Marissa Sweeney
Pronouns: she/her
Research Mentor(s): Russell Urie
Research Mentor School/College/Department: Biomedical Engineering / Engineering
Program:
Authors: Marissa Sweeney, Russell Urie
Session: Session 7: 4:40 pm – 5:30 pm
Poster: 51
Abstract
Heart transplantation is often the only treatment for severe cardiac diseases. One of the main causes of long-term mortality and morbidity in heart transplant recipients is cardiac allograft vasculopathy (CAV), also referred to as chronic rejection. Vasculopathy affects the vasculature of the allograft and is thought to be caused by both immune and non-immune factors. Endothelial cells and smooth muscle cells form the innermost layers of blood vessels; proliferation of these cells in vasculopathy causes thickening of blood vessels and arteries, ultimately leading to ischemia and graft loss. However, the complete pathogenesis of vasculopathy is unknown. Cardiac allograft vasculopathy affects 30% of patients within 5 years of transplantation and 50% within 10 years of transplantation. Once diagnosed, vasculopathy cannot be cured; however, some medications and procedures can decelerate progression if diagnosed early. Unfortunately, patients are often asymptomatic. Common invasive techniques, such as biopsies, are currently the most accurate in the detection and diagnosis of vasculopathy, especially in early stages of the disease; however, they are commonly accompanied by complications. Noninvasive techniques, including various imaging methods, come with little to no complications but are less accurate and rarely detect early signs of vasculopathy. There is a pressing need for a less invasive, more accurate method of detecting vasculopathy. With this in mind, we are looking to create a minimally invasive method of detecting presymptomatic and early stages of vasculopathy. Previously, the Shea Lab has used microporous scaffold implants made of polycaprolactone (PCL) to predict acute graft rejection. These studies showed that biomarkers of acute rejection can be found in the scaffold before rejection signs occur at the allograft site or in the blood. In this work, we carried out an experiment to see if the scaffolds also show early signs of chronic rejection. We implanted scaffolds under the skin of donor BALB/c (B/c), C57BL/6 (B6), and B6.C-H-2bm12 (Bm12) mice; after 14 days the scaffolds became vascularized and populated with donor cells. The now donor-populated scaffolds were then transferred to B6 and C57BL/6 Rag2-/- (Rag2KO) mice, each combination resulting in a varying level of immunocompatibility (i.e. syngeneic, minor mismatch allogeneic, major mismatch allogeneic) in the immune competent B6 mice or the immune deficient Rag2KO mice. In syngeneic compatibility, and compatibility with Rag2KO recipients, we expect no vasculopathy to occur. In the minor mismatch of Bm12 to B6, we expect to see vasculopathy and in the major mismatch of B/c to B6 we expect to see acute rejection. To detect vasculopathy, we explanted three scaffolds from each mouse before transfer and at days 28 and 52 after transfer. We used flow cytometry to look at the number and phenotypes of endothelial cells, macrophages, T cells, and natural killer cells in the scaffolds. We also use histology to section and stain the scaffolds, allowing us to observe the vasculature location and assess vessel thickening. A minimally-invasive method of detecting early signs of vasculopathy could create a new avenue of personalized transplant recipient care, such as immunosuppression regimens
