The Promise of Induced Pluripotent Stem Cell–Derived Cardiomyocytes to Treat Heart Failure

HomeCirculation: Heart FailureVol. 11, No. 10The Promise of Induced Pluripotent Stem Cell–Derived Cardiomyocytes to Treat Heart Failure Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBThe Promise of Induced Pluripotent Stem Cell–Derived Cardiomyocytes to Treat Heart Failure Jordan J. Lancaster, PhD, Jen Watson Koevary, PhD, Ikeotunye Royal Chinyere, BS and Steven Goldman, MD Jordan J. LancasterJordan J. Lancaster Jordan Lancaster, PhD, Sarver Heart Center, University of Arizona, 1501 N Campbell Ave, PO Box 245046, Tucson, AZ 85724. Email E-mail Address: [email protected] Sarver Heart Center, University of Arizona, Tucson (J.J.L., I.R.C., S.G.) , Jen Watson KoevaryJen Watson Koevary Sarver Heart Center, University of Arizona, Tucson (J.J.L., I.R.C., S.G.) , Ikeotunye Royal ChinyereIkeotunye Royal Chinyere Sarver Heart Center, University of Arizona, Tucson (J.J.L., I.R.C., S.G.) and Steven GoldmanSteven Goldman Sarver Heart Center, University of Arizona, Tucson (J.J.L., I.R.C., S.G.) Originally published12 Oct 2018https://doi.org/10.1161/CIRCHEARTFAILURE.118.005425Circulation: Heart Failure. 2018;11:e005425Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 12, 2018: Previous Version of Record Scientists in Japan are now performing a clinical trial using human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) to treat chronic heart failure (CHF).1 In this trial, cardiothoracic surgeons will implant cell sheets of iPSC-CMs on the epicardial surface of the heart in patients with CHF. This trial builds on earlier work with cell-based therapy where investigators injected cells directly into the myocardium or into the coronary arteries. Here, we focus on the development of iPSC-CMs to treat CHF with an emphasis on using tissue engineering (TE) approaches to deliver these cells.Clinical ProblemThere is clearly a need for new treatments for end-stage CHF. Assist devices and heart transplantations are limited by cost, surgical burden, and the latter by donor supply.2 Treatments for CHF, with the exception of heart transplants, do not address the specific underlying pathology in ischemic heart failure, that is, loss of cardiomyocytes. The first work in cell-based therapy for CHF was transplanting skeletal myoblasts followed by injecting several bone marrow–derived cells, mesenchymal-derived stem cells, CD34+, adipose, and cardiosphere derived cells. With the exception of the skeletal myoblasts, these approaches have proven safe and well tolerated but with limited long-term efficacy.3 These limitations may have been because of using incorrect therapeutic cells or suboptimal delivery methods.Induced Pluripotent Stem CellsIn 2012, the Nobel Prize in Physiology or Medicine was awarded to John B. Gurdon and Shinya Yamanaka for the discovery that adult differentiated cells can be reprogrammed to become pluripotent and can be used to generate an almost unlimited source of any type of human cell. These cells include cardiac progenitors and terminally differentiated cardiomyocytes, mesenchymal stem cells, endothelial progenitor cells, and vascular smooth muscle cells.4 The potential of iPSC-CMs to regenerate cardiomyocytes has been recently reviewed in an American Heart Association Consensus Statement that concluded that although cell therapy has potential, among other suggestions, methods of delivery need further study.5 Although iPSC-CMs can be delivered using injection based modalities, they could also provide building blocks for enhanced delivery approaches, such as engineering a Human Cardiac Patch.6TE for CHFThe aim of TE is to overcome the lack of benefit with cell injections that is attributed to poor delivery at the injection site and poor survival, limiting the duration of functional benefit, which may be because of (1) lack of structural support, and (2) limited nutrient/blood supply and injection site wash out. There are a number of TE approaches that have the potential to deliver iPSC-CMs to the heart. The limited scope of this review does not allow for complete descriptions of all available tissue-engineered approaches; however, the most advanced approaches include cell sheets, shape memory scaffolds, tissue decellularization/recellularization, 3-dimensional printing, fibrin, and matrix patches.7–13Our ApproachWe have developed a TE cardiac graft composed of a bioabsorbable scaffold embedded with fibroblasts and iPSC-CMs that is implanted on the epicardial surface of the heart. The scaffold, paired with fibronectin and collagen extracellular matrix deposits from the fibroblasts, provides matrix support for iPSC-CMs and a robust structure permitting handling and manipulation during surgical implantation. In preclinical models of CHF, the graft reverses maladaptive left ventricular remodeling, activates endogenous growth factor secretion, and improves myocyte density, left ventricular systolic and diastolic function, electrical propagation, myocardial blood flow, and is not proarrhythmic.14,15Autologous Versus AllogeneicThe initial approach to cell therapy proposed utilizing autologous cells for cell survival without the need for immune suppression. The downside of autologous approaches is that cell collection and processing to create a patient-specific product is time consuming and costly. Stability of the lines, especially from older donors needs to be considered as in the autologous iPSC macular degeneration trial in Japan that now using allogeneic cells.16 Allogeneic cells can improve safety and potency by using healthy donors and decrease costs to improve availability by manufacturing in bulk.Immune SuppressionThe currently active Japanese CHF trial administers allogeneic iPSC-CMs with immune suppression. The use of immune suppression is based on the belief that human iPSC-CMs are not immune privileged and the need for long-term cell survival.17 There is evidence of lack of engraftment even with immune suppression.11 An approach to potentially avoid immune suppression is to develop cell banks from donors with known human leukocyte antigens and then match donor iPSCs with recipients. The necessity to maintain human leukocyte antigens cell banks and generate products from each bank would be expensive, limiting its appeal. It is also possible to use gene editing to create iPSCs with reduced cell surface markers to limit or diminish an immune response (http://www.universalcells.com/technology). It is unclear if either of these approaches will result in cell survival. Furthermore, some investigators believe that cell survival is not required for functional benefit, but there are minimal data to support this. We need to understand the immunologic profiles and mechanisms of action of cells to determine if immune suppression is needed and, if so, the appropriate regimen for clinical trials.17 We believe that duration of benefit can outlast cell survival and the duration of cell survival required may be application specific.Mechanism of ActionA criticism of work with iPSC-CM cell therapy is that we do not understand the mechanisms of action of these cells in treating CHF. Most investigators favor paracrine effects, such as growth factor/cytokine secretion and possibly exosomes generated from iPSC-derivatives.18 The specific paracrine stimulation profile may vary by cell type and be unique to the delivery approach. There are other challenges of cardiac TE, including the need to understand which cell or combination of cells are needed, how to provide vascularization of the tissue, and how to support cell integration into these platforms.19 Suggestions have been made that we should not proceed into clinical trials until we have a better understanding of mechanisms of action. It is important to remember that drugs for CHF, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and β-adrenergic receptor blockers were approved without knowing their specific mechanisms in CHF.ConclusionsAlthough there is still much work to be done to achieve optimal functional benefit, the investigators in Japan using iPSC-CMs to treat patients with CHF are to be congratulated for moving the field forward.1DisclosuresDrs. Lancaster, Koevary, and Goldman have a financial interest in Avery Therapeutics, a biotechnology company that is commercializing platform technologies to deliver cell-based therapies for clinical use. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Guest Editor for this article was Kenneth B. Margulies, MD.Jordan Lancaster, PhD, Sarver Heart Center, University of Arizona, 1501 N Campbell Ave, PO Box 245046, Tucson, AZ 85724. Email [email protected]arizona.eduReferences1. Cyranoski D. Reprogrammed stem cells approved to mend hearts Japanese study is only the second application of induced pluripotent stem cells in people.Nature. 2018; 557:619–20.CrossrefMedlineGoogle Scholar2. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the American Heart Association.Circulation. 2018; 137:e67–e492. doi: 10.1161/CIR.0000000000000558LinkGoogle Scholar3. Nguyen PK, Rhee JW, Wu JC. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review.JAMA Cardiol. 2016; 1:831–841. doi: 10.1001/jamacardio.2016.2225CrossrefMedlineGoogle Scholar4. Karakikes I, Ameen M, Termglinchan V, Wu JC. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes.Circ Res. 2015; 117:80–88. doi: 10.1161/CIRCRESAHA.117.305365LinkGoogle Scholar5. Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisén J, Giacca M, Hare JM, Houser S, Lee RT, Marbán E, Martin JF, Molkentin JD, Murry CE, Riley PR, Ruiz-Lozano P, Sadek HA, Sussman MA, Hill JA. Cardiomyocyte regeneration: a consensus statement.Circulation. 2017; 136:680–686. doi: 10.1161/CIRCULATIONAHA.117.029343LinkGoogle Scholar6. Zhang J, Zhu W, Radisic M, Vunjak-Novakovic G. Can we engineer a human cardiac patch for therapy?Circ Res. 2018; 123:244–265. doi: 10.1161/CIRCRESAHA.118.311213LinkGoogle Scholar7. Kawamura M, Miyagawa S, Miki K, Saito A, Fukushima S, Higuchi T, Kawamura T, Kuratani T, Daimon T, Shimizu T, Okano T, Sawa Y. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model.Circulation. 2012; 126(11suppl 1):S29–S37. doi: 10.1161/CIRCULATIONAHA.111.084343LinkGoogle Scholar8. Montgomery M, Ahadian S, Davenport Huyer L, Lo Rito M, Civitarese RA, Vanderlaan RD, Wu J, Reis LA, Momen A, Akbari S, Pahnke A, Li RK, Caldarone CA, Radisic M. Flexible shape-memory scaffold for minimally invasive delivery of functional tissues.Nat Mater. 2017; 16:1038–1046. doi: 10.1038/nmat4956CrossrefMedlineGoogle Scholar9. Taylor DA, Sampaio LC, Ferdous Z, Gobin AS, Taite LJ. Decellularized matrices in regenerative medicine.Acta Biomater. 2018; 74:74–89. doi: 10.1016/j.actbio.2018.04.044CrossrefMedlineGoogle Scholar10. Wnorowski A, Wu JC. 3-dimensionally printed, native- like scaffolds for myocardial tissue engineering.Circ Res. 2017; 120:1224–1226. doi: 10.1161/CIRCRESAHA.117.310862LinkGoogle Scholar11. Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Parouchev A, Cacciapuoti I, Al-Daccak R, Benhamouda N, Blons H, Agbulut O, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Charron D, Tartour E, Tachdjian G, Desnos M, Larghero J. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction.J Am Coll Cardiol. 2018; 71:429–438. doi: 10.1016/j.jacc.2017.11.047CrossrefMedlineGoogle Scholar12. Schmuck EG, Mulligan JD, Ertel RL, Kouris NA, Ogle BM, Raval AN, Saupe KW. Cardiac fibroblast-derived 3D extracellular matrix seeded with mesenchymal stem cells as a novel device to transfer cells to the ischemic myocardium.Cardiovasc Eng Technol. 2014; 5:119–131. doi: 10.1007/s13239-013-0167-1CrossrefMedlineGoogle Scholar13. Gao L, Kupfer ME, Jung JP, Yang L, Zhang P, Da Sie Y, Tran Q, Ajeti V, Freeman BT, Fast VG, Campagnola PJ, Ogle BM, Zhang J. Myocardial tissue engineering with cells derived from human-induced pluripotent stem cells and a native-like, high-resolution, 3-dimensionally printed scaffold.Circ Res. 2017; 120:1318–1325. doi: 10.1161/CIRCRESAHA.116.310277LinkGoogle Scholar14. Lancaster JJ, Juneman E, Arnce SA, Johnson NM, Qin Y, Witte R, Thai H, Kellar RS, Ek Vitorin J, Burt J, Gaballa MA, Bahl JJ, Goldman S. An electrically coupled tissue-engineered cardiomyocyte scaffold improves cardiac function in rats with chronic heart failure.J Heart Lung Transplant. 2014; 33:438–445. doi: 10.1016/j.healun.2013.12.004CrossrefMedlineGoogle Scholar15. Lancaster JJ, Koevary J, Chinyere I, Juneman E, Goldman S. Cardiac grafts from human IPSC ventricular pure or heterogeneous cardiomyocytes display synchronized spontaneous contraction and reduce ventricular tachycardia in rats with chronic heart failure.J Cardiac Fail. 2017; 23:S90.CrossrefMedlineGoogle Scholar16. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M. Autologous induced stem-cell-derived retinal cells for macular degeneration.N Engl J Med. 2017; 376:1038–1046. doi: 10.1056/NEJMoa1608368CrossrefMedlineGoogle Scholar17. Pearl JI, Kean LS, Davis MM, Wu JC. Pluripotent stem cells: immune to the immune system?Sci Transl Med. 2012; 4:164ps25. doi: 10.1126/scitranslmed.3005090CrossrefMedlineGoogle Scholar18. Jung JH, Fu X, Yang PC. Exosomes generated from iPSC- derivatives: new direction for stem cell therapy in human heart diseases.Circ Res. 2017; 120:407–417. doi: 10.1161/CIRCRESAHA.116.309307LinkGoogle Scholar19. Ogle BM, Bursac N, Domian I, Huang NF, Menasché P, Murry CE, Pruitt B, Radisic M, Wu JC, Wu SM, Zhang J, Zimmermann W-H, Novakovic GV. Distilling complexity to advance cardiac tissue engineering.Sci Transl Med. 2016: 8:342ps13. doi: 10.1126/scitranslmed.aad2304CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By He X, Liang J, Paul C, Huang W, Dutta S and Wang Y (2022) Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair, Cells, 10.3390/cells11233914, 11:23, (3914) Vadakke‐Madathil S and Chaudhry H (2022) Concepts of Cell Therapy and Myocardial Regeneration Interventional Cardiology, 10.1002/9781119697367.ch30, (322-328), Online publication date: 3-Jun-2022. Park H, De Jesus Morales K, Bheri S, Kassouf B and Davis M (2021) Bidirectional Relationship Between Cardiac Extracellular Matrix and Cardiac Cells in Ischemic Heart Disease, Stem Cells, 10.1002/stem.3445, 39:12, (1650-1659), Online publication date: 1-Dec-2021. Cruz-Samperio R, Jordan M and Perriman A (2021) Cell augmentation strategies for cardiac stem cell therapies, Stem Cells Translational Medicine, 10.1002/sctm.20-0489, 10:6, (855-866), Online publication date: 1-Jun-2021. October 2018Vol 11, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.118.005425PMID: 30354396 Originally publishedOctober 12, 2018 Keywordsinducedpluripotent stem cellendothelial progenitor cellstissue engineeringheart failurebone marrowPDF download Advertisement SubjectsBasic Science ResearchCell TherapyHeart FailureStem CellsTranslational Studies