TY - JOUR
T1 - Transplantation of allogeneic pericytes improves myocardial vascularization and reduces interstitial fibrosis in a swine model of reperfused acute myocardial infarction
AU - Alvino, Valeria Vincenza
AU - Fernández-Jiménez, Rodrigo
AU - Rodriguez-Arabaolaza, Iker
AU - Slater, Sadie
AU - Mangialardi, Giuseppe
AU - Avolio, Elisa
AU - Spencer, Helen
AU - Culliford, Lucy
AU - Hassan, Sakinah
AU - Ballesteros, Lorena Sueiro
AU - Herman, Andrew
AU - Ayaon-Albarrán, Ali
AU - Galán-Arriola, Carlos
AU - Sánchez-González, Javier
AU - Hennessey, Helena
AU - Delmege, Catherine
AU - Ascione, Raimondo
AU - Emanueli, Costanza
AU - Angelini, Gianni Davide
AU - Ibanez, Borja
AU - Madeddu, Paolo
N1 - Publisher Copyright:
© 2018 The Authors.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Background--Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model. Methods and Results--We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone. Conclusions--Immunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.
AB - Background--Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model. Methods and Results--We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone. Conclusions--Immunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.
KW - Angiogenesis
KW - Cell therapy
KW - Large animal models
KW - Myocardial infarction
KW - Pericytes
UR - http://www.scopus.com/inward/record.url?scp=85040924925&partnerID=8YFLogxK
U2 - 10.1161/JAHA.117.006727
DO - 10.1161/JAHA.117.006727
M3 - Article
C2 - 29358198
AN - SCOPUS:85040924925
SN - 2047-9980
VL - 7
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 2
M1 - e006727
ER -