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Transplantation of normal and decellularized syngeneic, allogeneic and xenogeneic cardiac tissue in mice and non-human primates

Doctoral thesis
Authors Ketaki Methe
Date of public defense 2020-03-27
ISBN 978-91-7833-855-9
Publisher Göteborgs universitet
Publication year 2020
Published at Institute of Clinical Sciences, Department of Surgery
Language en
Links hdl.handle.net/2077/63243
Keywords Decellularization, Cardiac tissue, Syngeneic, Allogeneic, Xenogeneic, Non-human primate
Subject categories Surgery

Abstract

Introduction Because of the restricted inherent capacity of regeneration and healing, transplantation is the only treatment for end-stage heart failure but it has limitations of donor shortage and graft rejection. Cardiac tissue engineering strategies might help to alleviate this problem. Organ specific, biocompatible and biodegradable extracellular matrices (ECM) could be the preferred option for a suitable scaffolding material. However, clinical trials with these matrices is still not routine practice. Experimental and clinical data suggest variable outcomes after implanting decellularized (DC) scaffolds. Hence, the immunological properties of ECM and future perspectives need to be addressed. In this report we chose to study cardiac ECM to better understand its immune potential. Methods A decellularizing protocol using whole porcine heart using Triton X-100 and SDC was developed. The resultant acellular cardiac matrix was analyzed for its structural, functional and mechanical strength. The same protocol was adapted to DC mouse, pig and baboon cardiac hearts. The DC ECM was further tested for its immunological potential by implantation into mouse and baboon recipients, followed by histological and immune histological examinations. Further evaluation of the immunological properties was carried out by proteomics-bioinformatics studies using Mass Spectrometry analysis at the University Core facility. Finally, DC ECM from mouse and pig were implanted into mouse recipients to better understand responses to ECM in syngeneic, allogeneic and xenogeneic settings. Results Serial perfusion of Triton X-100 and SDC was effective in removing all cellular and nuclear materials from whole porcine hearts. It thoroughly decellularized ECM scaffolds from cardiac tissue with cytoskeletal elements of cardio-myocytes remaining largely intact. We observed differences in the immune response for the same ECM scaffolds in mouse and baboon recipients, respectively. In mouse, the responses were more donor specific, and allogeneic scaffolds had a higher immune potential than syngeneic scaffolds. Furthermore, proteomic-bioinformatic analyses revealed the presence of protein S-100, α-laminin and annexin A1 in the mouse DC ECM. In pig scaffolds, we identified, coagulation factor V (fV), fibrilline, spondin 1, and hyaluronan, whereas insulin growth factor (IGF) and periostin were observed in DC ECM of baboon scaffolds. These proteins are known to be immunomodulatory and their immune potential in regard to DC ECM scaffolds should be further tested. We found a distinct immune response for syngeneic, allogeneic and xenogeneic scaffolds after implantation. The allogeneic and xenogeneic immune responses were both T-cell driven, however, the development of these responses were different for DC ECM of allogeneic and xenogeneic scaffolds, respectively. Conclusion DC ECM has favorable properties as a scaffolding material. The evaluation protocol of DC processes described in this thesis requires further development of the immunological potential. The host immune responses cannot be generalized as they are donor species specific. The ECM proteins themselves seem to be immunogenic which might explain differences in the distinct immune responses shown by the recipients. Keywords: Decellularization, Cardiac tissue, Syngeneic, Allogeneic, Xenogeneic, Non-human primate

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