Stem Cell Reviews and Reports (2021) 17:1928–1930 https://doi.org/10.1007/s12015-021-10190-2 Our Journey Through Advanced Therapies to Reduce Post‑Infarct Scarring Santiago Roura1,2,3,4 · Marta Monguió‑Tortajada1,2,3 · Cristina Prat‑Vidal1,2,3,5 · Carolina Gálvez‑Montón1,2,3 · Antoni Bayes‑Genis1,2,3,6,7 Accepted: 17 May 2021 / Published online: 22 May 2021 © The Author(s) 2021 “As you set out for Ithaka able to repopulate decellularised cardiac tissue (porcine myocardium or human pericardium) with MSCs to gener- hope your road is a long one, ate small (2 ­cm2) tissue engineering constructs or grafts with full of adventure, full of discovery.” preserved macromechanical and micromechanical proper- Ithaka. C.P. Cavafy: Collected Poems 1975 ties. The resulting three-dimensional (3-D) porous biopros- We have read with interest the paper of Lin et al. in Stem theses or bioimplants, which could also be engineered to Cell Reviews and Reports summarising the contributions of include sophisticated electronic systems for online monitor- cardiac adipose tissue to treat myocardial infarction (MI) ing of myocardial tissue performance and repair, were valu- [1]. Meaningful advances in rapid reperfusion strategies able for limiting post-infarct sequelae in pigs [3–5]. and pharmacological management of patients with MI have In light of this promising experience, we then focused on reduced dramatically its mortality rates. Nevertheless, dis- manufacturing a clinical-size (12–16 ­cm2), engineered bio- ease sequelae remain, including myocardial scarring ensu- implant by combining good manufacturing practice (GMP)- ing heart failure. This has promoted a variety of innovative grade human Wharton’s jelly-derived allogeneic MSCs and therapeutic endeavours to reduce infarct scars. A couple of a decellularised human cadaveric pericardial matrix. Thus, decades ago, in the early days of the cardiac regeneration over the past year, this novel advanced therapy medicinal journey, cell-based therapy emerged as a promising option to product (ATMP), termed PeriCord, was completed and regenerate post-infarcted myocardium through the implanta- approved by the Spanish Agency of Medicines and Medical tion of pro-regenerative cells. In this context, we began to Devices for clinical use. Preliminary safety data from the grow mesenchymal stromal cells (MSCs) in vitro, mostly first roll-in patient treated with PeriCord has already been from cardiac adipose tissue biopsies. These cells improved reported in the context of the phase I PERISCOPE trial cardiac function, and reduced scar size in the MI murine (the PERIcardial matrix with mesenchymal Stem Cells fOr model [2]. Moreover, by using peptide hydrogels, we were the treatment of PatiEnts with infarcted myocardial tissue; EudraCT no. 2018-001964-49; clinicalTrials.gov identifier: NCT03798353), which is still enrolling patients [6]. * Santiago Roura sroura@igtp.cat Alternatively, we conceived and tested the Adipose Graft Transposition Procedure (AGTP), a surgical approach that 1 ICREC Research Program, Health Science Research Institute smartly integrates cell therapy with cardiac tissue engineer- Germans Trias I Pujol, Can Ruti Campus, Badalona, Spain ing. AGTP is based on the dissection of a vascularised flap 2 Heart Institute (iCor), Germans Trias I of autologous pericardial adipose tissue to cover the scarred PujolUniversityHospital, Badalona, Spain area, and limits myocardial remodelling by exerting benefi- 3 CIBERCV, Instituto de Salud CarlosIII, Madrid, Spain cial effects on left ventricular function recovery. Interest- 4 Faculty of Medicine, University of Vic-Central University ingly, this strategy also avoids the use of non-autologous of Catalonia, Vic, Spain cells and ex vivo manipulation. A phase I clinical study 5 Institut D’Investigació Biomèdica de Bellvitge - IDIBELL, (the AGTP-I trial, NCT01473433) has already proven its L’Hospitalet de Llobregat, Barcelona, Spain safety in humans [7], and a phase II-III multicentre clinical 6 Cardiology Service, Germans Trias I Pujol University trial (the AGTP-II trial, NCT02798276) which is currently Hospital, Badalona, Spain recruiting patients, will provide meaningful data on efficacy. 7 Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain Stem Cell Reviews and Reports (2021) 17:1928–1930 1929 In present times, as Lin et al. convincingly point out, the Data Availability Not applicable. expanded knowledge regarding the limited regeneration capacity of the adult human heart, and the short lifespan Code Availability Not applicable. of delivered MSCs, have led the scientific community to reconsider the most suited strategies aimed at reducing myo- Declarations cardial injury. Thus, rather than focusing on the regeneration Ethics Approval Not applicable. of an already carved scar and the differentiation capacities of MSCs, effort has shifted towards the modulation of the exac- Consent to Participate Not applicable. erbated inflammatory response that worsens cardiac tissue damage after MI, and using the immunoregulatory proper- Consent for Publication Not applicable. ties of the MSCs themselves and their secreted extracellular vesicles (EVs) to exploit this window of opportunity. In this Conflicts of Interest The authors declare no conflicts of interest. context, we have recently provided new data on the design Open Access This article is licensed under a Creative Commons Attri- and features of 3-D biocompatible cell-free cardiac grafts for bution 4.0 International License, which permits use, sharing, adapta- the local delivery of multifunctional cardiac adipose MSC- tion, distribution and reproduction in any medium or format, as long EVs, and their effects 6 days from implantation in pigs [8]. as you give appropriate credit to the original author(s) and the source, In specific, porcine MSC-EVs are powerful pro-angiogenic provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are and immune modulatory agents, in terms of both prolifera- included in the article’s Creative Commons licence, unless indicated tion and cytokine response abrogation (something not yet otherwise in a credit line to the material. If material is not included in fully elucidated in swine), actively recruit pro-reparative the article’s Creative Commons licence and your intended use is not allogeneic cells (thus they would be capable of promoting permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a tissue repair by host or endogenous progenitor cells), and copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. can be confined and locally administered, increasing the on-site EV amount. As a preliminary short-term functional description, implanted nanosized vesicles trigger neovascu- larisation and reduce the number of infiltrating macrophages References and T cells. Indeed, we now expect to confirm whether this next generation of small-size decellularised pericardial 1. Lin, Y., Ding, S., Chen, Y., Xiang, M., & Xie, Y. (2021). Car- matrix-based bioimplant comprising MSC-EVs attains long- diac adipose tissue contributes to cardiac repair: A review. term scar healing and cardiac function recovery, and can be Stem Cell Reviews and Reports. https:// ​ d oi. ​ o rg/ ​ 1 0. ​ 1 007/​ s12015-​020-​10097-4. clinically scalable and biomanufactured under GMP require- 2. Bayes-Genis, A., Soler-Botija, C., Farré, J., Sepúlveda, P., Raya, ments to a novel allogeneic ATMP, as it has been achieved A., Roura, S., Prat-Vidal, C., Gálvez-Montón, C., Montero, J. A., for PeriCord. Büscher, D., & Izpisúa Belmonte, J. C. (2010). Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. Journal of Molecular and Cellular Cardiol- ogy, 49(5), 2771–2780. Acknowledgements The authors especially thank all past and current 3. Prat-Vidal, C., Gálvez-Montón, C., Puig-Sanvicens, V., Sanchez, members of the ICREC Research Lab, as well as our external col- B., Díaz-Güemes, I., Bogónez-Franco, P., Perea-Gil, I., Casas- laborators for invaluable efforts and help during the achievement of Solà, A., Roura, S., Llucià-Valldeperas, A., Soler- Botija, C., the set of advanced biotherapies—cells, tissues, engineered matrices, Sánchez-Margallo, F. M., Semino, C. E., Bragos, R., & Bayes- electronic monitoring and nanovesicles—described here. Genis, A. (2014). Online monitoring of myocardial bioprosthesis for cardiac repair. International Journal of Cardiology, 174(3), Authors’ Contributions The authors approved the final manuscript as 654–661. submitted and agree to be accountable for all aspects of the work. 4. Gálvez-Montón, C., Bragós, R., Soler-Botija, C., Díaz-Güemes, I., Prat-Vidal, C., Crisóstomo, V., Sánchez-Margallo, F. M., Llucià- Funding This work was supported by grants from the Spanish Valldeperas, A., Bogónez-Franco, P., Perea-Gil, I., Roura, S., & Ministry of Economy and Competitiveness- MINECO (SAF2017- Bayes-Genis, A. (2017). Noninvasive assessment of an engineered 84324-C2-1-R and PID-2019-11137RB-I00), Instituto de Salud bioactive graft in myocardial infarction: Impact on cardiac func- Carlos III (PI17/01487, PI18/00256, PIC18/00014, ICI19/00039, tion and scar healing. Stem Cells Translational Medicine, 6(2), PI19/01788, and ICI20/00135) funds, Red de Terapia Celular-TerCel 647–655. (RD16/00111/0006), CIBER Cardiovascular (CB16/11/00403) pro- 5. Perea-Gil, I., Prat-Vidal, C., Gálvez-Montón, C., Roura, S., Llucià- jects, as part of the Plan Nacional de I + D + I, and co-funded by ISCIII- Valldeperas, A., Soler-Botija, C., Iborra-Egea, O., Díaz-Güemes, Subdirección General de Evaluación y el Fondo Europeo de Desar- I., Crisóstomo, V., Sánchez-Margallo, F. M., & Bayes- Genis, A. rollo Regional (FEDER) by the Generalitat de Catalunya [SGR2017 (2016). A cell-enriched engineered myocardial graft limits infarct 00483, SLT002/16/00234], and the CERCA Programme/Generalitat size and improves cardiac function: Pre-clinical study in the por- de Catalunya, “la Caixa” Banking Foundation, Sociedad Española de cine myocardial infarction model. JACC: Basic to Translational Cardiología, and Societat Catalana de Cardiologia. Medicine., 1(5), 360–372. 1930 Stem Cell Reviews and Reports (2021) 17:1928–1930 6. Prat-Vidal, C., Rodríguez-Gómez, L., Aylagas, M., Nieto-Nicolau, 8. Monguió-Tortajada, M., Prat-Vidal, C., Moron-Font, M., Clos- N., Gastelurrutia, P., Agustí, E., Gálvez-Montón, C., Jorba, I., Sansalvador, M., Calle, A., Gastelurrutia, P., Cserkoova, A., Teis, A., Monguió-Tortajada, M., Roura, S., Vives, J., Torrents- Morancho, A., Ramírez, A., Rosell, A., Bayes-Genis, A., Gálvez- Zapata, S., Coca, M. I., Reales, L., Cámara-Rosell, M. L., Cediel, Montón, C., Borràs, F. E., & Roura, S. (2021). Local administra- G., Coll, C., Farré, R., … Bayes-Genis, A. (2020). First-in-human tion of porcine immunomodulatory, chemotactic and angiogenic PeriCord cardiac bioimplant: Scalability and GMP manufactur- extracellular vesicles using engineered cardiac scaffolds for myo- ing of an allogeneic engineered tissue graft. eBioMedicine, 54, cardial infarction. Bioactive Materials, 6(10), 3314–3327. 102729. 7. Bayes-Genis, A., Gastelurrutia, P., Cámara, M. L., Teis, A., Publisher’s Note Springer Nature remains neutral with regard to Lupón, J., Llibre, C., Zamora, E., Alomar, X., Ruyra, X., Roura, jurisdictional claims in published maps and institutional affiliations. S., Revilla, A., San Román, J. A., & Gálvez-Montón, C. (2016). First-in-man safety and efficacy of the Adipose Graft Transposi- tion Procedure (AGTP) in patients with a myocardial scar. eBio- Medicine, 7, 248–254.