Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering
  • 1.

    Bloom, D. E. et al. The Global Economic Burden of Non-communicable Diseases. Geneva: World Economic Forum (2011).

  • 2.

    Roth, G. A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70, 1–25 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  • 3.

    N. Engl. J. Med. 348, 2007–2018 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  • 4.

    Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 5.

    Menasché, P. et al. The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117, 1189–1200 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  • 6.

    Assmus, B. et al. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ. Fail. 3, 89–96 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  • 7.

    Eur. J. Fail. 12, 721–729 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  • 8.

    Menasché, P. et al. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur. J. 36, 2011–2017 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  • 9.

    Kastrup, J. et al. Direct intramyocardial plasmid vascular endothelial growth factor-A 165 gene therapy in patients with stable severe angina pectoris: a randomized double-blind placebo-controlled study: the Euroinject One trial. J. Am. Coll. Cardiol. 45, 982–988 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 10.

    Zohlnhofer, D. et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients. JAMA 295, 1003–1010 (2006).

  • 11.

    Gao, R. et al. A phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J. Am. Coll. Cardiol. 55, 1907–1914 (2010).

    CAS  PubMed  Article  Google Scholar 

  • 12.

    Chien, K. R. et al. Regenerating the field of cardiovascular cell therapy. Nat. Biotechnol. 37, 232–237 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 13.

    Nat. Protoc. 11, 1775–1781 (2016).

    CAS  PubMed  Article  Google Scholar 

  • 14.

    Madonna, R. et al. ESC Working Group on Cellular Biology of the Position paper for Cardiovascular Research: tissue engineering and cell-based therapies for cardiac repair in ischemic heart disease and heart failure. Cardiovasc. Res. 115, 488–500 (2019).

  • 15.

    Zhao, Y. et al. Towards chamber specific heart-on-a-chip for drug testing applications. Adv. Drug Deliv. Rev. 165, 60–76 (2020).

  • 16.

    Circ. Res. 118, 368–370 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 17.

    Litviňuková, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).

  • 18.

    Hescheler, J. et al. Morphological, biochemical, and electrophysiological characterization of a clonal cell (H9c2) line from rat heart. Circ. Res. 69, 1476–1486 (1991).

    CAS  PubMed  Article  Google Scholar 

  • 19.

    Claycomb, W. C. et al. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl Acad. Sci. USA 95, 2979–2984 (1998).

    CAS  PubMed  Article  Google Scholar 

  • 20.

    Eschenhagen, T. et al. Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. FASEB J. 11, 683–694 (1997).

    CAS  PubMed  Article  Google Scholar 

  • 21.

    Carrier, R. L. et al. Cardiac tissue engineering: cell seeding, cultivation parameters, and tissue construct characterization. Biotechnol. Bioeng. 64, 580–589 (1999).

    CAS  PubMed  Article  Google Scholar 

  • 22.

    Watson, S. A. et al. Preparation of viable adult ventricular myocardial slices from large and small mammals. Nat. Protoc. 12, 2623–2639 (2017).

    CAS  PubMed  Article  Google Scholar 

  • 23.

    Banyasz, T. et al. Transformation of adult rat cardiac myocytes in primary culture. Exp. Physiol. 93, 370–382 (2008).

    PubMed  Article  Google Scholar 

  • 24.

    Watson, S. A. et al. Biomimetic electromechanical stimulation to maintain adult myocardial slices in vitro. Nat. Commun. 10, 1–15 (2019).

  • 25.

    Fischer, C. et al. Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro. Nat. Commun. 10, 1–12 (2019).

    CAS  Article  Google Scholar 

  • 26.

    Davidson, M. M. et al. Novel cell lines derived from adult human ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 39, 133–147 (2005).

    CAS  PubMed  Article  Google Scholar 

  • 27.

    Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Article  Google Scholar 

  • 28.

    Cell 126, 663–676 (2006).

  • 29.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Article  Google Scholar 

  • 30.

    Nat. Rev. Cardiol. 13, 333–349 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 31.

    EMBO J. 33, 409–417 (2014).

  • 32.

    Burridge, P. W. et al. Chemically defned generation of human cardiomyocytes. Nat. Methods 11, 855–860 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 33.

    Ueno, S. et al. Biphasic role for Wnt/β-catenin signaling in cardiac specification in zebrafish and embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 9685–9690 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 34.

    Lian, X. et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc. Natl Acad. Sci. USA 109, E1848–E1857 (2012).

  • 35.

    ACS Chem. Biol. 6, 192–197 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 36.

    Lian, X. et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat. Protoc. 8, 162–175 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 37.

    Squire, J. M. Architecture and function in the muscle sarcomere. Curr. Opin. Struct. Biol. 7, 247–257 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 38.

    Gerdes, A. M. et al. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 86, 426–430 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 39.

    Mollova, M. et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc. Natl Acad. Sci. USA 110, 1446–1451 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 40.

    Olivetti, G. et al. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J. Mol. Cell. Cardiol. 28, 1463–1477 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 41.

    Wei, S. et al. T-tubule remodeling during transition from hypertrophy to heart failure. Circ. Res. 107, 520–531 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 42.

    Circulation 101, 2586–2594 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 43.

    Circ. Res. 113, 1219–1230 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 44.

    Porter, G. A. et al. Bioenergetics, mitochondria, and cardiac myocyte differentiation. Prog. Pediatr. Cardiol. 31, 75–81 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  • 45.

    Circ. Res. 74, 1065–1070 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 46.

    Peters, N. S. et al. Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium. Circulation 90, 713–725 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 47.

    Stem Cells Dev. 22, 1991–2002 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 48.

    Snir, M. et al. Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. Circ. Physiol. 285, 2355–2363 (2003).

    Article  Google Scholar 

  • 49.

    Vreeker, A. et al. Assembly of the cardiac intercalated disk during pre- and postnatal development of the human heart. PLoS ONE 9, e94722 (2014).

  • 50.

    Stem Cells 25, 3038–3044 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 51.

    Lieu, D. K. et al. Absence of transverse tubules contributes to non-uniform Ca2+ wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 18, 1493–1500 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 52.

    Stem Cells Int. 2017, 5153625 (2017).

  • 53.

    Schaaf, S. et al. Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology. PLoS ONE 6, e26397 (2011).

  • 54.

    Sasaki, D. et al. Contractile force measurement of human induced pluripotent stem cell-derived cardiac cell sheet-tissue. PLoS ONE 13, e0198026 (2018).

  • 55.

    J. Cardiovasc. Pharmacol. 56, 130–140 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 56.

    Chung, S. et al. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat. Clin. Pract. Cardiovasc. Med. 4, 60–67 (2007).

    Article  CAS  Google Scholar 

  • 57.

    Circ. Res. 113, 603–616 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 58.

    Van Der Velden, J. et al. Isometric tension development and its calcium sensitivity in skinned myocyte-sized preparations from different regions of the human heart. Cardiovasc. Res. 42, 706–719 (1999).

    PubMed  Article  PubMed Central  Google Scholar 

  • 59.

    Hasenfuss, G. et al. Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species. Circ. Res. 68, 836–846 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 60.

    Circulation 85, 1743–1750 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 61.

    Pieske, B. et al. Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy: functional evidence for alterations in intracellular Ca2+ handling. J. Clin. Invest. 98, 764–776 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 62.

    Mannhardt, I. et al. Human engineered heart tissue: analysis of contractile force. Stem Cell Rep. 7, 29–42 (2016).

    CAS  Article  Google Scholar 

  • 63.

    Huebsch, N. et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep. 6, 1–12 (2016).

    Article  CAS  Google Scholar 

  • 64.

    Card. Electrophysiol. Clin. 3, 23–45 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  • 65.

    Dangman, K. H. et al. Electrophysiologic characteristics of human ventricular and Purkinje fibers. Circulation 65, 362–368 (1982).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 66.

    Satin, J. et al. Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. J. Physiol. 559, 479–496 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 67.

    Mummery, C. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107, 2733–2740 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 68.

    Ribeiro, M. C. et al. Functional maturation of human pluripotent stem cell derived cardiomyocytes invitro – correlation between contraction force andelectrophysiology. Biomaterials 51, 138–150 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 69.

    Scheel, O. et al. Action potential characterization of human induced pluripotent stem cell-derived cardiomyocytes using automated patch-clamp technology. Assay Drug Dev. Technol. 12, 457–469 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 70.

    Biol. Open 7, bio035030 (2018).

  • 71.

    Bers, D. M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 72.

    PLoS ONE 8, e55266 (2013).

  • 73.

    Riedel, M. et al. Functional and pharmacological analysis of cardiomyocytes differentiated from human peripheral blood mononuclear-derived pluripotent stem cells. Stem Cell Rep. 3, 131–141 (2014).

    CAS  Article  Google Scholar 

  • 74.

    Thompson, S. A. et al. Engraftment of human embryonic stem cell derived cardiomyocytes improves conduction in an arrhythmogenic in vitro model. J. Mol. Cell. Cardiol. 53, 15–23 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 75.

    Circ. Res. 10, 306–312 (1962).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 76.

    Circulation 47, 776–785 (1973).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 77.

    Physiol. Genomics 44, 245–258 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 78.

    Front. Cell Dev. Biol. 5, 50 (2017).

  • 79.

    J. Physiol. 598, 2941–2956 (2020).

  • 80.

    Kamakura, T. et al. Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture. Circ. J. 77, 1307–1314 (2013).

    CAS  PubMed  Article  Google Scholar 

  • 81.

    Ebert, A. et al. Proteasome-dependent regulation of distinct metabolic states during long-term culture of human ipsc-derived cardiomyocytes. Circ. Res. 125, 90–103 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 82.

    Shiba, Y. et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538, 388–391 (2016).

  • 83.

    Stem Cell Rep. 8, 278–289 (2017).

    CAS  Article  Google Scholar 

  • 84.

    Radisic, M. et al. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc. Natl Acad. Sci. USA 101, 18129–18134 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 85.

    Tandon, N. et al. Electrical stimulation systems for cardiac tissue engineering. Nat. Protoc. 4, 155–173 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 86.

    J. Mol. Cell. Cardiol. 41, 633–641 (2006).

    CAS  PubMed  Article  Google Scholar 

  • 87.

    Godier-Furnémont, A. F. G. et al. Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation. Biomaterials 60, 82–91 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 88.

    Kroll, K. et al. Electro-mechanical conditioning of human iPSC-derived cardiomyocytes for translational research. Prog. Biophys. Mol. Biol. 130, 212–222 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 89.

    Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781–787 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 90.

    Zimmermann, W. H. et al. Tissue engineering of a differentiated cardiac muscle construct. Circ. Res. 90, 223–230 (2002).

    CAS  PubMed  Article  Google Scholar 

  • 91.

    Hansen, A. et al. Development of a drug screening platform based on engineered heart tissue. Circ. Res. 107, 35–44 (2010).

    CAS  PubMed  Article  Google Scholar 

  • 92.

    Biomaterials 111, 66–79 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 93.

    Breckwoldt, K. et al. Differentiation of cardiomyocytes and generation of human engineered heart tissue. Nat. Protoc. 12, 1177–1197 (2017).

    CAS  PubMed  Article  Google Scholar 

  • 94.

    Ulmer, B. M. et al. Contractile work contributes to maturation of energy metabolism in hiPSC-derived cardiomyocytes. Stem Cell Rep. 10, 834–847 (2018).

    CAS  Article  Google Scholar 

  • 95.

    Uzun, A. U. et al. Ca2+-currents in human induced pluripotent stem cell-derived cardiomyocytes effects of two different culture conditions. Front. Pharmacol. 7, 300 (2016).

  • 96.

    Leonard, A. et al. Afterload promotes maturation of human induced pluripotent stem cell derived cardiomyocytes in engineered heart tissues. J. Mol. Cell. Cardiol. 118, 147–158 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 97.

    Abilez, O. J. et al. Passive stretch induces structural and functional maturation of engineered heart muscle as predicted by computational modeling. Stem Cells 36, 265–277 (2018).

    CAS  PubMed  Article  Google Scholar 

  • 98.

    Anal. Chem. 88, 9862–9868 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 99.

    Hirt, M. N. et al. Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation. J. Mol. Cell. Cardiol. 74, 151–161 (2014).

    CAS  PubMed  Article  Google Scholar 

  • 100.

    Ruan, J. L. et al. Mechanical stress conditioning and electrical stimulation promote contractility and force maturation of induced pluripotent stem cell-derived human cardiac tissue. Circulation 134, 1557–1567 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 101.

    Ronaldson-Bouchard, K. et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556, 239–243 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 102.

    Ribeiro, A. J. S. et al. Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness. Proc. Natl Acad. Sci. USA 112, 12705–12710 (2015).

    CAS  PubMed  Article  Google Scholar 

  • 103.

    Rodriguez, M. L. et al. Substrate stiffness, cell anisotropy, and cell-cell contact contribute to enhanced structural and calcium handling properties of human embryonic stem cell-derived cardiomyocytes. ACS Biomater. Sci. Eng. 5, 3876–3888 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 104.

    Acta Biomater. 7, 3285–3293 (2011).

    CAS  PubMed  Article  Google Scholar 

  • 105.

    Feaster, T. K. et al. Matrigel mattress: a method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 117, 995–1000 (2015).

  • 106.

    Papadaki, M. et al. Tissue engineering of functional cardiac muscle: molecular, structural, and electrophysiological studies. Am. J. Physiol. Circ. Physiol. 280, 168–178 (2001).

    Article  Google Scholar 

  • 107.

    Chen, Y. et al. Engineering a freestanding biomimetic cardiac patch using biodegradable poly(lactic-co-glycolic acid) (PLGA) and human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs). Macromol. Biosci. 15, 426–436 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 108.

    Jongpaiboonkit, L. et al. An adaptable hydrogel array format for 3-dimensional cell culture and analysis. Biomaterials 29, 3346–3356 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 109.

    Chun, Y. W. et al. Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes. Biomaterials 67, 52–64 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 110.

    Feinberg, A. W. et al. Muscular thin films for building actuators and powering devices. Science 317, 1366–1370 (2007).

    CAS  PubMed  Article  Google Scholar 

  • 111.

    Herron, T. J. et al. Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function. Circ. Arrhythmia Electrophysiol. 9, e003638 (2016).

  • 112.

    Fong, A. H. et al. Three-dimensional adult cardiac extracellular matrix promotes maturation of human induced pluripotent stem cell-derived cardiomyocytes. Tissue Eng. Part A 22, 1016–1025 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 113.

    Garreta, E. et al. Myocardial commitment from human pluripotent stem cells: rapid production of human heart grafts. Biomaterials 98, 64–78 (2016).

    CAS  PubMed  Article  Google Scholar 

  • 114.

    Guyette, J. P. et al. Bioengineering human myocardium on native extracellular matrix. Circ. Res. 118, 56–72 (2016).

    CAS  PubMed  Article  Google Scholar 

  • 115.

    Circ. Res. 110, 1023–1034 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 116.

    Abecasis, B. et al. Unveiling the molecular crosstalk in a human induced pluripotent stem cell-derived cardiac model. Biotechnol. Bioeng. 116, 1245–1252 (2019).

    CAS  PubMed  Article  Google Scholar 

  • 117.

    Dunn, K. K. et al. Coculture of endothelial cells with human pluripotent stem cell-derived cardiac progenitors reveals a differentiation stage-specific enhancement of cardiomyocyte maturation. Biotechnol. J. 14, 1800725 (2019).

  • 118.

    Burridge, P. W. et al. Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. Am. J. Transl. Res. 6, 724–735 (2014).

    PubMed  PubMed Central  Google Scholar 

  • 119.

    Shimizu, T. et al. Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensional cell sheet manipulation technique and temperature-responsive cell culture surfaces. Circ. Res. 90, e40–e48 (2002).

  • 120.

    Correia, C. et al. 3D aggregate culture improves metabolic maturation of human pluripotent stem cell derived cardiomyocytes. Biotechnol. Bioeng. 115, 630–644 (2018).

    CAS  PubMed  Article  Google Scholar 

  • 121.

    Eng, G. et al. Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes. Nat. Commun. 7, 1–10 (2016).

    Google Scholar 

  • 122.

    Ma, Z. et al. Self-organizing human cardiac microchambers mediated by geometric confinement. Nat. Commun. 6, 1–10 (2015).

  • 123.

    Goldfracht, I. et al. Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications. Acta Biomater. 92, 145–159 (2019).

    CAS  PubMed  Article  Google Scholar 

  • 124.

    Boudou, T. et al. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng. Part A 18, 910–919 (2012).

    CAS  PubMed  Article  Google Scholar 

  • 125.

    Biomaterials 35, 3819–3828 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 126.

    Shadrin, I. Y. et al. Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues. Nat. Commun. 8, 1–15 (2017).

  • 127.

    Macqueen, L. A. et al. A tissue-engineered scale model of the heart ventricle. Nat. Biomed. Eng. 2, 930–941 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 128.

    Thavandiran, N. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc. Natl Acad. Sci. USA 110, E4698–E4707 (2013).

  • 129.

    Abecasis, B. et al. Toward a microencapsulated 3D hiPSC-derived in vitro cardiac microtissue for recapitulation of human heart microenvironment features. Front. Bioeng. Biotechnol. 8, 1163 (2020).

    Article  Google Scholar 

  • 130.

    Giacomelli, E. et al. Human-iPSC-derived cardiac stromal cells enhance maturation in 3D cardiac microtissues and reveal non-cardiomyocyte contributions to heart disease. Cell Stem Cell 26, 862–879 (2020).

  • 131.

    Ronaldson-Bouchard, K. et al. Engineering of human cardiac muscle electromechanically matured to an adult-like phenotype. Nat. Protoc. 14, 2781–2817 (2019).

  • 132.

    Yang, X. et al. Fatty acids enhance the maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Rep. 13, 657–668 (2019).

    CAS  Article  Google Scholar 

  • 133.

    Hu, D. et al. Metabolic maturation of human pluripotent stem cellderived cardiomyocytes by inhibition of HIF1α and LDHA. Circ. Res. 123, 1066–1079 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 134.

    Correia, C. et al. Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Sci. Rep. 7, 1–17 (2017).

    CAS  Article  Google Scholar 

  • 135.

    Li, M. et al. Thyroid hormone action in postnatal heart development. Stem Cell Res. 13, 582–591 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 136.

    Yang, X. et al. Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J. Mol. Cell. Cardiol. 72, 296–304 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 137.

    Parikh, S. S. et al. Thyroid and glucocorticoid hormones promote functional T-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 121, 1323–1330 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 138.

    Yoshida, S. et al. Maturation of human induced pluripotent stem cell-derived cardiomyocytes by soluble factors from human mesenchymal stem cells. Mol. Ther. 26, 2681–2695 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 139.

    Circ. Res. 87, 781–788 (2000).

  • 140.

    Sucharov, C. C. et al. A β1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction. Am. J. Physiol. Circ. Physiol. 291, 1299–1308 (2006).

    Article  CAS  Google Scholar 

  • 141.

    Patrizio, M. et al. cAMP-mediated β-adrenergic signaling negatively regulates Gq-coupled receptor-mediated fetal gene response in cardiomyocytes. J. Mol. Cell. Cardiol. 45, 761–769 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 142.

    Földes, G. et al. Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy? J. Mol. Cell. Cardiol. 50, 367–376 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 143.

    Lieu, D. K. et al. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Arrhythmia Electrophysiol. 6, 191–201 (2013).

    Article  Google Scholar 

  • 144.

    Liu, J. et al. Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression. Am. J. Physiol. Cell Physiol. 297, 152–159 (2009).

    Article  CAS  Google Scholar 

  • 145.

    Chow, M. Z. et al. Epigenetic regulation of the electrophysiological phenotype of human embryonic stem cell-derived ventricular cardiomyocytes: insights for driven maturation and hypertrophic growth. Stem Cells Dev. 22, 2678–2690 (2013).

  • 146.

    PLoS ONE 7, e45010 (2012).

  • 147.

    Biermann, M. et al. Epigenetic priming of human pluripotent stem cell‐derived cardiac progenitor cells accelerates cardiomyocyte maturation. Stem Cells 37, 910–923 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 148.

    Babiarz, J. E. et al. Determination of the human cardiomyocyte mRNA and miRNA differentiation network by fine-scale profiling. Stem Cells Dev. 21, 1956–1965 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 149.

    Kumar, N. et al. Assessment of temporal functional changes and miRNA profiling of human iPSC-derived cardiomyocytes. Sci. Rep. 9, 1–16 (2019).

    Google Scholar 

  • 150.

    Kuppusamy, K. T. et al. Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc. Natl Acad. Sci. USA 112, E2785–E2794 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 151.

    Lu, T. Y. et al. Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways. J. Mol. Cell. Cardiol. 63, 146–154 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 152.

    Fu, J. D. et al. Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS ONE 6, e27417 (2011).

  • 153.

    Poon, E. N. Y. et al. Integrated transcriptomic and regulatory network analyses identify microRNA-200c as a novel repressor of human pluripotent stem cell-derived cardiomyocyte differentiation and maturation. Cardiovasc. Res. 114, 894–906 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 154.

    Lee, D. S. et al. Defined microRNAs induce aspects of maturation in mouse and human embryonic-stem-cell-derived cardiomyocytes. Cell Rep. 12, 1960–1967 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 155.

    Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 156.

    Zhou, Y. et al. Comparative gene expression analyses reveal distinct molecular signatures between differentially reprogrammed cardiomyocytes. Cell Rep. 20, 3014–3024 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 157.

    Moroni, L. et al. Biofabrication strategies for 3D in vitro models and regenerative medicine. Nat. Rev. Mater. 3, 21–37 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 158.

    Adv. Mater. 21, 3307–3329 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 159.

    Malda, J. et al. 25th anniversary article: engineering hydrogels for biofabrication. Adv. Mater. 25, 5011–5028 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 160.

    Lee, S. et al. Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness. Biomaterials 131, 111–120 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 161.

    Kerscher, P. et al. Direct hydrogel encapsulation of pluripotent stem cells enables ontomimetic differentiation and growth of engineered human heart tissues. Biomaterials 83, 383–395 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 162.

    Nanotechnology 25, 014011 (2014).

  • 163.

    Annu. Rev. Biomed. Eng. 16, 247–276 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 164.

    Rodriguez, M. L. et al. Measuring the contractile forces of human induced pluripotent stem cell-derived cardiomyocytes with arrays of microposts. J. Biomech. Eng. 136, 051005 (2014).

  • 165.

    Biomaterials 27, 3675–3683 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  • 166.

    Biomaterials 32, 3233–3243 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 167.

    Ott, H. C. et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 168.

    Oberwallner, B. et al. Preparation of cardiac extracellular matrix scaffolds by decellularization of human myocardium. J. Biomed. Mater. Res. A 102, 3263–3272 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  • 169.

    Pati, F. et al. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat. Commun. 5, 1–11 (2014).

    Article  CAS  Google Scholar 

  • 170.

    Perea-Gil, I. et al. A cell-enriched engineered myocardial graft limits infarct size and improves cardiac function: pre-clinical study in the porcine myocardial infarction model. JACC Basic Transl. Sci. 1, 360–372 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  • 171.

    Tissue Eng. Part A 16, 2017–2027 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 172.

    Johnson, T. D. et al. Human versus porcine tissue sourcing for an injectable myocardial matrix hydrogel. Biomater. Sci. 2, 735–744 (2014).

    CAS  Article  Google Scholar 

  • 173.

    Bejleri, D. et al. A bioprinted cardiac patch composed of cardiac-specific extracellular matrix and progenitor cells for heart repair. Adv. Healthc. Mater. 7, 1800672 (2018).

  • 174.

    Noor, N. et al. 3D printing of personalized thick and perfusable cardiac patches and hearts. Adv. Sci. 6, 1900344 (2019).

  • 175.

    Zhao, Y. et al. A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell 176, 913–927 (2019).

  • 176.

    Engelmayr, G. C. et al. Accordion-like honeycombs for tissue engineering of cardiac anisotropy. Nat. Mater. 7, 1003–1010 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 177.

    Tian, B. et al. Macroporous nanowire nanoelectronic scaffolds for synthetic tissues. Nat. Mater. 11, 986–994 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 178.

    Feiner, R. et al. Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function. Nat. Mater. 15, 679–685 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 179.

    Proc. Natl Acad. Sci. USA 109, E3414–E3423 (2012).

  • 180.

    Zhang, B. et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat. Mater. 15, 669–678 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 181.

    Gouveia, P. J. et al. Flexible nanofilms coated with aligned piezoelectric microfibers preserve the contractility of cardiomyocytes. Biomaterials 139, 213–228 (2017).

    CAS  PubMed  Article  Google Scholar 

  • 182.

    Nano Lett. 10, 2257–2261 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 183.

    Castilho, M. et al. Melt electrowriting allows tailored microstructural and mechanical design of scaffolds to advance functional human myocardial tissue formation. Adv. Funct. Mater. 28, 1803151 (2018).

  • 184.

    Nat. Biotechnol. 32, 773–785 (2014).

    CAS  PubMed  Article  Google Scholar 

  • 185.

    Hinton, T. J. et al. Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Sci. Adv. 1, e1500758 (2015).

  • 186.

    Lee, A. et al. 3D bioprinting of collagen to rebuild components of the human heart. Science 365, 482–487 (2019).

    CAS  PubMed  Article  Google Scholar 

  • 187.

    Zhang, Y. S. et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials 110, 45–59 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 188.

    Proc. Natl Acad. Sci. USA 113, 3179–3184 (2016).

    CAS  PubMed  Article  Google Scholar 

  • 189.

    Grigoryan, B. et al. Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Science 364, 458–464 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 190.

    Skylar-Scott, M. A. et al. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Sci. Adv. 5, eaaw2459 (2019).

  • 191.

    Bernal, P. N. et al. Volumetric bioprinting of complex living-tissue constructs within seconds. Adv. Mater. 31, 1904209 (2019).

  • 192.

    Fordyce, C. B. et al. Cardiovascular drug development: is it dead or just hibernating? J. Am. Coll. Cardiol. 65, 1567–1582 (2015).

    PubMed  Article  Google Scholar 

  • 193.

    Trends Pharmacol. Sci. 30, 536–545 (2009).

    CAS  PubMed  Article  Google Scholar 

  • 194.

    Annu. Rev. Pharmacol. Toxicol. 58, 83–103 (2018).

    CAS  PubMed  Article  Google Scholar 

  • 195.

    Polonchuk, L. et al. Cardiac spheroids as promising in vitro models to study the human heart microenvironment. Sci. Rep. 7, 1–12 (2017).

    CAS  Article  Google Scholar 

  • 196.

    Lab Chip 13, 3599–3608 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 197.

    Marsano, A. et al. Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues. Lab Chip 16, 599–610 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 198.

    Feric, N. T. et al. Engineered cardiac tissues generated in the biowire II: a platform for human-based drug discovery. Toxicol. Sci. 172, 89–97 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  • 199.

    Chramiec, A. et al. Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety. Lab Chip 20, 4357–4372 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 200.

    Lind, J. U. et al. Cardiac microphysiological devices with flexible thin-film sensors for higher-throughput drug screening. Lab Chip 17, 3692–3703 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 201.

    Zhao, Y. et al. A multimaterial microphysiological platform enabled by rapid casting of elastic microwires. Adv. Healthc. Mater. 8, 1801187 (2019).

  • 202.

    Lab Chip 17, 2395–2420 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 203.

    Sun, N. et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci. Transl. Med. 4, 130ra47 (2012).

  • 204.

    Burridge, P. W. et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 22, 547–556 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 205.

    Lan, F. et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell 12, 101–113 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 206.

    Lee, J. et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature 572, 335–340 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 207.

    Te Riele, A. S. J. M. et al. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc. Res. 113, 102–111 (2017).

    Article  CAS  Google Scholar 

  • 208.

    Kodo, K. et al. iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy. Nat. Cell Biol. 18, 1031–1042 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 209.

    Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–230 (2011).

  • 210.

    Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–236 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 211.

    Matsa, E. et al. Transcriptome profiling of patient-specific human iPSC-cardiomyocytes predicts individual drug safety and efficacy responses in vitro. Cell Stem Cell 19, 311–325 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 212.

    Sharma, A. et al. High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Sci. Transl. Med. 9, eaaf2584 (2017).

  • 213.

    Smith, J. G. W. et al. Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits. Stem Cell Rep. 11, 1226–1243 (2018).

    CAS  Article  Google Scholar 

  • 214.

    de la Roche, J. et al. Comparing human iPSC-cardiomyocytes versus HEK293T cells unveils disease-causing effects of Brugada mutation A735V of NaV1.5 sodium channels. Sci. Rep. 9, 1–14 (2019).

  • 215.

    2+ signaling. Cell Calcium 73, 104–111 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 216.

    Mosqueira, D. et al. /Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur. J. 39, 3879–3892 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 217.

    Hinson, J. T. et al. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349, 982–986 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 218.

    Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 219.

    Goldfracht, I. et al. Generating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes. Nat. Commun. 11, 1–15 (2020).

    Article  CAS  Google Scholar 

  • 220.

    Proc. Natl Acad. Sci. USA 110, 9770–9775 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 221.

    Sadeghi, A. H. et al. Engineered 3D cardiac fibrotic tissue to study fibrotic remodeling. Adv. Healthc. Mater. 6, 1601434 (2017).

  • 222.

    Zhang, Y. S. et al. Bioprinted thrombosis-on-a-chip. Lab Chip 16, 4097–4105 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 223.

    Vikhorev, P. G. et al. Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Sci. Rep. 7, 1–11 (2017).

    CAS  Article  Google Scholar 

  • 224.

    Prondzynski, M. et al. Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy. EMBO Mol. Med. 11, e11115 (2019).

  • 225.

    Madonna, R. et al. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the : cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur. J. 37, 1789–1798 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  • 226.

    Sluijter, J. P. G. et al. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the of the European Society of Cardiology. Cardiovasc. Res. 114, 19–34 (2018).

  • 227.

    Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  • 228.

    Terrovitis, J. et al. Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J. Am. Coll. Cardiol. 54, 1619–1626 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  • 229.

    Gaetani, R. et al. Cardiospheres and tissue engineering for myocardial regeneration: potential for clinical application. J. Cell. Mol. Med. 14, 1071–1077 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  • 230.

    Hou, D. et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112, I-150–I-156 (2005).

  • 231.

    Riegler, J. et al. Human engineered heart muscles engraft and survive long term in a rodent myocardial infarction model. Circ. Res. 117, 720–730 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 232.

    Pecha, S. et al. Human iPS cell-derived engineered heart tissue does not affect ventricular arrhythmias in a guinea pig cryo-injury model. Sci. Rep. 9, 1–12 (2019).

    CAS  Article  Google Scholar 

  • 233.

    Weinberger, F. et al. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Sci. Transl. Med. 8, 363ra148 (2016).

  • 234.

    Gao, L. et al. Large cardiac muscle patches engineered from human induced-pluripotent stem cell-derived cardiac cells improve recovery from myocardial infarction in swine. Circulation 137, 1712–1730 (2018).

    PubMed  Article  Google Scholar 

  • 235.

    Mawad, D. et al. A conducting polymer with enhanced electronic stability applied in cardiac models. Sci. Adv. 2, e1601007 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 236.

    Ye, L. et al. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15, 750–761 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 237.

    Gaetani, R. et al. Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. Biomaterials 61, 339–348 (2015).

    CAS  PubMed  Article  Google Scholar 

  • 238.

    Feyen, D. A. M. et al. Gelatin microspheres as vehicle for cardiac progenitor cells delivery to the myocardium. Adv. Healthc. Mater. 5, 1071–1079 (2016).

    CAS  PubMed  Article  Google Scholar 

  • 239.

    Li, J. et al. Human pluripotent stem cell-derived cardiac tissue-like constructs for repairing the infarcted myocardium. Stem Cell Rep. 9, 1546–1559 (2017).

    CAS  Article  Google Scholar 

  • 240.

    Kawamura, M. et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation 126, S29–S37 (2012).

  • 241.

    Landa, N. et al. Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation 117, 1388–1396 (2008).

    CAS  PubMed  Article  Google Scholar 

  • 242.

    Seif-Naraghi, S. B. et al. Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction. Sci. Transl. Med. 5, 173ra25 (2013).

  • 243.

    Lin, X. et al. A viscoelastic adhesive epicardial patch for treating myocardial infarction. Nat. Biomed. Eng. 3, 632–643 (2019).

    CAS  PubMed  Article  Google Scholar 

  • 244.

    Card. Electrophysiol. Clin. 7, 357–370 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  • 245.

    JAMA Cardiol. 1, 953–962 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  • 246.

    Madonna, R. Human-induced pluripotent stem cells: in quest of clinical applications. Mol. Biotechnol. 52, 193–203 (2012).

  • 247.

    Breitbach, M. et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110, 1362–1369 (2007).

    CAS  PubMed  Article  Google Scholar 

  • 248.

    Blin, G. et al. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J. Clin. Invest. 120, 1125–1139 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 249.

    Circulation 109, 3154–3157 (2004).

    PubMed  Article  Google Scholar 

  • 250.

    Adv. Drug Deliv. Rev. 114, 184–192 (2017).

    CAS  PubMed  Article  Google Scholar 

  • 251.

    Menasché, P. et al. Transplantation of human embryonic stem cell–derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 71, 429–438 (2018).

    PubMed  Article  Google Scholar 

  • 252.

    Mewhort, H. E. M. et al. Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery. J. Lung Transplant. 35, 661–670 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  • 253.

    J. Thorac. Cardiovasc. Surg. 147, e41–e43 (2014).

  • 254.

    J. Thorac. Cardiovasc. Surg. 147, 1650–1659 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 255.

    Traverse, J. H. et al. First-in-man study of a cardiac extracellular matrix hydrogel in early and late myocardial infarction patients. JACC Basic Transl. Sci. 4, 659–669 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  • 256.

    Frey, N. et al. Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-in-man study. Circ. Cardiovasc. Interv. 7, 806–812 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  • 257.

    Rao, S. V. et al. Bioabsorbable intracoronary matrix for prevention of ventricular remodeling after myocardial infarction. J. Am. Coll. Cardiol. 68, 715–723 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  • 258.

    Rao, S. V. et al. A randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction: Rationale and design of the PRESERVATION I trial. Am. J. 170, 929–937 (2015).

  • 259.

    Anker, S. D. et al. A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial). Eur. J. 36, 2297–2309 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 260.

    Mann, D. L. et al. One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure. Eur. J. Fail. 18, 314–325 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  • 261.

    Lee, R. J. et al. The feasibility and safety of Algisyl-LVRTM as a method of left ventricular augmentation in patients with dilated cardiomyopathy: initial first in man clinical results. Int. J. Cardiol. 199, 18–24 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  • 262.

    Puymirat, E. et al. Can mesenchymal stem cells induce tolerance to cotransplanted human embryonic stem cells? Mol. Ther. 17, 176–182 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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