Advancing Myocardial Infarction Treatment: Harnessing Multi-Layered Recellularized Cardiac Patches with Fetal Myocardial Scaffolds and Acellular Amniotic Membrane.

Publisher: Springer Country of Publication: United States NLM ID: 101531846 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1869-4098 (Electronic) Linking ISSN: 1869408X NLM ISO Abbreviation: Cardiovasc Eng Technol Subsets: MEDLINE

Original Publication: New York, NY : Springer

Myocardial Infarction*/pathology ; Myocardial Infarction*/physiopathology ; Myocardial Infarction*/metabolism ; Myocardial Infarction*/therapy ; Rats, Wistar* ; Myocytes, Cardiac*/transplantation ; Myocytes, Cardiac*/pathology ; Myocytes, Cardiac*/metabolism ; Amnion*/transplantation ; Disease Models, Animal* ; Tissue Scaffolds*; Animals ; Humans ; Cells, Cultured ; Tissue Engineering ; Decellularized Extracellular Matrix/chemistry ; Time Factors ; Regeneration ; Gestational Age ; Ventricular Function, Left ; Myocardium/pathology ; Myocardium/metabolism ; Neovascularization, Physiologic ; Male ; Female

Purpose: Myocardial infarction (MI) is a leading cause of irreversible functional cardiac tissue loss, requiring novel regenerative strategies. This study assessed the potential therapeutic efficacy of recellularized cardiac patches, incorporating fetal myocardial scaffolds with rat fetal cardiomyocytes and acellular human amniotic membrane, in adult Wistar rat models of MI.
Methods: Decellularized myocardial tissue was obtained from 14 to 16 week-old human fetuses that had been aborted. Chemical detergents (0.1% EDTA and 0.2% sodium dodecyl sulfate) were used to prepare the fetal extracellular matrix (ECM), which was characterized for bio-scaffold microstructure and biocompatibility via scanning electron microscopy (SEM) and MTT assay, respectively. Neonatal cardiomyocytes were extracted from the ventricles of one-day-old Wistar rats' littermates and characterized through immunostaining against Connexin-43 and α-smooth muscle actin. The isolated cells were seeded onto decellularized tissues and covered with decellularized amniotic membrane. Sixteen healthy adult Wistar rats were systematically allocated to control and MI groups. MI was induced via arterial ligation. Fourteen days post-operation, the MI group was received the engineered patches. Following a two-week post-implantation period, the animals were euthanized, and the hearts were harvested for the graft evaluation.
Results: Histological analysis, DAPI staining, and ultra-structural examination corroborated the successful depletion of cellular elements, while maintaining the integrity of the fetal ECM and architecture. Subsequent histological and immunohistochemichal (IHC) evaluations confirmed effective cardiomyocyte seeding on the scaffolds. The application of these engineered patches in MI models resulted in increased angiogenesis, reduced fibrosis, and restricted scar tissue formation, with the implanted cardiomyocytes remaining viable at graft sites, indicating prospective in vivo cell viability.
Conclusions: This study suggests that multi-layered recellularized cardiac patches are a promising surgical intervention for myocardial infarction, showcasing significant potential by promoting angiogenesis, mitigating fibrosis, and minimizing scar tissue formation in MI models. These features are pivotal for enhancing the therapeutic outcomes in MI patients, focusing on the restoration of the myocardial structure and function post-infarction.
Competing Interests: Declarations. Ethics Approval: This study was performed in line with the Ethics Guidelines of the Tehran University of Medical Sciences (TUMS). Approval was granted by Ethics committee of TUMS (No.: IR.TUMS.CHMC.REC.1396.4766). Disclosures: The research purpose and the study protocol were explained to the donors’ families, and informed consent forms were collected for donation and application of human tissues. No human studies were carried out by the authors for this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees. Competing Interests: The authors have no relevant financial or non-financial interests to disclose.
(© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O’Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS (2019) Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 139 (10):e56-e528. doi: https://doi.org/10.1161/cir.0000000000000659. (PMID: 10.1161/cir.000000000000065930700139)
Samak M, Hinkel R (2019) Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects. Cells 8 (12). doi: https://doi.org/10.3390/cells8121530.
Ye J, Yeghiazarians Y (2014) Cardiac stem cell therapy: review of the native cardiac progenitor cells and future direction. Journal of cardiovascular pharmacology 63 (2):85–94. doi: https://doi.org/10.1097/FJC.0b013e318299ebc0. (PMID: 10.1097/FJC.0b013e318299ebc023674056)
Attar A, Bahmanzadegan Jahromi F, Kavousi S, Monabati A, Kazemi AJScr, therapy (2021) Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials. 12 (1):1–11.
Frey N, Linke A, Süselbeck T, Müller-Ehmsen J, Vermeersch P, Schoors D, Rosenberg M, Bea F, Tuvia S, Leor J (2014) Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-in-man study. Circulation Cardiovascular interventions 7 (6):806–812. doi: https://doi.org/10.1161/circinterventions.114.001478. (PMID: 10.1161/circinterventions.114.00147825351198)
Mabotuwana NS, Rech L, Lim J, Hardy SA, Murtha LA, Rainer PP, Boyle AJ (2022) Paracrine Factors Released by Stem Cells of Mesenchymal Origin and their Effects in Cardiovascular Disease: A Systematic Review of Pre-clinical Studies. Stem cell reviews and reports 18 (8):2606–2628. doi: https://doi.org/10.1007/s12015-022-10429-6. (PMID: 10.1007/s12015-022-10429-6358968609622561)
Braunwald EJCr (2018) Cell-based therapy in cardiac regeneration: an overview. 123 (2):132–137.
Segers VF, Lee RTJN (2008) Stem-cell therapy for cardiac disease. 451 (7181):937–942.
Pattar SS, Fatehi Hassanabad A, Fedak PWJFiCM (2019) Application of bioengineered materials in the surgical management of heart failure. 6:123.
Berry MF, Engler AJ, Woo YJ, Pirolli TJ, Bish LT, Jayasankar V, Morine KJ, Gardner TJ, Discher DE, Sweeney HLJAJoP-H, Physiology C (2006) Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. 290 (6):H2196-H2203.
Lyon A, Harding S (2007) The potential of cardiac stem cell therapy for heart failure. Current opinion in pharmacology 7 (2):164–170. doi: https://doi.org/10.1016/j.coph.2006.10.003. (PMID: 10.1016/j.coph.2006.10.00317275411)
Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF (2002) Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. Journal of applied physiology (Bethesda, Md: 1985) 92 (1):288–296. doi: https://doi.org/10.1152/jappl.2002.92.1.288.
Fujimoto KL, Clause KC, Liu LJ, Tinney JP, Verma S, Wagner WR, Keller BB, Tobita KJTEPA (2011) Engineered fetal cardiac graft preserves its cardiomyocyte proliferation within postinfarcted myocardium and sustains cardiac function. 17 (5–6):585–596.
Lock MC, Darby JRT, Soo JY, Brooks DA, Perumal SR, Selvanayagam JB, Seed M, Macgowan CK, Porrello ER, Tellam RL, Morrison JL (2019) Differential Response to Injury in Fetal and Adolescent Sheep Hearts in the Immediate Post-myocardial Infarction Period. Frontiers in physiology 10:208. doi: https://doi.org/10.3389/fphys.2019.00208. (PMID: 10.3389/fphys.2019.00208308909616412108)
Sattler S, Fairchild P, Watt FM, Rosenthal N, Harding SE (2017) The adaptive immune response to cardiac injury-the true roadblock to effective regenerative therapies? NPJ Regenerative medicine 2:19. doi: https://doi.org/10.1038/s41536-017-0022-3. (PMID: 10.1038/s41536-017-0022-3293023555677967)
Oh H, Ito H, Sano S (2016) Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases. Journal of cardiology 68 (5):361–367. doi: https://doi.org/10.1016/j.jjcc.2016.04.010. (PMID: 10.1016/j.jjcc.2016.04.01027341741)
Li L, Baroja ML, Majumdar A, Chadwick K, Rouleau A, Gallacher L, Ferber I, Lebkowski J, Martin T, Madrenas J, Bhatia M (2004) Human embryonic stem cells possess immune-privileged properties. Stem cells (Dayton, Ohio) 22 (4):448–456. doi: https://doi.org/10.1634/stemcells.22-4-448. (PMID: 10.1634/stemcells.22-4-44815277692)
Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RCJN (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. 428 (6983):668–673.
Jiang S, Haider HK, Idris NM, Salim A, Ashraf MJCr (2006) Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. 99 (7):776–784.
Maghin E, Garbati P, Quarto R, Piccoli M, Bollini SJFiB, Biotechnology (2020) Young at heart: combining strategies to rejuvenate endogenous mechanisms of cardiac repair. 8:447.
Perez-Estenaga I, Prosper F, Pelacho BJIJoMS (2018) Allogeneic mesenchymal stem cells and biomaterials: the perfect match for cardiac repair? 19 (10):3236.
Liu N, Ye X, Yao B, Zhao M, Wu P, Liu G, Zhuang D, Jiang H, Chen X, He YJBM (2021) Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration. 6 (5):1388–1401.
Thankam FG, Agrawal DKJJoctr (2020) Infarct zone: a novel platform for exosome trade in cardiac tissue regeneration. 13 (5):686–701.
Kameli SM, Khorramirouz R, Eftekharzadeh S, Fendereski K, Daryabari SS, Tavangar SM, Kajbafzadeh AMJJoBMRPA (2018) Application of tissue-engineered pericardial patch in rat models of myocardial infarction. 106 (10):2670–2678.
Khorramirouz R, Kameli SM, Fendereski K, Daryabari SS, Kajbafzadeh A-MJRM (2019) Evaluating the efficacy of tissue-engineered human amniotic membrane in the treatment of myocardial infarction. 14 (2):113–126.
Oberwallner B, Brodarac A, Choi YH, Saric T, Anić P, Morawietz L, Stamm CJJobmrPA (2014) Preparation of cardiac extracellular matrix scaffolds by decellularization of human myocardium. 102 (9):3263–3272.
Oberwallner B, Brodarac A, Anić P, Šarić T, Wassilew K, Neef K, Choi Y-H, Stamm CJEJoC-TS (2015) Human cardiac extracellular matrix supports myocardial lineage commitment of pluripotent stem cells. 47 (3):416–425.
Behfar A, Yamada S, Crespo-Diaz R, Nesbitt JJ, Rowe LA, Perez-Terzic C, Gaussin V, Homsy C, Bartunek J, Terzic A (2010) Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. Journal of the American College of Cardiology 56 (9):721–734. doi: https://doi.org/10.1016/j.jacc.2010.03.066. (PMID: 10.1016/j.jacc.2010.03.066207238022932958)
O’Cearbhaill ED, Ng KS, Karp JM (2014) Emerging medical devices for minimally invasive cell therapy. Mayo Clinic proceedings 89 (2):259–273. doi: https://doi.org/10.1016/j.mayocp.2013.10.020.
Fujimoto KL, Clause KC, Liu LJ, Tinney JP, Verma S, Wagner WR, Keller BB, Tobita K (2011) Engineered fetal cardiac graft preserves its cardiomyocyte proliferation within postinfarcted myocardium and sustains cardiac function. Tissue engineering Part A 17 (5–6):585–596. doi: https://doi.org/10.1089/ten.TEA.2010.0259. (PMID: 10.1089/ten.TEA.2010.025920868205)
Chong JJ, Murry CE (2014) Cardiac regeneration using pluripotent stem cells–progression to large animal models. Stem cell research 13 (3 Pt B):654–665. doi: https://doi.org/10.1016/j.scr.2014.06.005.
Laflamme MA, Murry CE (2011) Heart regeneration. Nature 473 (7347):326–335. doi: https://doi.org/10.1038/nature10147. (PMID: 10.1038/nature10147215938654091722)
Tang J, Wang J, Huang K, Ye Y, Su T, Qiao L, Hensley MT, Caranasos TG, Zhang J, Gu ZJSa (2018) Cardiac cell–integrated microneedle patch for treating myocardial infarction. 4 (11):eaat9365.
Huang K, Ozpinar EW, Su T, Tang J, Shen D, Qiao L, Hu S, Li Z, Liang H, Mathews KJStm (2020) An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs. 12 (538):eaat9683.
Chen L, Tredget EE, Wu PY, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PloS one 3 (4):e1886. doi: https://doi.org/10.1371/journal.pone.0001886. (PMID: 10.1371/journal.pone.0001886183826692270908)
Blume GG, Machado-Júnior PAB, Paludo Bertinato G, Simeoni RB, Francisco JC, Guarita-Souza LC (2021) Tissue-engineered amniotic membrane in the treatment of myocardial infarction: a systematic review of experimental studies. American journal of cardiovascular disease 11 (1):1–11. (PMID: 338159148012283)
Shinde AV, Humeres C, Frangogiannis NGJBeBA-MBoD (2017) The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. 1863 (1):298–309.
Deus IA, Mano JF, Custodio CAJAB (2020) Perinatal tissues and cells in tissue engineering and regenerative medicine. 110:1–14.
Mazzone L, Pratsinis M, Pontiggia L, Reichmann E, Meuli MJPsi (2016) Successful grafting of tissue-engineered fetal skin. 32:1177–1182.
Wang Z, Long DW, Huang Y, Chen WC, Kim K, Wang YJAb (2019) Decellularized neonatal cardiac extracellular matrix prevents widespread ventricular remodeling in adult mammals after myocardial infarction. 87:140–151.
Kajbafzadeh A-M, Tafti SHA, Khorramirouz R, Sabetkish S, Kameli SM, Orangian S, Rabbani S, Oveisi N, Golmohammadi M, Kashani ZJC, Banking T (2017) Evaluating the role of autologous mesenchymal stem cell seeded on decellularized pericardium in the treatment of myocardial infarction: an animal study. 18:527–538.

96-03-84-36498 Tehran University of Medical Sciences and Health Services

Keywords: Amniotic membrane; Cardiomyocyte; Fetal extracellular matrix; Myocardial infarction; Tissue engineering

0 (Decellularized Extracellular Matrix)

Date Created: 20240812 Date Completed: 20241216 Latest Revision: 20241216

20241217

10.1007/s13239-024-00744-z

39133349