A Heterotopic Heart Transplantation Model to Investigate Cardiac Regeneration

The heart, in contrast to other tissues, exhibits a limited regenerative capacity making it vulnerable to irreparable damage [1]. Despite significant advances in pharmacological and clinical treatment, heart disease remains one of the primary causes of morbidity and mortality worldwide with post - myocardial infarction (MI) heart failure (HF) being one of the major contributors [2]. For the past 25 years, heart transplantation (HT) has been the most effective therapeutic option for patients with end- stage HF [3]. Donor heart ischemia-reperfusion (I/R) injury during the transplantation process can result in primary graft dysfunction. Although the exact sequence of events in the patho-physiology of I/R injury remains unknown, the role of inflammation has become increasingly clear [4]. In this perspective, bone marrow mesenchymal stromal cells (BM-MSCs) are under extensive investigation as potential therapy for I/R injury, since BM-MSCs are able to exert immune regulatory and reparative effects [5].The advent of stem cell biology provided a framework to challenge the notion that the heart is a terminally differentiated organ with recent reports revealing myocardial mitotic activity in both health and disease states [6] and further demonstration of small dividing cells in the heart express cardiac markers with stem cell properties of self-renewal and differentiation [7]. These findings raised questions regarding the identity and origin of these putative cardiac progenitor cells, the paracrine signaling involved in their mobilization and differentiation and whether these cells can repair damaged myocardium [8].Heterotopic heart transplantation (HHT) in rodents is an important and valuable model for studying graft vasculopathy, to evaluate new immunosuppressive strategies, to understand the mechanisms of rejection and tolerance and to monitor tissue regeneration after transplant [9]. The overall goal of this doctoral dissertation was to use a novel cervical HHT in rats as a tool to investigate cardiac regeneration. First, we investigated the therapeutic effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a HHT model associated with I/R injury. We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neovascularization and decreased cardiomyocyte apoptosis of the transplanted heart.Second, we investigated whether cardiac cells could be mobilized by cardiac injury and, if so, to identify and characterize the putative stem cell type in a HHT model associated with acute MI. We demonstrated that cells expressing a host transgenic marker (GFP) were detectable in the injured recipient six and sixteen days post-MI at higher percentage in the peri-infarcted - and within the infarcted tissue with characteristics of mature adult cardiomyocytes, myofibroblasts, endothelial and smooth muscle cells which significantly contributed to the repopulation of the damaged myocardium.

Keywords: Cardiac Regeneration
Heterotopic heart transplantation
Mesenchymal Stromal Cells
Myocardial Infarction
Stem Cells
Transgenic rats
Advisor: Armand, Keating