Myocardial Tissue Engineering for Regenerative Applications
- 676 Downloads
Purpose of Review
This review provides an overview of the current state of tissue-engineered heart repair with a special focus on the anticipated modes of action of tissue-engineered therapy candidates and particular implications as to transplant immunology.
Myocardial tissue engineering technologies have made tremendous advances in recent years. Numerous different strategies are under investigation and have reached different stages on their way to clinical translation. Studies in animal models demonstrated that heart repair requires either remuscularization by delivery of bona fide cardiomyocytes or paracrine support for the activation of endogenous repair mechanisms. Tissue engineering approaches result in enhanced cardiomyocyte retention and sustained remuscularization, but may also be explored for targeted paracrine or mechanical support. Some of the more advanced tissue engineering approaches are already tested clinically; others are at late stages of pre-clinical development. Process optimization towards cGMP compatibility and clinical scalability of contractile engineered human myocardium is an essential step towards clinical translation. Long-term allograft retention can be achieved under immune suppression. HLA matching may be an option to enhance graft retention and reduce the need for comprehensive immune suppression.
Tissue-engineered heart repair is entering the clinical stage of the translational pipeline. Like in any effective therapy, side effects must be anticipated and carefully controlled. Allograft implantation under immune suppression is the most likely clinical scenario. Strategies to overcome transplant rejection are evolving and may further boost the clinical acceptance of tissue-engineered heart repair.
KeywordsTissue engineering Engineered heart muscle Pluripotent stem cells Regeneration Remuscularization Heart failure Transplant immunology
Compliance with Ethical Standards
Buntaro Fujita is supported by an Adumed research stipend. Wolfram-Hubertus Zimmermann is supported by the DZHK (German Center for Cardiovascular Research), the German Federal Ministry for Science and Education (BMBF FKZ 13GW0007A [CIRM-ET3]), the German Research Foundation (DFG ZI 708/10-1; SFB 937 TP18, SFB 1002 TPs C04, S1; IRTG 1618 RP12), the European Union FP7 CARE-MI, the Foundation Leducq, and the NIH (U01HL099997).
Conflict of Interest
The Universities of Hamburg and Göttingen have field several patent applications based on the original work by the Zimmermann lab. Patents have been acquired or licensed by Tissue Systems Holding GmbH (TSH), myriamed GmbH (myr), and Repairon GmbH (Rep). Patents issued with licenses are WO2008058917 and WO2015025030; patents pending with licenses are WO2015/040142 and EP 13182437 A 20130830. Wolfram-Hubertus Zimmermann is a co-founder and an uncompensated scientific advisor of TSH, myr, and Rep. Buntaro Fujita declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent
This review article does not contain any original data obtained from human or animal subjects.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 2.Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.CrossRefPubMedGoogle Scholar
- 3.Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report—2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:1158–69.CrossRefPubMedGoogle Scholar
- 9.•• Tiburcy M, Hudson JE, Balfanz P, et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modelling and repair. Circulation. 2017;135:1832–47. This study developed a universally applicable protocol for the generation of engineered human myocardium (EHM) under fully defined GMP-compatible conditions from ESC- or iPSC-derived cardiomyocytes and fibroblasts in a collagen type I hydrogel. CrossRefPubMedGoogle Scholar
- 10.•• Menasche P, Vanneaux V, Hagege A, et al. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur Heart J. 2015;36:2011–7. This is the first report on the implantation of human ESC-derived cardiac progenitor cell allografts in a fibrin matrix in patients with heart failure. CrossRefPubMedGoogle Scholar
- 12.Miyagawa S, Domae K, Yoshikawa Y, et al. Phase I clinical trial of autologous stem cell-sheet transplantation therapy for treating cardiomyopathy. J Am Heart Assoc. 2017;6.Google Scholar
- 20.Soong PL, Tiburcy M, Zimmermann WH. Cardiac differentiation of human embryonic stem cells and their assembly into engineered heart muscle. Curr Protoc Cell Biol. 2012;Chapter 23:Unit23 8.Google Scholar
- 34.Vukadinovic-Nikolic Z, Andree B, Dorfman SE, et al. Generation of bioartificial heart tissue by combining a three-dimensional gel-based cardiac construct with decellularized small intestinal submucosa. Tissue Eng A. 2014;20:799–809.Google Scholar
- 44.Anker SD, Coats AJ, Cristian G, 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 Heart J. 2015;36:2297–309.CrossRefPubMedPubMedCentralGoogle Scholar
- 58.Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation. 2006;113:1287–94.CrossRefPubMedGoogle Scholar
- 61.Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308:2369–79.CrossRefPubMedPubMedCentralGoogle Scholar
- 64.Malliaras K, Makkar RR, Smith RR, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol. 2014;63:110–22.CrossRefPubMedGoogle Scholar
- 66.Homma J, Sekine H, Matsuura K, Yamato M, Shimizu T. Myoblast cell sheet transplantation enhances the endogenous regenerative abilities of infant hearts in rats with myocardial infarction. J Tissue Eng Regen Med. 2015.Google Scholar
- 79.• Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell. 2012;11:147–52. Important overview on the concept and limitations of the identification und use of HLA-homozygous iPSC-allografts. CrossRefPubMedGoogle Scholar