utrecht, Dep Scheikunde, Tooke, D.M., Spek, A.L., Reedijk, J., and Kannappan, R
- Published
- 2004
16. NF-κB addiction and its role in cancer: ‘one size does not fit all’
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Chaturvedi, M M, primary, Sung, B, additional, Yadav, V R, additional, Kannappan, R, additional, and Aggarwal, B B, additional
- Published
- 2010
- Full Text
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17. Jatropha Biodiesel Development And Characterization For Use As A Fuel In Compression Ignition Engines
- Author
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Manjula, P, primary, Manoharan, N, additional, Palanisamy, E, additional, and Kannappan, R, additional
- Published
- 2009
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18. Identification and Characterization of Cathepsin D in a Highly Purified Sialidase from Starfish A. pectinifera
- Author
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Kannappan, R., primary, Satoh, Y., additional, Iriyama, N., additional, Ando, M., additional, Sawada, M. T., additional, Takahashi, N., additional, Furuhata, K., additional, and Uda, Y., additional
- Published
- 2007
- Full Text
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19. Preparation and properties of a triply bridged antiferromagnetically coupled binuclear copper(II) complex [Cu2L(OAc)2]ClO4 {L=2,6-bis[(N-methyl piperazin-1-yl) methyl]-4-bromo phenol}
- Author
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Rajendiran, T.M, primary, Kannappan, R, additional, Venkatesan, R, additional, Sambasiva Rao, P, additional, and Kandaswamy, M, additional
- Published
- 1999
- Full Text
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20. Intervention Program for the Prevention of Alcohol Abuse
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Kannappan, R., primary
- Published
- 1993
- Full Text
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21. Hydrodynamics and mass transport in rotary disk contactors.
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Laddha, G. S., Degaleesan, T. E., and Kannappan, R.
- Published
- 1978
- Full Text
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22. Hydrogel Biosensor Array Platform Indexed by Shape
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Meiring, J. E., Schmid, M. J., Grayson, S. M., Rathsack, B. M., Johnson, D. M., Kirby, R., Kannappan, R., Manthiram, K., Hsia, B., Hogan, Z. L., Ellington, A. D., Pishko, M. V., and Willson, C. G.
- Abstract
A multi-analyte sensor array platform has been developed which consists of analyte specific features that are indexed by shape. The array features are batch-fabricated lithographically from poly(ethylene glycol) diacrylate hydrogel pre-polymer and can accommodate a wide variety of different sensing chemistries. Depending on the physical scale of the sensing moiety, it is either copolymerized to the hydrogel matrix (e.g., oligonucleotides, aptamers), or it is merely physically encapsulated, an important strategy for preserving the biological activity of the larger and more complex sensing elements (e.g., antibodies, proteins, cells). This three-dimensional hydrogel sensor platform has an advantage over two-dimensional platforms in that it offers an increased signal density, and because the array is constructed of poly(ethylene glycol), it has virtually no background noise due to nonspecific adsorption of labeled analytes. To highlight the capabilities of this platform to make high signal-to-noise measurements using diverse sensing chemistries, two demonstrations are described herein that illustrate the platform's efficacy in oligonucleotide sensing and cell-based sensing.
- Published
- 2004
23. Screening Test and Alcoholism
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Kannappan, R.
- Published
- 1988
- Full Text
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24. Neuroprotection by spice-derived nutraceuticals: You are what you eat.
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Kannappan, R., Gupta, SC., Kim, JH., Reuter, S., and Aggarwal, BB.
- Published
- 2014
- Full Text
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25. Myocyte repolarization modulates myocardial function in aging dogs
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David A. D'Alessandro, Marco Luciani, Thomas H. Hintze, Giulia Borghetti, Ewa Wybieralska, Edward G. Barrett, Khaled Qanud, Maria Cimini, Christopher Royer, Polina Goichberg, Alex Matsuda, Elizabeth Kertowidjojo, Eric Zhang, Yu Zhou, Andrea Sorrentino, Ramaswamy Kannappan, Piero Anversa, Antonio Cannatà, Andrew Webster, Annarosa Leri, Marianna Meo, Oriyanhan Wunimenghe, Marcello Rota, Sergio Signore, Robert E. Michler, and Sorrentino A, Signore S, Qanud K, Borghetti G, Meo M, Cannata A, Zhou Y, Wybieralska E, Luciani M, Kannappan R, Zhang E, Matsuda A, Webster A, Cimini M, Kertowidjojo E, D'Alessandro DA, Wunimenghe O, Michler RE, Royer C, Goichberg P, Leri A, Barrett EG, Anversa P, Hintze TH, Rota M
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Male ,0301 basic medicine ,Inotrope ,Aging ,medicine.medical_specialty ,Physiology ,Population ,Action Potentials ,Hemodynamics ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Ventricular hypertrophy ,contractile reserve ,Physiology (medical) ,Internal medicine ,myocardium ,medicine ,Animals ,Ventricular Function ,Myocyte ,Repolarization ,Myocytes, Cardiac ,Decompensation ,Myopathy ,education ,education.field_of_study ,medicine.disease ,030104 developmental biology ,Endocrinology ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Muscle Mechanics and Ventricular Function - Abstract
Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.
- Published
- 2016
26. Age-Associated Defects in EphA2 Signaling Impair the Migration of Human Cardiac Progenitor Cells
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Ramaswamy Kannappan, Maria Cimini, Polina Goichberg, Andrea Sorrentino, Jan Kajstura, Yingnan Bai, Marcello Rota, Annarosa Leri, Fumihiro Sanada, Sergio Signore, Piero Anversa, and Goichberg P, Kannappan R, Cimini M, Bai Y, Sanada F, Sorrentino A, Signore S, Kajstura J, Rota M, Anversa P, Leri A
- Subjects
Male ,Aging ,business.industry ,Regeneration (biology) ,Myocardium ,Receptor, EphA2 ,Motility ,EPH receptor A2 ,Article ,Cell biology ,Adult Stem Cells ,stem cells ,Cell Movement ,Physiology (medical) ,Medicine ,Ephrin ,Humans ,Female ,Signal transduction ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Ex vivo ,Adult stem cell ,Signal Transduction - Abstract
BACKGROUND: Aging negatively impacts on the function of resident human cardiac progenitor cells (hCPCs). Effective regeneration of the injured heart requires mobilization of hCPCs to the sites of damage. In the young heart, signaling by the guidance receptor EphA2 in response to the ephrin A1 ligand promotes hCPC motility and improves cardiac recovery after infarction. METHODS AND RESULTS: We report that old hCPCs are characterized by cell-autonomous inhibition of their migratory ability ex vivo and impaired translocation in vivo in the damaged heart. EphA2 expression was not decreased in old hCPCs; however, the elevated level of reactive oxygen species in aged cells induced post-translational modifications of the EphA2 protein. EphA2 oxidation interfered with ephrin A1-stimulated receptor auto-phosphorylation, activation of Src family kinases, and caveolin-1-mediated internalization of the receptor. Cellular aging altered the EphA2 endocytic route, affecting the maturation of EphA2-containing endosomes and causing premature signal termination. Overexpression of functionally intact EphA2 in old hCPCs corrected the defects in endocytosis and downstream signaling, enhancing cell motility. Based on the ability of phenotypically young hCPCs to respond efficiently to ephrin A1, we developed a novel methodology for the prospective isolation of live hCPCs with preserved migratory capacity and growth reserve. CONCLUSIONS: Our data demonstrate that the ephrin A1/EphA2 pathway may serve as a target to facilitate trafficking of hCPCs in the senescent myocardium. Importantly, EphA2 receptor function can be implemented for the selection of hCPCs with high therapeutic potential, a clinically relevant strategy that does not require genetic manipulation of stem cells.
- Published
- 2013
27. Rhabdomyolysis associated with tapentadol abuse.
- Author
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Kannappan R, Pasupuleti MR, Sibbala B, and Venugopal S
- Abstract
Competing Interests: There are no conflicts of interest.
- Published
- 2024
- Full Text
- View/download PDF
28. A Review of Myositis-Associated Interstitial Lung Disease.
- Author
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Kannappan R, Kumar R, Cichelli K, and Brent LH
- Abstract
There is a well-established relationship between different subsets of idiopathic inflammatory myopathies (IIMs, myositis) and interstitial lung disease (ILD), with lung complications sometimes presenting prior to myopathic manifestations. The subtypes of myositis include those that are strongly associated with ILD, such as polymyositis (PM) and dermatomyositis (DM). Research has shown that in certain patients, these can then be further divided into subtypes using myositis-specific antibodies (MSAs), which are specific for myositis, and myositis-associated antibodies (MAAs), which can be found in myositis in overlap syndromes with other connective tissue diseases (CTDs). Notably, certain MSAs and MAAs are associated with ILD in patients with myositis. The clinical presentations of ILD in patients with myositis can vary widely and can be insidious in onset and difficult to diagnose. As ILD can progress rapidly in some cases, it is essential that clinicians are able to identify and diagnose ILD in patients with myositis. For this reason, the aim of this review is to highlight the clinical features, diagnostic criteria, important histopathologic, laboratory, and radiographic features, and treatment modalities for those patients with myositis-associated ILD.
- Published
- 2024
- Full Text
- View/download PDF
29. Chronic Δ9-tetrahydrocannabinol treatment has dose-dependent effects on open field exploratory behavior and [ 3 H] SR141716A receptor binding in the rat brain.
- Author
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Freeman-Striegel L, Hamilton J, Kannappan R, Bell T, Robison L, and Thanos PK
- Subjects
- Rats, Animals, Rimonabant metabolism, Rimonabant pharmacology, Rats, Sprague-Dawley, Exploratory Behavior, Brain metabolism, Dronabinol pharmacology, Cannabinoids pharmacology
- Abstract
Aims: Acute and chronic Δ
9 -THC exposure paradigms affect the body differently. More must be known about the impact of chronic Δ9 -THC on cannabinoid-1 (CB1R) and mu-opioid (MOR) receptor levels in the brain. The present study examined chronic Δ9 -THC's effects on CB1R and MOR levels and locomotor activity., Main Methods: Adolescent Sprague-Dawley rats were given daily intraperitoneal injections of Δ9 -THC [0.75mg/kg (low dose or LD) or 2.0 mg/kg (high dose or HD)] or vehicle for 24 days, and locomotion in the open field was tested after the first and fourth weeks of chronic Δ9 -THC exposure. Brains were harvested at the end of treatment. [3 H] SR141716A and [3 H] DAMGO autoradiography assessed CB1R and MOR levels, respectively., Key Findings: Relative to each other, chronic HD rats showed reduced vertical plane (VP) entries and time, while LD rats had increased VP entries and time for locomotion, as assessed by open-field testing; no effects were found relative to the control. Autoradiography analyses showed that HD Δ9 -THC significantly decreased CB1R binding relative to LD Δ9 -THC in the cingulate (33%), primary motor (42%), secondary motor (33%) somatosensory (38%), rhinal (38%), and auditory (50%) cortices; LD Δ9 -THC rats displayed elevated binding in the primary motor (33% increase) and hypothalamic (33% increase) regions compared with controls. No significant differences were observed in MOR binding for the LD or HD compared to the control., Significance: These results demonstrate that chronic Δ9 -THC dose-dependently altered CB1R levels throughout the brain and locomotor activity in the open field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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30. von Willebrand Factor and Angiopoietin-2 are Sensitive Biomarkers of Pulsatility in Continuous-Flow Ventricular Assist Device Patients.
- Author
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Nguyen KT, Hecking J, Berg IC, Kannappan R, Donoghue L, Ismail E, Cheng X, Giridharan GA, and Sethu P
- Subjects
- Adult, Humans, von Willebrand Factor, Endothelial Cells, Angiopoietin-2, Hemorrhage etiology, Biomarkers, Heart-Assist Devices adverse effects, von Willebrand Diseases etiology
- Abstract
Nonsurgical bleeding occurs in a significant proportion of patients implanted with continuous-flow ventricular assist devices (CF-VADs) and is associated with nonphysiologic flow with diminished pulsatility. An in vitro vascular pulse perfusion model seeded with adult human aortic endothelial cells (HAECs) was used to identify biomarkers sensitive to changes in pulsatility. Diminished pulsatility resulted in an ~45% decrease in von Willebrand factor (vWF) levels from 9.80 to 5.32 ng/ml (n = 5, p < 0.05) and a threefold increase in angiopoietin-2 (ANGPT-2) levels from 775.29 to 2471.93 pg/ml (n = 5, p < 0.05) in cultured HAECs. These changes are in agreement with evaluation of patient blood samples obtained pre-CF-VAD implant and 30-day postimplant: a decrease in plasma vWF level by 50% from ~45.59 to ~22.49 μg/ml (n = 15, p < 0.01) and a 64% increase in plasma ANGPT-2 level from 7,073 to 11,615 pg/ml (n = 8, p < 0.05). This study identified vWF and ANGPT-2 as highly sensitive to changes in pulsatility, in addition to interleukin-6 (IL-6), IL-8, and tumor necrosis-α (TNF-α). These biomarkers may help determine the optimal level of pulsatility and help identify patients at high risk of nonsurgical bleeding., Competing Interests: Disclosure: G.A.G. has served as a consultant for NuPulseCV, but this manuscript does not directly pertain to the device of NuPulseCV. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)
- Published
- 2023
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31. MicroRNA-181c-5p modulates phagocytosis efficiency in bone marrow-derived macrophages.
- Author
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Singh S, Henderson J, Patil M, Dubey PK, Dubey S, Kannappan R, Zhang J, and Krishnamurthy P
- Subjects
- Humans, Inflammation, Macrophage Activation, Macrophages metabolism, Phagocytosis, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Objective and Design: Phagocytosis and clearance of apoptotic cells are essential for inflammation resolution, efficient wound healing, and tissue homeostasis. MicroRNAs are critical modulators of macrophage polarization and function. The current study aimed to investigate the role of miR-181c-5p in macrophage phagocytosis., Materials and Methods: miR-181c-5p was identified as a potential candidate in microRNA screening of RAW264.7 macrophages fed with apoptotic cells. To investigate the role of miR-181c-5p in phagocytosis, the expression of miR-181c-5p was assessed in phagocyting bone marrow-derived macrophages. Phagocytosis efficiency was measured by fluorescence microscopy. Gain- and loss-of-function studies were performed using miR-181c-5p-specific mimic and inhibitor. The expression of the phagocytosis-associated genes and proteins of interest was evaluated by RT
2 profiler PCR array and western blotting, respectively., Results: miR-181c-5p expression was significantly upregulated in the phagocyting macrophages. Furthermore, mimic-induced overexpression of miR-181c-5p resulted in the increased phagocytic ability of macrophages. Moreover, overexpression of miR-181c-5p resulted in upregulation of WAVE-2 in phagocyting macrophages, suggesting that miR-181c-5p may regulate cytoskeletal arrangement during macrophage phagocytosis., Conclusion: Altogether, our data provide a novel function of miR-181c-5p in macrophage biology and suggest that targeting macrophage miR-181c-5p in injured tissues might improve clearance of dead cells and lead to efficient inflammation resolution., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2022
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32. Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease.
- Author
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Budhathoki S, Graham C, Sethu P, and Kannappan R
- Subjects
- Aged, Aging, Cellular Senescence genetics, Doxorubicin, Heart, Humans, Cardiovascular Diseases complications, Myocardial Infarction pathology
- Abstract
Due to the rapidly growing number of older people worldwide and the concomitant increase in cardiovascular complications, there is an urgent need for age-related cardiac disease modeling and drug screening platforms. In the present study, we developed a cardiac tissue chip model that incorporates hemodynamic loading and mimics essential aspects of the infarcted aging heart. We induced cellular senescence in H9c2 myoblasts using low-dose doxorubicin treatment. These senescent cells were then used to engineer cardiac tissue fibers, which were subjected to hemodynamic stresses associated with pressure-volume changes in the heart. Myocardial ischemia was modeled in the engineered cardiac tissue via hypoxic treatment. Our results clearly show that acute low-dose doxorubicin treatment-induced senescence, as evidenced by morphological and molecular markers, including enlarged and flattened nuclei, DNA damage response foci, and increased expression of cell cycle inhibitor p16INK4a, p53, and ROS. Under normal hemodynamic load, the engineered cardiac tissues demonstrated cell alignment and retained cardiac cell characteristics. Our senescent cardiac tissue model of hypoxia-induced myocardial infarction recapitulated the pathological disease hallmarks such as increased cell death and upregulated expression of ANP and BNP. In conclusion, the described methodology provides a novel approach to generate stress-induced aging cardiac cell phenotypes and engineer cardiac tissue chip models to study the cardiovascular disease pathologies associated with aging., (© 2021 S. Karger AG, Basel.)
- Published
- 2022
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33. microRNA-377 Signaling Modulates Anticancer Drug-Induced Cardiotoxicity in Mice.
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Henderson J, Dubey PK, Patil M, Singh S, Dubey S, Namakkal Soorappan R, Kannappan R, Sethu P, Qin G, Zhang J, and Krishnamurthy P
- Abstract
Doxorubicin (DOX, an anthracycline) is a widely used chemotherapy agent against various forms of cancer; however, it is also known to induce dose-dependent cardiotoxicity leading to adverse complications. Investigating the underlying molecular mechanisms and strategies to limit DOX-induced cardiotoxicity might have potential clinical implications. Our previous study has shown that expression of microRNA-377 (miR-377) increases in cardiomyocytes (CMs) after cardiac ischemia-reperfusion injury in mice, but its specific role in DOX-induced cardiotoxicity has not been elucidated. In the present study, we investigated the effect of anti-miR-377 on DOX-induced cardiac cell death, remodeling, and dysfunction. We evaluated the role of miR-377 in CM apoptosis, its target analysis by RNA sequencing, and we tested the effect of AAV9-anti-miR-377 on DOX-induced cardiotoxicity and mortality. DOX administration in mice increases miR-377 expression in the myocardium. miR-377 inhibition in cardiomyocyte cell line protects against DOX-induced cell death and oxidative stress. Furthermore, RNA sequencing and Gene Ontology (GO) analysis revealed alterations in a number of cell death/survival genes. Intriguingly, we observed accelerated mortality and enhanced myocardial remodeling in the mice pretreated with AAV9-anti-miR-377 followed by DOX administration as compared to the AAV9-scrambled-control-pretreated mice. Taken together, our data suggest that in vitro miR-377 inhibition protects against DOX-induced cardiomyocyte cell death. On the contrary, in vivo administration of AAV9-anti-miR-377 increases mortality in DOX-treated mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Henderson, Dubey, Patil, Singh, Dubey, Namakkal Soorappan, Kannappan, Sethu, Qin, Zhang and Krishnamurthy.)
- Published
- 2021
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34. Fabrication and characterization of a thick, viable bi-layered stem cell-derived surrogate for future myocardial tissue regeneration.
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Pretorius D, Kahn-Krell AM, LaBarge WC, Lou X, Kannappan R, Pollard AE, Fast VG, Berry JL, Eberhardt AW, and Zhang J
- Subjects
- Animals, Humans, Mice, Myocardium, Myocytes, Cardiac, Tissue Engineering methods, Endothelial Cells, Induced Pluripotent Stem Cells
- Abstract
Cardiac tissue surrogates show promise for restoring mechanical and electrical function in infarcted left ventricular (LV) myocardium. For these cardiac surrogates to be useful in vivo , they are required to support synchronous and forceful contraction over the infarcted region. These design requirements necessitate a thickness sufficient to produce a useful contractile force, an area large enough to cover an infarcted region, and prevascularization to overcome diffusion limitations. Attempts to meet these requirements have been hampered by diffusion limits of oxygen and nutrients (100-200 µm) leading to necrotic regions. This study demonstrates a novel layer-by-layer (LbL) fabrication method used to produce tissue surrogates that meet these requirements and mimic normal myocardium in form and function. Thick (1.5-2 mm) LbL cardiac tissues created from human induced pluripotent stem cell-derived cardiomyocytes and endothelial cells were assessed, in vitro , over a 4-week period for viability (<5.6 ± 1.4% nectrotic cells), cell morphology, viscoelastic properties and functionality. Viscoelastic properties of the cardiac surrogates were determined via stress relaxation response modeling and compared to native murine LV tissue. Viscoelastic characterization showed that the generalized Maxwell model of order 4 described the samples well (0.7 < R
2 < 0.98). Functional performance assessment showed enhanced t-tubule network development, gap junction communication as well as conduction velocity (16.9 ± 2.3 cm s-1 ). These results demonstrate that LbL fabrication can be utilized successfully in creating complex, functional cardiac surrogates for potential therapeutic applications., (Creative Commons Attribution license.)- Published
- 2021
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35. Role of exosomal microRNA signatures: An emerging factor in preeclampsia-mediated cardiovascular disease.
- Author
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Murugesan S, Saravanakumar L, Powell MF, Rajasekaran NS, Kannappan R, and Berkowitz DE
- Subjects
- Cardiovascular Diseases diagnosis, Cardiovascular Diseases physiopathology, Female, Humans, MicroRNAs analysis, Pre-Eclampsia diagnosis, Pre-Eclampsia physiopathology, Pregnancy, Pregnancy Complications, Cardiovascular diagnosis, Pregnancy Complications, Cardiovascular genetics, Pregnancy Complications, Cardiovascular physiopathology, Transcriptome physiology, Cardiovascular Diseases genetics, Exosomes genetics, MicroRNAs physiology, Pre-Eclampsia genetics
- Abstract
Preeclampsia (PE) and vascular dysfunction are major causes of maternal and neonatal morbidity and mortality. Although extensively studied, the complete understanding of the pathophysiology behind PE remains unclear. Current reports indicate that exosomes are essential mediators in PE-related cardiovascular disease (CVDs). Exosomes are synthesized from multivesicular bodies (MVB) and contain functionally active microRNAs miRNAs). These miRNAs have been shown to mediate physiological and pathological functions through autocrine, paracrine, and endocrine signaling mechanisms. The role of miRNAs in pregnant women with PE has been studied extensively. However, little is known about the effect of exosomal miRNAs (exomiR) in PE. This paper will review and discuss the existing evidence for exomiR function in PE and highlight the need for future studies to explore the role that exomiR signatures have in cardiovascular dysfunction associated with PE., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare in this manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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36. DNA damage-free iPS cells exhibit potential to yield competent cardiomyocytes.
- Author
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Miller JM, Mardhekar NM, Pretorius D, Krishnamurthy P, Rajasekaran NS, Zhang J, and Kannappan R
- Subjects
- Cells, Cultured, Cellular Reprogramming Techniques methods, Humans, Induced Pluripotent Stem Cells metabolism, Ion Channels genetics, Ion Channels metabolism, Myocardial Contraction, Myocytes, Cardiac metabolism, Myocytes, Cardiac physiology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Cell Differentiation, DNA Damage, Induced Pluripotent Stem Cells cytology, Myocytes, Cardiac cytology
- Abstract
DNA damage accrued in induced pluripotent stem cell (iPSC)-derived cardiomyocytes during in vitro culture practices lessens their therapeutic potential. We determined whether DNA-damage-free iPSCs (DdF-iPSCs) can be selected using stabilization of p53, a transcription factor that promotes apoptosis in DNA-damaged cells, and differentiated them into functionally competent DdF cardiomyocytes (DdF-CMs). p53 was activated using Nutlin-3a in iPSCs to selectively kill the DNA-damaged cells, and the stable DdF cells were cultured further and differentiated into CMs. Both DdF-iPSCs and DdF-CMs were then characterized. We observed a significant decrease in the expression of reactive oxygen species and DNA damage in DdF-iPSCs compared with control (Ctrl) iPSCs. Next-generation RNA sequencing and Ingenuity Pathway Analysis revealed improved molecular, cellular, and physiological functions in DdF-iPSCs. The differentiated DdF-CMs had a compact beating frequency between 40 and 60 beats/min accompanied by increased cell surface area. Additionally, DdF-CMs were able to retain the improved molecular, cellular, and physiological functions after differentiation from iPSCs, and, interestingly, cardiac development network was prominent compared with Ctrl-CMs. Enhanced expression of various ion channel transcripts in DdF-CMs implies DdF-CMs are of ventricular CMs and mature compared with their counterparts. Our results indicated that DdF-iPSCs could be selected through p53 stabilization using a small-molecule inhibitor and differentiated into ventricular DdF-CMs with fine-tuned molecular signatures. These iPSC-derived DdF-CMs show immense clinical potential in repairing injured myocardium. NEW & NOTEWORTHY Culture-stress-induced DNA damage in stem cells lessens their performance. A robust small-molecule-based approach, by stabilizing/activating p53, to select functionally competent DNA-damage-free cells from a heterogeneous population of cells is demonstrated. This protocol can be adopted by clinics to select DNA-damage-free cells before transplanting them to the host myocardium. The intact DNA-damage-free cells exhibited with fine-tuned molecular signatures and improved cellular functions. DNA-damage-free cardiomyocytes compared with control expressed superior cardiomyocyte functional properties, including, but not limited to, enhanced ion channel signatures. These DNA-intact cells would better engraft, survive, and, importantly, improve the cardiac function of the injured myocardium.
- Published
- 2020
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37. Cardiac Tissue Chips (CTCs) for Modeling Cardiovascular Disease.
- Author
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Rogers AJ, Miller JM, Kannappan R, and Sethu P
- Subjects
- Animals, Cells, Cultured, Equipment Design, Fibroblasts cytology, Heart physiology, Rats, Tissue Array Analysis methods, Tissue Culture Techniques methods, Cardiovascular Diseases physiopathology, Models, Cardiovascular, Myocardium cytology, Tissue Array Analysis instrumentation, Tissue Culture Techniques instrumentation
- Abstract
Objective: Cardiovascular research and regenerative strategies have been significantly limited by the lack of relevant cell culture models that can recreate complex hemodynamic stresses associated with pressure-volume changes in the heart., Methods: To address this issue, we designed a biomimetic cardiac tissue chip (CTC) model where encapsulated cardiac cells can be cultured in three-dimensional (3-D) fibres and subjected to hemodynamic loading to mimic pressure-volume changes seen in the left ventricle. These 3-D fibres are suspended within a microfluidic chamber between two posts and integrated within a flow loop. Various parameters associated with heart function, like heart rate, peak-systolic pressure, end-diastolic pressure and volume, end-systolic pressure and volume, and duration ratio between systolic and diastolic, can all be precisely manipulated, allowing culture of cardiac cells under developmental, normal, and disease states., Results: We describe two examples of how the CTC can significantly impact cardiovascular research by reproducing the pathophysiological mechanical stresses associated with pressure overload and volume overload. Our results using H9c2 cells, a cardiomyogenic cell line, clearly show that culture within the CTC under pathological hemodynamic loads accurately induces morphological and gene expression changes, similar to those seen in both hypertrophic and dilated cardiomyopathy. Under pressure overload, the cells within the CTC see increased hypertrophic remodeling and fibrosis, whereas cells subject to prolonged volume overload experience significant changes to cellular aspect ratio through thinning and elongation of the engineered tissue., Conclusions: These results demonstrate that the CTC can be used to create highly relevant models where hemodynamic loading and unloading are accurately reproduced for cardiovascular disease modeling.
- Published
- 2019
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38. Correction: Maturation of three-dimensional, hiPSC-derived cardiomyocyte spheroids utilizing cyclic, uniaxial stretch and electrical stimulation.
- Author
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LaBarge W, Mattapally S, Kannappan R, Fast VG, Pretorius D, Berry JL, and Zhang J
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0219442.].
- Published
- 2019
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39. Scaffold-Free Bioprinter Utilizing Layer-By-Layer Printing of Cellular Spheroids.
- Author
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LaBarge W, Morales A, Pretorius D, Kahn-Krell AM, Kannappan R, and Zhang J
- Abstract
Free from the limitations posed by exogenous scaffolds or extracellular matrix-based materials, scaffold-free engineered tissues have immense clinical potential. Biomaterials may produce adverse responses, interfere with cell-cell interaction, or affect the extracellular matrix integrity of cells. The scaffold-free Kenzan method can generate complex tissues using spheroids on an array of needles but could be inefficient in terms of time, as it moves and places only a single spheroid at a time. We aimed to design and construct a novel scaffold-free bioprinter that can print an entire layer of spheroids at once, effectively reducing the printing time. The bioprinter was designed using computer-aided design software and constructed from machined, 3D printed, and commercially available parts. The printing efficiency and the operating precision were examined using Zirconia and alginate beads, which mimic spheroids. In less than a minute, the printer could efficiently pick and transfer the beads to the printing surface and assemble them onto the 4 × 4 needles. The average overlap coefficient between layers was measured and found to be 0.997. As a proof of concept using human induced pluripotent stem cell-derived spheroids, we confirmed the ability of the bioprinter to place cellular spheroids onto the needles efficiently to print an entire layer of tissue. This novel layer-by-layer, scaffold-free bioprinter is efficient and precise in operation and can be easily scaled to print large tissues.
- Published
- 2019
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40. Functionally Competent DNA Damage-Free Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Myocardial Repair.
- Author
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Kannappan R, Turner JF, Miller JM, Fan C, Rushdi AG, Rajasekaran NS, and Zhang J
- Subjects
- Animals, Apoptosis, Cell Differentiation, Cell Separation, Coronary Stenosis therapy, Coronary Vessels, Disease Models, Animal, Genes, p53, Graft Survival, Imidazoles pharmacology, Induced Pluripotent Stem Cells chemistry, Ligation, Mice, Mice, SCID, Myocytes, Cardiac cytology, Piperazines pharmacology, DNA Damage, Induced Pluripotent Stem Cells cytology, Myocytes, Cardiac transplantation
- Published
- 2019
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41. Maturation of three-dimensional, hiPSC-derived cardiomyocyte spheroids utilizing cyclic, uniaxial stretch and electrical stimulation.
- Author
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LaBarge W, Mattappally S, Kannappan R, Fast VG, Pretorius D, Berry JL, and Zhang J
- Abstract
Functional myocardium derived from human induced pluripotent stem cells (hiPSCs) can be impactful for cardiac disease modeling, drug testing, and the repair of injured myocardium. However, when hiPSCs are differentiated into cardiomyocytes, they do not possess characteristics of mature myocytes which limits their application in these endeavors. We hypothesized that mechanical and electrical stimuli would enhance the maturation of hiPSC-derived cardiomyocyte (hiPSC-CM) spheroids on both a structural and functional level, potentially leading to a better model for drug testing as well as cell therapy. Spheroids were generated with hiPSC-CM. For inducing mechanical stimulation, they were placed in a custom-made device with PDMS channels and exposed to cyclic, uniaxial stretch. Spheroids were electrically stimulated in the C-Pace EP from IONOptix for 7 days. Following the stimulations, the spheroids were then analyzed for cardiomyocyte maturation. Both stimulated groups of spheroids possessed enhanced transcript and protein expressions for key maturation markers, such as cTnI, MLC2v, and MLC2a, along with improved ultrastructure of the hiPSC-CMs in both groups with enhanced Z-band/Z-body formation, fibril alignment, and fiber number. Optical mapping showed that spheroids exposed to electrical stimulation were able to capture signals at increasing rates of pacing up to 4 Hz, which failed in unstimulated spheroids. Our results clearly indicate that a significantly improved myocyte maturation can be achieved by culturing iPSC-CMs as spheroids and exposing them to cyclic, uniaxial stretch and electrical stimulation., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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42. Assessing Stem Cell DNA Integrity for Cardiac Cell Therapy.
- Author
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Miller JM, Mardhekar NM, Rajasekaran V, Zhang J, and Kannappan R
- Subjects
- Cell Proliferation, Cellular Senescence, DNA analysis, DNA genetics, Humans, Cell- and Tissue-Based Therapy methods, DNA chemistry, DNA Damage, Heart Diseases therapy, Myocytes, Cardiac cytology, Stem Cell Transplantation standards, Stem Cells cytology
- Abstract
Stem and stem-cell-derived cells have immense potential as a regenerative therapy for various degenerative diseases. DNA is the storehouse of genetic data in all cells, including stem cells, and its integrity is fundamental to its regenerative ability. Stem cells undergo rapid propagation in labs to achieve the necessary numbers for transplantation. Accelerated cell growth leads to the loss of DNA integrity by accumulated metabolites, such as reactive oxygen, carbonyl, and alkylating agents. Transplanting these cells would result in poor engraftment and regeneration of the deteriorating organ. Moreover, transplanting DNA-damaged cells leads to mutations, DNA instability, cellular senescence, and possibly, life-threatening diseases such as cancer. Therefore, there is an immediate need for a quality control method to evaluate the cell's suitability for transplantation. Here, we provide step-by-step protocols for the assessment of the DNA integrity of stem cells prior to cell transplantation.
- Published
- 2019
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43. Transactivation domain of p53 regulates DNA repair and integrity in human iPS cells.
- Author
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Kannappan R, Mattapally S, Wagle PA, and Zhang J
- Subjects
- Acid Anhydride Hydrolases metabolism, Cell Cycle Checkpoints, Cells, Cultured, Checkpoint Kinase 2 metabolism, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA-Binding Proteins metabolism, Doxorubicin toxicity, Genomic Instability, Humans, Induced Pluripotent Stem Cells drug effects, MRE11 Homologue Protein metabolism, Protein Domains, Tumor Suppressor Protein p53 chemistry, Tumor Suppressor Protein p53 genetics, DNA Repair, Induced Pluripotent Stem Cells metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human induced pluripotent stem cells (hiPSCs) has never been studied. p53-TAD was knocked out in iPSCs using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD knockout (KO) cells were characterized by accelerated proliferation, decreased population doubling time, and unaltered Bcl-2, Bcl-2-binding component 3, insulin-like growth factor 1 receptor, and Bax and altered Mdm2, p21, and p53-induced death domain transcript expression. In p53-TAD KO cells, the p53-regulated DNA repair proteins xeroderma pigmentosum group A, DNA polymerase H, and DNA-binding protein 2 expression were found to be reduced compared with p53 wild-type cells. Exposure to a low dose of doxorubicin (Doxo) induced similar DNA damage and DNA damage response (DDR) as measured by RAD50 and MRE11 expression, checkpoint kinase 2 activation, and γH2A.X recruitment at DNA strand breaks in both cell groups, indicating that silence of p53-TAD does not affect the DDR mechanism upstream of p53. After removal of Doxo, p53 wild-type hiPSCs underwent DNA repair, corrected their damaged DNA, and restored DNA integrity. Conversely, p53-TAD KO hiPSCs did not undergo complete DNA repair and failed to restore DNA integrity. More importantly, continuous culture of p53-TAD KO hiPSCs underwent G
2 /M cell cycle arrest and expressed the cellular senescent marker p16INK4a . Our data clearly show that silence of the TAD of p53 did not affect DDR but affected the DNA repair process, implying the crucial role of p53-TAD in maintaining DNA integrity. Therefore, activating p53-TAD domain using small molecules may promote DNA repair and integrity of cells and prevent cellular senescence.- Published
- 2018
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44. Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice.
- Author
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Mattapally S, Zhu W, Fast VG, Gao L, Worley C, Kannappan R, Borovjagin AV, and Zhang J
- Subjects
- Animals, Calcium Signaling, Cells, Cultured, HEK293 Cells, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Myocardial Contraction, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, Spheroids, Cellular metabolism, Stem Cell Transplantation methods, Induced Pluripotent Stem Cells cytology, Myocardial Infarction therapy, Myocytes, Cardiac transplantation, Spheroids, Cellular transplantation
- Abstract
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
2+ 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. NEW & NOTEWORTHY Spheroids fuse in culture to produce structures with uniformly distributed cells. Furthermore, human cardiac lineage-induced pluripotent stem cells in cardiomyocytes in adjacent fused spheroids became electromechanically coupled as the fusions matured in vitro, and when the spheroids were combined with a biological matrix and administered as a patch over the infarcted region of mouse hearts, the engraftment rate exceeded 25%, and the treatment was associated with significant improvements in cardiac function via a paracrine mechanism, where exosomes released from the spheroid patch.- Published
- 2018
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45. Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine.
- Author
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Gao L, Gregorich ZR, Zhu W, Mattapally S, Oduk Y, Lou X, Kannappan R, Borovjagin AV, Walcott GP, Pollard AE, Fast VG, Hu X, Lloyd SG, Ge Y, and Zhang J
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Endothelial Cells metabolism, Endothelial Cells pathology, Gene Expression Regulation, Humans, Induced Pluripotent Stem Cells physiology, Myocardial Infarction genetics, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocytes, Cardiac pathology, Myocytes, Smooth Muscle pathology, Recovery of Function, Sus scrofa, Time Factors, Tissue Scaffolds, Transplantation, Heterologous, Ventricular Function, Left, Ventricular Remodeling, Endothelial Cells transplantation, Induced Pluripotent Stem Cells transplantation, Myocardial Infarction surgery, Myocardium pathology, Myocytes, Cardiac transplantation, Myocytes, Smooth Muscle transplantation, Regeneration genetics, Stem Cell Transplantation methods, Tissue Engineering methods
- Abstract
Background: Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform., Methods: In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch., Results: The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival., Conclusions: We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity., (© 2017 American Heart Association, Inc.)
- Published
- 2018
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46. VEGF nanoparticles repair the heart after myocardial infarction.
- Author
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Oduk Y, Zhu W, Kannappan R, Zhao M, Borovjagin AV, Oparil S, and Zhang JJ
- Subjects
- Angiogenesis Inducing Agents chemistry, Animals, Cells, Cultured, Delayed-Action Preparations, Disease Models, Animal, Drug Carriers, Drug Compounding, Human Umbilical Vein Endothelial Cells drug effects, Humans, Mice, Inbred NOD, Mice, SCID, Myocardial Contraction drug effects, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Polylactic Acid-Polyglycolic Acid Copolymer chemistry, Recovery of Function, Time Factors, Vascular Endothelial Growth Factor A chemistry, Angiogenesis Inducing Agents administration & dosage, Myocardial Infarction drug therapy, Nanoparticles, Neovascularization, Physiologic drug effects, Vascular Endothelial Growth Factor A administration & dosage, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects
- Abstract
Vascular endothelial growth factor (VEGF) is a well-characterized proangiogenic cytokine that has been shown to promote neovascularization in hearts of patients with ischemic heart disease but can also lead to adverse effects depending on the dose and mode of delivery. We investigated whether prolonged exposure to a low dose of VEGF could be achieved by encapsulating VEGF in polylactic coglycolic acid nanoparticles and whether treatment with VEGF-containing nanoparticles improved cardiac function and protected against left ventricular remodeling in the hearts of mice with experimentally induced myocardial infarction. Polylactic coglycolic acid nanoparticles with a mean diameter of ~113 nm were generated via double emulsion and loaded with VEGF; the encapsulation efficiency was 53.5 ± 1.7% (107.1 ± 3.3 ng VEGF/mg nanoparticles). In culture, VEGF nanoparticles released VEGF continuously for at least 31 days, and in a murine myocardial infarction model, VEGF nanoparticle administration was associated with significantly greater vascular density in the peri-infarct region, reductions in infarct size, and improvements in left ventricular contractile function 4 wk after treatment. Thus, our study provides proof of principle that nanoparticle-mediated delivery increases the angiogenic and therapeutic potency of VEGF for the treatment of ischemic heart disease. NEW & NOTEWORTHY Vascular endothelial growth factor (VEGF) is a well-characterized proangiogenic cytokine but has a short half-life and a rapid clearance rate. When encapsulated in nanoparticles, VEGF was released for 31 days and improved left ventricular function in infarcted mouse hearts. These observations indicate that our new platform increases the therapeutic potency of VEGF.
- Published
- 2018
- Full Text
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47. Oxytocin alters cell fate selection of rat neural progenitor cells in vitro.
- Author
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Palanisamy A, Kannappan R, Xu Z, Martino A, Friese MB, Boyd JD, Crosby G, and Culley DJ
- Subjects
- Animals, Astrocytes cytology, Astrocytes drug effects, Cell Differentiation drug effects, Cell Lineage drug effects, Cell Proliferation drug effects, Cells, Cultured, Down-Regulation drug effects, Female, Humans, Neural Stem Cells cytology, Neural Stem Cells metabolism, Neurogenesis drug effects, Neuroglia cytology, Neuroglia drug effects, Neurons cytology, Neurons drug effects, Oligodendroglia cytology, Oligodendroglia drug effects, Oxytocin administration & dosage, Oxytocin metabolism, Placenta metabolism, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Sprague-Dawley, Receptors, Oxytocin metabolism, Neural Stem Cells drug effects, Oxytocin toxicity
- Abstract
Synthetic oxytocin (sOT) is widely used during labor, yet little is known about its effects on fetal brain development despite evidence that it reaches the fetal circulation. Here, we tested the hypothesis that sOT would affect early neurodevelopment by investigating its effects on neural progenitor cells (NPC) from embryonic day 14 rat pups. NPCs expressed the oxytocin receptor (OXTR), which was downregulated by 45% upon prolonged treatment with sOT. Next, we examined the effects of sOT on NPC death, apoptosis, proliferation, and differentiation using antibodies to NeuN (neurons), Olig2 (oligodendrocytes), and GFAP (astrocytes). Treated NPCs were analysed with unbiased high-throughput immunocytochemistry. Neither 6 nor 24 h exposure to 100 pM or 100 nM sOT had an effect on viability as assessed by PI or CC-3 immunocytochemistry. Similarly, sOT had negligible effect on NPC proliferation, except that the overall rate of NPC proliferation was higher in the 24 h compared to the 6 h group regardless of sOT exposure. The most significant finding was that sOT exposure caused NPCs to select a predominantly neuronal lineage, along with a concomitant decrease in glial cells. Collectively, our data suggest that perinatal exposure to sOT can have neurodevelopmental consequences for the fetus, and support the need for in vivo anatomical and behavioral studies in offspring exposed to sOT in utero.
- Published
- 2018
- Full Text
- View/download PDF
48. Hemodynamic Stimulation Using the Biomimetic Cardiac Tissue Model (BCTM) Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
- Author
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Rogers AJ, Kannappan R, Abukhalifeh H, Ghazal M, Miller JM, El-Baz A, Fast VG, and Sethu P
- Subjects
- Biomimetics instrumentation, Biomimetics methods, Cell Culture Techniques methods, Cell Line, Equipment Design, Humans, Myocytes, Cardiac ultrastructure, Sarcomeres ultrastructure, Cell Culture Techniques instrumentation, Cell Differentiation, Hemodynamics, Induced Pluripotent Stem Cells cytology, Myocytes, Cardiac cytology
- Abstract
Human induced pluripotent stem cell (hiPSC)-derived cardio-myocytes (hiPSC-CMs) hold great promise for cardiovascular disease modeling and regenerative medicine. However, these cells are both structurally and functionally -immature, primarily due to their differentiation into cardiomyocytes occurring under static culture which only reproduces biomolecular cues and ignores the dynamic hemo-dynamic cues that shape early and late heart development during cardiogenesis. To evaluate the effects of hemodynamic stimuli on hiPSC-CM maturation, we used the biomimetic cardiac tissue model to reproduce the hemodynamics and pressure/volume changes associated with heart development. Following 7 days of gradually increasing stimulation, we show that hemodynamic loading results in (a) enhanced alignment of the cells and extracellular matrix, (b) significant increases in genes associated with physiological hypertrophy, (c) noticeable changes in sarcomeric organization and potential changes to cellular metabolism, and (d) a significant increase in fractional shortening, suggestive of a positive force frequency response. These findings suggest that culture of hiPSC-CMs under conditions that accurately reproduce hemodynamic cues results in structural orga-nization and molecular signaling consistent with organ growth and functional maturation., (© 2019 S. Karger AG, Basel.)
- Published
- 2018
- Full Text
- View/download PDF
49. Single-cell analysis of the fate of c-kit-positive bone marrow cells.
- Author
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Czarna A, Sanada F, Matsuda A, Kim J, Signore S, Pereira JD, Sorrentino A, Kannappan R, Cannatà A, Hosoda T, Rota M, Crea F, Anversa P, and Leri A
- Abstract
The plasticity of c-kit-positive bone marrow cells (c-kit-BMCs) in tissues different from their organ of origin remains unclear. We tested the hypothesis that c-kit-BMCs are functionally heterogeneous and only a subgroup of these cells possesses cardiomyogenic potential. Population-based assays fall short of identifying the properties of individual stem cells, imposing on us the introduction of single cell-based approaches to track the fate of c-kit-BMCs in the injured heart; they included viral gene-tagging, multicolor clonal-marking and transcriptional profiling. Based on these strategies, we report that single mouse c-kit-BMCs expand clonally within the infarcted myocardium and differentiate into specialized cardiac cells. Newly-formed cardiomyocytes, endothelial cells, fibroblasts and c-kit-BMCs showed in their genome common sites of viral integration, providing strong evidence in favor of the plasticity of a subset of BMCs expressing the c-kit receptor. Similarly, individual c-kit-BMCs, which were infected with multicolor reporters and injected in infarcted hearts, formed cardiomyocytes and vascular cells organized in clusters of similarly colored cells. The uniform distribution of fluorescent proteins in groups of specialized cells documented the polyclonal nature of myocardial regeneration. The transcriptional profile of myogenic c-kit-BMCs and whole c-kit-BMCs was defined by RNA sequencing. Genes relevant for engraftment, survival, migration, and differentiation were enriched in myogenic c-kit-BMCs, a cell subtype which could not be assigned to a specific hematopoietic lineage. Collectively, our findings demonstrate that the bone marrow comprises a category of cardiomyogenic, vasculogenic and/or fibrogenic c-kit-positive cells and a category of c-kit-positive cells that retains an undifferentiated state within the damaged heart., Competing Interests: P.A. is a member of Autologous Regeneration LLP. P.A. and A.L. are members of AAL Scientifics Inc. The remaining authors declare no competing financial interests.
- Published
- 2017
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50. p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo.
- Author
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Kannappan R, Matsuda A, Ferreira-Martins J, Zhang E, Palano G, Czarna A, Cabral-Da-Silva MC, Bastos-Carvalho A, Sanada F, Ide N, Rota M, Blasco MA, Serrano M, Anversa P, and Leri A
- Subjects
- Animals, Blotting, Western, Cell Differentiation genetics, Cell Proliferation genetics, Cells, Cultured, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 metabolism, Female, Gene Expression, Heart physiopathology, Histones metabolism, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Myocytes, Cardiac cytology, Myocytes, Cardiac transplantation, Reverse Transcriptase Polymerase Chain Reaction, Stem Cell Transplantation methods, Stem Cells cytology, Tumor Suppressor Protein p53 genetics, Diabetes Mellitus, Experimental metabolism, Myocardium metabolism, Myocytes, Cardiac metabolism, Stem Cells metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein. Old CPCs with increased p53 dosage showed a superior ability to sustain oxidative stress, repair DNA damage and restore cell division. With doxorubicin, a larger fraction of CPCs carrying an extra-copy of the p53 allele recruited γH2A.X reestablishing DNA integrity. Enhanced p53 expression resulted in a superior tolerance to oxidative stress in vivo by providing CPCs with defense mechanisms necessary to survive in the milieu of the diabetic heart; they engrafted in regions of tissue injury and in three days acquired the cardiomyocyte phenotype. The biological advantage provided by the increased dosage of p53 in CPCs suggests that this genetic strategy may be translated to humans to increase cellular engraftment and growth, critical determinants of successful cell therapy for the failing heart., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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