Cellular and Molecular Bioengineering

, Volume 11, Issue 5, pp 321–336 | Cite as

Pre-Conditioning Stem Cells in a Biomimetic Environment for Enhanced Cardiac Tissue Repair: In Vitro and In Vivo Analysis

  • Aparna R. Chakravarti
  • Settimio Pacelli
  • Perwez Alam
  • Samik Bagchi
  • Saman Modaresi
  • Andras Czirok
  • Rafeeq P. H. Ahmed
  • Arghya PaulEmail author



Stem cell-based therapies represent a valid approach to restore cardiac function due to their beneficial effect in reducing scar area formation and promoting angiogenesis. However, their translation into the clinic is limited by the poor differentiation and inability to secrete sufficient therapeutic factors. To address this issue, several strategies such as genetic modification and biophysical pre-conditioning have been used to enhance the efficacy of stem cells for cardiac tissue repair.


In this study, a biomimetic approach was used to mimic the natural mechanical stimulation of the myocardium tissue. Specifically, human adipose-derived stem cells (hASCs) were cultured on a thin gelatin methacrylamide (GelMA) hydrogel disc and placed on top of a beating cardiomyocyte layer. qPCR studies and metatranscriptomic analysis of hASCs gene expression were investigated to confirm the correlation between mechanical stimuli and cardiomyogenic differentiation. In vivo intramyocardial delivery of pre-conditioned hASCs was carried out to evaluate their efficacy to restore cardiac function in mice hearts post-myocardial infarction.


The cyclic strain generated by cardiomyocytes significantly upregulated the expression of both mechanotransduction and cardiomyogenic genes in hASCs as compared to the static control group. The inherent angiogenic secretion profile of hASCs was not hindered by the mechanical stimulation provided by the designed biomimetic system. Finally, in vivo analysis confirmed the regenerative potential of the pre-conditioned hASCs by displaying a significant improvement in cardiac function and enhanced angiogenesis in the peri-infarct region.


Overall, these findings indicate that cyclic strain provided by the designed biomimetic system is an essential stimulant for hASCs cardiomyogenic differentiation, and therefore can be a potential solution to improve stem-cell based efficacy for cardiovascular repair.


Mechanical stimulation Myogenic differentiation Angiogenesis Cardiac repair 



AP acknowledges an investigator grant provided by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the NIH Award Number P20GM103638 and Umbilical Cord Matrix Project fund from State of Kansas. RPHA acknowledges the support from National Institute of Health (NIH) Grant 1R01HL-10690. AC acknowledges support from AHA 16GRNT31030030 and NIH GM102801. Research reported in this publication was made possible by the services of Dr. Erik Lundquist and Ms. Jennifer Hackett at the KU Genome Sequencing Core. The authors also acknowledge the services provided by Dr. Stuart Macdonald and Ms. Boryana S Koseva at the KU-INBRE Bioinformatics Core. This core lab is supported by an Institutional Development Award (IDeA) from the NIGMS (P20GM103418) from the NIH. We also gratefully thank Ms. Heather Shinogle of the University of Kansas Microscopy and Analytical Imaging Laboratory for her assistance with confocal fluorescence microscopy. We further acknowledge Ms. Dona Gréta Isai from the University of Kansas Medical Center for her help in the non-invasive image analysis of cardiomyocytes contractility.

Conflict of interest

Aparna R. Chakravarti, Settimio Pacelli, Perwez Alam, Samik Bagchi, Saman Modaresi, Andras Czirok, Rafeeq P.H. Ahmed, and Arghya Paul declare no conflict of interests.

Ethical Standards

All animal studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23 revised 1985) and approved by IACUC. No human studies were carried out by the authors for this article. Only commercially obtained cells were used.

Supplementary material

12195_2018_543_MOESM1_ESM.docx (206 kb)
Supplementary material 1 (DOCX 206 kb)

Supplementary material 2 (WMV 12,122 kb)

Supplementary material 3 (WMV 60,309 kb)

Supplementary material 4 (WMV 41,200 kb)


  1. 1.
    Aboalola, D., and V. K. M. Han. Different effects of insulin-like growth factor-1 and insulin-like growth factor-2 on myogenic differentiation of human mesenchymal stem cells. Stem Cells Int. 2017. Scholar
  2. 2.
    Arif, M., R. Pandey, P. Alam, S. Jiang, S. Sadayappan, A. Paul, and R. P. H. Ahmed. MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents. J. Mol. Med. 95:1369–1385, 2017.CrossRefGoogle Scholar
  3. 3.
    Augiere, C., S. Megy, R. El Malti, A. Boland, L. El Zein, B. Verrier, A. Mégarbané, J.-F. Deleuze, and P. Bouvagnet. A novel alpha cardiac actin (ACTC1) mutation mapping to a domain in close contact with myosin heavy chain leads to a variety of congenital heart defects, arrhythmia and possibly midline defects. PLoS ONE 10:0127903, 2015.CrossRefGoogle Scholar
  4. 4.
    Beier, J. P., F. F. Bitto, C. Lange, D. Klumpp, A. Arkudas, O. Bleiziffer, A. M. Boos, and U. Kneser. Myogenic differentiation of mesenchymal stem cells co-cultured with primary myoblasts. Cell Biol. Int. 35:397–406, 2011.CrossRefGoogle Scholar
  5. 5.
    Chao, W., and P. A. D’Amore. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 19:111–120, 2008.CrossRefGoogle Scholar
  6. 6.
    Chen, T. H., C. Y. Chen, H. C. Wen, C. C. Chang, H. D. Wang, C. P. Chuu, and C. H. Chang. YAP promotes myogenic differentiation via the MEK5-ERK5 pathway. FASEB J.: Off. Publ. Fed. Soc. Exp. Biol. 31:2963–2972, 2017.CrossRefGoogle Scholar
  7. 7.
    Cho, J., P. Zhai, Y. Maejima, and J. Sadoshima. Myocardial injection with GSK-3β-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction. Circ. Res. 108:478–489, 2011.CrossRefGoogle Scholar
  8. 8.
    Dai, R., Z. Wang, R. Samanipour, K.-I. Koo, and K. Kim. Adipose-derived stem cells for tissue engineering and regenerative medicine applications. Stem Cells Int. 201:19, 2016.Google Scholar
  9. 9.
    D’Angelo, F., R. Tiribuzi, I. Armentano, J. M. Kenny, S. Martino, and A. Orlacchio. Mechanotransduction: tuning stem cells fate. J. Funct. Biomater. 2:67–87, 2011.CrossRefGoogle Scholar
  10. 10.
    Dong, A., J. Shen, M. Zeng, and P. A. Campochiaro. Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress. Proc. Natl. Acad. Sci. 108:14614–14619, 2011.CrossRefGoogle Scholar
  11. 11.
    Dupont, S., L. Morsut, M. Aragona, E. Enzo, S. Giulitti, M. Cordenonsi, F. Zanconato, J. Le Digabel, M. Forcato, S. Bicciato, N. Elvassore, and S. Piccolo. Role of YAP/TAZ in mechanotransduction. Nature. 474:179–183, 2011.CrossRefGoogle Scholar
  12. 12.
    Epp, T. A., I. M. Dixon, H. Y. Wang, M. J. Sole, and C. C. Liew. Structural organization of the human cardiac alpha-myosin heavy chain gene (MYH6). Genomics 18:505–509, 1993.CrossRefGoogle Scholar
  13. 13.
    Fischer, K. M., C. T. Cottage, W. Wu, S. Din, N. A. Gude, D. Avitable, P. Quijada, B. L. Collins, J. Fransioli, and M. A. Sussman. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase: Fischer: Pim-1 kinase enhances myocardial regeneration. Circulation 120:2077–2087, 2009.CrossRefGoogle Scholar
  14. 14.
    Frangogiannis, N. G. Pathophysiology of myocardial infarction. Compr. Physiol. 5:1841–1875, 2015.CrossRefGoogle Scholar
  15. 15.
    Furukawa, K. T., K. Yamashita, N. Sakurai, and S. Ohno. The epithelial circumferential actin belt regulates YAP/TAZ through nucleocytoplasmic shuttling of merlin. Cell Rep. 20(6):1435–1447, 2017.CrossRefGoogle Scholar
  16. 16.
    Go, A. S., D. Mozaffarian, V. L. Roger, E. J. Benjamin, J. D. Berry, and W. B. Borden. Executive summary: heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127:143–152, 2013.CrossRefGoogle Scholar
  17. 17.
    Gwak, S.-J., S. H. Bhang, I.-K. Kim, S.-S. Kim, S.-W. Cho, and O. Jeon. The effect of cyclic strain on embryonic stem cell-derived cardiomyocytes. Biomaterials 29:844–856, 2008.CrossRefGoogle Scholar
  18. 18.
    Haider, H., Y. J. Lee, S. Jiang, R. P. Ahmed, M. Ryon, and M. Ashraf. Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells. Am. J. Physiol. 299:H1395–H1404, 2010.Google Scholar
  19. 19.
    Heng, B. C., H. K. Haider, E. K.-W. Sim, T. Cao, and S. C. Ng. Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro. Cardiovasc. Res. 62:34–42, 2004.CrossRefGoogle Scholar
  20. 20.
    Herberts, C. A., M. S. G. Kwa, and H. P. H. Hermsen. Risk factors in the development of stem cell therapy. J. Transl. Med. 9:29, 2011.CrossRefGoogle Scholar
  21. 21.
    Hu, X., S. P. Yu, J. L. Fraser, Z. Lu, M. E. Ogle, J. A. Wang, and L. Wei. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J. Thorac Cardiovasc. Surg. 135:799–808, 2008.CrossRefGoogle Scholar
  22. 22.
    Huang, Y., L. Zheng, X. Gong, X. Jia, W. Song, and M. Liu. Effect of cyclic strain on cardiomyogenic differentiation of rat bone marrow derived mesenchymal stem cells. PLoS ONE 7:e34960, 2012.CrossRefGoogle Scholar
  23. 23.
    Ilkovski, B., S. Clement, C. Sewry, K. N. North, and S. T. Cooper. Defining alpha-skeletal and alpha-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy. Neuromuscular Disord. 15:829–835, 2005.CrossRefGoogle Scholar
  24. 24.
    Kabaeva, Z. T., A. Perrot, B. Wolter, R. Dietz, N. Cardim, J. M. Correia, H. D. Schulte, A. A. Aldashev, M. M. Mirrakhimov, and K. J. Osterziel. Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Eur. J. Hum. Genet. 10:741–748, 2002.CrossRefGoogle Scholar
  25. 25.
    Kawai, T., T. Takahashi, M. Esaki, H. Ushikoshi, S. Nagano, and H. Fujiwara. Efficient cardiomyogenic differentiation of embryonic stem cell by fibroblast growth factor 2 and bone morphogenetic protein 2. Circ. J. 68:691–702, 2004.CrossRefGoogle Scholar
  26. 26.
    Kemp, T. J., T. J. Sadusky, M. Simon, R. Brown, M. Eastwood, D. A. Sassoon, and G. R. Coulton. Identification of a novel stretch-responsive skeletal muscle gene (Smpx). Genomics. 72:260–271, 2001.CrossRefGoogle Scholar
  27. 27.
    Klotz, B. J., D. Gawlitta, A. J. Rosenberg, J. Malda, and F. P. Melchels. Gelatin-methacryloyl hydrogels: towards biofabrication-based tissue repair. Trends Biotechnol. 34:394–407, 2016.CrossRefGoogle Scholar
  28. 28.
    Kok, L. D., S. K. Tsui, M. Waye, C. C. Liew, C. Y. Lee, and K. P. Fung. Cloning and characterization of a cDNA encoding a novel fibroblast growth factor preferentially expressed in human heart. Biochem. Biophys. Res. Commun. 255:717–721, 1999.CrossRefGoogle Scholar
  29. 29.
    Kubalak, S. W., W. C. Miller-Hance, T. X. O’Brien, E. Dyson, and K. R. Chien. Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis. J. Biol. Chem. 269:16961–16970, 1994.Google Scholar
  30. 30.
    Lanfear, D. E. Genetic variation in the natriuretic peptide system and heart failure. Heart Failure Rev. 15:219–228, 2010.CrossRefGoogle Scholar
  31. 31.
    Li, D., Z. Niu, W. Yu, Y. Qian, Q. Wang, Q. Li, Z. Yi, J. Luo, X. Wu, Y. Wang, R. J. Schwartz, and M. Liu. SMYD1, the myogenic activator, is a direct target of serum response factor and myogenin. Nucleic Acids Res. 37:7059–7071, 2009.CrossRefGoogle Scholar
  32. 32.
    Li, W., N. Ma, L.-L. Ong, C. Nesselmann, C. Klopsch, Y. Ladilov, D. Furlani, C. Piechaczek, J. M. Moebius, K. Lützow, A. Lendlein, C. Stamm, R. K. Li, G. Steinhoff. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem cells (Dayton, OH, U.S.), 25:2118-27, 2007.Google Scholar
  33. 33.
    Li, H., S. Zuo, Z. He, Y. Yang, Z. Pasha, Y. Wang, and M. Xu. Paracrine factors released by GATA-4 overexpressed mesenchymal stem cells increase angiogenesis and cell survival. Am. J. Physiol. 299:H1772–H1781, 2010.Google Scholar
  34. 34.
    Low, B. C., C. Q. Pan, G. V. Shivashankar, A. Bershadsky, M. Sudol, and M. Sheetz. YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth. FEBS Lett. 588:2663–2670, 2014.CrossRefGoogle Scholar
  35. 35.
    Matsumoto, R., T. Omura, M. Yoshiyama, T. Hayashi, S. Inamoto, K. R. Koh, K. Ohta, Y. Izumi, Y. Nakamura, K. Akioka, K. Takeuchi, and J. Yoshikawa. Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 25:1168–1173, 2005.CrossRefGoogle Scholar
  36. 36.
    Mazhari, R., and J. M. Hare. Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche. Nat. Clin. Pract. Cardiovasc. Med. Suppl 1:S21–S26, 2007.CrossRefGoogle Scholar
  37. 37.
    Mirotsou, M., T. M. Jayawardena, J. Schmeckpeper, M. Gnecchi, and V. J. Dzau. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J. Mol. Cell. Cardiol. 50:280–289, 2011.CrossRefGoogle Scholar
  38. 38.
    Mohri, Z., A. D. R. Hernandez, and R. Krams. The emerging role of YAP/TAZ in mechanotransduction. J. Thorac. Dis. 9:E507–E509, 2017.CrossRefGoogle Scholar
  39. 39.
    Mohsin, S., S. Siddiqi, B. Collins, and M. A. Sussman. Empowering adult stem cells for myocardial regeneration. Circ. Res. 109:1415–1428, 2011.CrossRefGoogle Scholar
  40. 40.
    Moulik, M., M. Vatta, S. H. Witt, A. M. Arola, R. T. Murphy, W. J. McKenna, A. M. Boriek, K. Oka, S. Labeit, N. E. Bowles, T. Arimura, A. Kimura, and J. A. Towbin. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. J. Am. Coll. Cardiol. 54:325–333, 2009.CrossRefGoogle Scholar
  41. 41.
    Nagao, K., N. Sowa, K. Inoue, M. Tokunaga, K. Fukuchi, K. Uchiyama, H. Ito, F. Hayashi, T. Makita, T. Inada, M. Tanaka, T. Kimura, and K. Ono. Myocardial expression level of neural cell adhesion molecule correlates with reduced left ventricular function in human cardiomyopathy. Circ. Heart Failure 7:351–358, 2014.CrossRefGoogle Scholar
  42. 42.
    Orr, N., R. Arnaout, L. J. Gula, D. A. Spears, P. Leong-Sit, Q. Li, W. Tarhuni, S. Reischauer, V. S. Chauhan, M. Borkovich, S. Uppal, A. Adler, S. R. Coughlin, D. Y. Stainier, and M. H. Gollob. A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat. Commun. 7:11303, 2016.CrossRefGoogle Scholar
  43. 43.
    Ou, L., W. Li, Y. Zhang, W. Wang, J. Liu, H. Sorg, D. Furlani, R. Gäbel, P. Mark, C. Klopsch, L. Wang, K. Lützow, A. Lendlein, K. Wagner, D. Klee, A. Liebold, R. K. Li, D. Kong, G. Steinhoff, and N. Ma. Intracardiac injection of matrigel induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model. J. Cell. Mol. Med. 15:1310–1318, 2011.CrossRefGoogle Scholar
  44. 44.
    Pacelli, S., R. Maloney, A. R. Chakravarti, J. Whitlow, S. Basu, S. Modaresi, S. Gehrke, and A. Paul. Controlling adult stem cell behavior using nanodiamond-reinforced hydrogel: implication in bone regeneration therapy. Sci. Rep. 7:6577, 2017.CrossRefGoogle Scholar
  45. 45.
    Pacelli, S., P. Paolicelli, I. Dreesen, S. Kobayashi, A. Vitalone, and M. A. Casadei. Injectable and photocross-linkable gels based on gellan gum methacrylate: a new tool for biomedical application. Int. J. Biol. Macromol. 72:1335–1342, 2015.CrossRefGoogle Scholar
  46. 46.
    Panciera, T., L. Azzolin, M. Cordenonsi, and S. Piccolo. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 18:758, 2017.CrossRefGoogle Scholar
  47. 47.
    Pandey, R., S. Velasquez, S. Durrani, M. Jiang, M. Neiman, J. S. Crocker, J. B. Benoit, J. Rubinstein, A. Paul, and A. Rafeeq. MicroRNA-1825 induces proliferation of adult cardiomyocytes and promotes cardiac regeneration post ischemic injury. Am. J. Transl. Res. 9:3120–3137, 2017.Google Scholar
  48. 48.
    Pankajakshan, D., and D. K. Agrawal. Mesenchymal stem cell paracrine factors in vascular repair and regeneration. J. Biomed. Technol. Res. 2014. Scholar
  49. 49.
    Pankajakshan, D., and D. K. Agrawal. Mesenchymal stem cell paracrine factors in vascular repair and regeneration. J. Biomed. Technol. Res. 2014. Scholar
  50. 50.
    Paul, A., Z. M. Binsalamah, A. A. Khan, S. Abbasia, C. B. Elias, D. Shum-Tim, and S. Prakash. A nanobiohybrid complex of recombinant baculovirus and Tat/DNA nanoparticles for delivery of Ang-1 transgene in myocardial infarction therapy. Biomaterials. 32:8304–8318, 2011.CrossRefGoogle Scholar
  51. 51.
    Paul, A., A. Hasan, H. A. Kindi, A. K. Gaharwar, V. T. S. Rao, M. Nikkhah, S. R. Shin, D. Krafft, M. R. Dokmeci, D. Shum-Tim, and A. Khademhosseini. Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS Nano. 8:8050–8062, 2014.CrossRefGoogle Scholar
  52. 52.
    Paul, A., M. Nayan, A. A. Khan, D. Shum-Tim, and S. Prakash. Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction. Int. J. Nanomed. 7:663–682, 2012.CrossRefGoogle Scholar
  53. 53.
    Paul, A., S. Srivastava, G. Chen, D. Shum-Tim, and S. Prakash. Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells. Cell Biochem. Biophys. 67:263–273, 2013.CrossRefGoogle Scholar
  54. 54.
    Pinto, J. R., M. S. Parvatiyar, M. A. Jones, J. Liang, M. J. Ackerman, and J. D. Potter. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J. Biol. Chem. 284:19090–19100, 2009.CrossRefGoogle Scholar
  55. 55.
    Pons, J., Y. Huang, J. Arakawa-Hoyt, D. Washko, J. Takagawa, J. Ye, W. Grossman, and S. Hua. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem. Biophys. Res. Commun. 376:419–422, 2008.CrossRefGoogle Scholar
  56. 56.
    Rajasingh, S., J. Thangavel, A. Czirok, S. Samanta, K. F. Roby, B. Dawn, and J. Rajasingh. Generation of functional cardiomyocytes from efficiently generated human iPSCs and a novel method of measuring contractility. PLoS ONE 10:0134093, 2015.CrossRefGoogle Scholar
  57. 57.
    Rosova, I., M. Dao, B. Capoccia, D. Link, and J. A. Nolta. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem cells 26:2173–2182, 2008.CrossRefGoogle Scholar
  58. 58.
    Schmelter, M., B. Ateghang, S. Helmig, M. Wartenberg, and H. Sauer. Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J. 20:1182–1184, 2006.CrossRefGoogle Scholar
  59. 59.
    Sun, L., M. Cui, Z. Wang, X. Feng, J. Mao, P. Chen, M. Kangtao, F. Chen, and C. Zhou. Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction. Biochem. Biophys. Res. Commun. 357:779–784, 2007.CrossRefGoogle Scholar
  60. 60.
    Sun, Q., Z. Zhang, and Z. Sun. The potential and challenges of using stem cells for cardiovascular repair and regeneration. Genes Dis. 1:113–119, 2014.CrossRefGoogle Scholar
  61. 61.
    Tang, J.-M., J.-N. Wang, L. Zhang, F. Zheng, J.-Y. Yang, X. Kong, L. Y. Guo, L. Chen, Y. Z. Huang, Y. Wan, and S. Y. Chen. VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc. Res. 91:402–411, 2011.CrossRefGoogle Scholar
  62. 62.
    Thakker, R., and P. Yang. Mesenchymal stem cell therapy for cardiac repair. Curr. Treat Options Cardiovasc. Med. 16:323, 2014.CrossRefGoogle Scholar
  63. 63.
    Tiso, N., M. Majetti, F. Stanchi, A. Rampazzo, R. Zimbello, A. Nava, and G. A. Danieli. Fine mapping and genomic structure of ACTN2, the human gene coding for the sarcomeric isoform of alpha-actinin-2, expressed in skeletal and cardiac muscle. Biochem. Biophys. Res. Commun. 265:256–259, 1999.CrossRefGoogle Scholar
  64. 64.
    Townsend, P. J., H. Farza, C. MacGeoch, N. K. Spurr, R. Wade, R. Gahlmann, M. H. Yacoub, and P. J. Barton. Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q. Genomics. 21:311–316, 1994.CrossRefGoogle Scholar
  65. 65.
    Trapnell, C., B. A. Williams, G. Pertea, A. Mortazavi, G. Kwan, M. J. van Baren, S. L. Salzberg, B. J. World, L. Pachter. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28:511–515, 2010.CrossRefGoogle Scholar
  66. 66.
    Turbay, D., S. B. Wechsler, K. M. Blanchard, and S. Izumo. Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx. Mol. Med. 2:86–96, 1996.Google Scholar
  67. 67.
    Van Den Bulcke, A. I., B. Bogdanov, N. De Rooze, E. H. Schacht, M. Cornelissen, and H. Berghmans. Structural and rheological properties of methacrylamide modified gelatin hydrogels. Biomacromolecules 1:31–38, 2000.CrossRefGoogle Scholar
  68. 68.
    Villard, E., L. Duboscq-Bidot, P. Charron, A. Benaiche, V. Conraads, N. Sylvius, and M. Komajda. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur Heart J. 26:794–803, 2005.CrossRefGoogle Scholar
  69. 69.
    Wade, R., R. Eddy, T. B. Shows, and L. Kedes. cDNA sequence, tissue-specific expression, and chromosomal mapping of the human slow-twitch skeletal muscle isoform of troponin I. Genomics 7:346–357, 1990.CrossRefGoogle Scholar
  70. 70.
    Waters, R., P. Alam, S. Pacelli, A. R. Chakravarti, R. P. H. Ahmed, and A. Paul. Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue. Acta Biomater. 2017. Scholar
  71. 71.
    Waters, R., S. Pacelli, R. Maloney, I. Medhi, R. P. H. Ahmed, and A. Paul. Stem cell secretome-rich nanoclay hydrogel: a dual action therapy for cardiovascular regeneration. Nanoscale 8:7371–7376, 2016.CrossRefGoogle Scholar
  72. 72.
    Wickham, H. ggplot2. Wiley Interdiscip. Rev. 3:180–185, 2011.CrossRefGoogle Scholar
  73. 73.
    Xia, X., and S.-C. Zhang. Genetic Modification of human embryonic stem cells. Biotechnol. Genet. Eng. Rev. 24:297–309, 2007.CrossRefGoogle Scholar
  74. 74.
    Youssef, A., D. Aboalola, and V. K. M. Han. The roles of insulin-like growth factors in mesenchymal stem cell niche. Stem Cells Int. 201:9453108, 2017.Google Scholar
  75. 75.
    Yue, K., G. T. de Santiago, M. M. Alvarez, A. Tamayol, N. Annabi, and A. Khademhosseini. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials. 73:254–271, 2015.CrossRefGoogle Scholar
  76. 76.
    Zannad, F., N. Agrinier, and F. Alla. Heart failure burden and therapy. Europace 11(Suppl 5):v1–v9, 2009.CrossRefGoogle Scholar
  77. 77.
    Zeng, J., Y. Wang, Y. Wei, A. Xie, Y. Lou, and M. Zhang. Co-culture with cardiomyocytes induces mesenchymal stem cells to differentiate into cardiomyocyte-like cells and express heart development-associated genes. Cell Res. 18:S62, 2008.CrossRefGoogle Scholar
  78. 78.
    Zhao, L., T. Johnson, and D. Liu. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res. Ther. 8:125, 2017.CrossRefGoogle Scholar

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© Biomedical Engineering Society 2018

Authors and Affiliations

  1. 1.Biointel Research Laboratory, Department of Chemical and Petroleum Engineering, School of EngineeringUniversity of KansasLawrenceUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of CincinnatiCincinnatiUSA
  3. 3.Department of Civil, Environmental, and Architectural EngineeringUniversity of KansasLawrenceUSA
  4. 4.Department of Anatomy and Cell BiologyUniversity of Kansas, Medical CenterKansas CityUSA
  5. 5.Water Technology GroupBlack and Veatch CorporationWalnut CreekUSA

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