Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction

Abstract

BackgroundTransplantation 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 ResultsWe 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.ConclusionsImmunologic 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.

Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation

“…It may be possible that paracrine factors interacting with, or released from, pericytes are responsible for vasoconstriction of coronary capillaries. If this is proven true, the phenomenon may have been responsible for the lack of increased contractility seen in the recent swine MI model reported by us . This would also indicate the potential of pericytes as a drug target for the treatment of ischemia as well as chronic hypertension.…”

“…As previously described, some pericyte populations are susceptible to phenotypic changes in culture . This instability seems be limited to phenotypic expression, as no genetic instability has been found through several passaging of human APCs and downregulation of CD34 has also been reported in various other cell types as a common artefact of cell culture . Nonetheless, before transplanting a cell population into a patient, the effects of mutations must be fully explored to ensure they are not harmful or a factor in tumor formation .…”

“…Furthermore, an interesting and yet unresolved controversy surrounds the preclinical choice of using human cells or the corresponding animal products, which may better simulate the current allogeneic/autologous approach of clinical cell therapy. To begin responding to this question in relation to pericytes, we recently performed the first study of human and swine APC therapy in a large animal model of acute reperfused MI . In vitro cytotoxicity experiments and in vivo engraftment studies indicate rejection of human APCs, due to xenogeneic antigen recognition by swine T cells.…”

“…There is still disagreement with what constitutes a pericytes due to the lack of an exclusive and specific marker. This discrepancy has resulted in diverse nomenclature being used to describe the same cell population and variable methodologies of isolations, making it difficult to compare results between research groups . We suggest that until a specific marker is identified, a defined nomenclature, marker array and functionality test should be established for pericyte subpopulations.…”

It Takes Two: Endothelial-Perivascular Cell Cross-Talk in Vascular Development and Disease

“…Common markers which are expressed in perivascular cells include neuron-glial antigen-2 (NG2), CD146, α-smooth muscle actin (α-SMA), and platelet derived growth factor receptor-β (PDGFR-β). Endothelial and haematopoietic specific markers such as CD31, VE-cadherin, von Willebrand factor and CD45 should be absent ( 15 , 22 – 25 ).…”