Bicuspid aortic valves (BAV) are the most common congenital cardiovascular malformation with incidence of 0.9-2% of the general population and affecting approximately 4 million people in the US. The aneurysm of the proximal aorta occurs in approximately 50% of the BAVs. Various materials have been used for aneurysm repair or bypass grafting including Dacron or PTFE grafts. Unfortunately, current vascular grafts are susceptible to infection, and have no growth potential. Notch 1 gene mutation has been identified in families with BAV and observed in approximately 4% of sporadic cases of BAV. The mice with Notch1 mutation show the BAV phenotype. Our long term goal of this project is to utilize BAV-patient’s specific iPS cells to dissect the cellular and molecular mechanisms of TAA formation in BAV patients and eventually generate patient’s specific vascular graft to treat the TAA in BAV patients. To achieve our goal, first, we will develop iPS cells from individual Notch1mut-BAV patients (BAV with aneurysm) and the control group (subjects with normal aortic valve and aorta) with lentivirus or protein molecules. The Notch1 mutation is then corrected with ZFN or Talen technology in vitro to generated corrected Notch1mut-BAV iPS (designated as cNotch1mut-BAV-iPS). All Notch1mut-BAV, cNotch1mu-BAV and the control iPS cells are characterized for pleuripotency. Second, the Notch1mut-BAV-iPS cells, cNotch1mut-BAV-iPS and the control iPS cells will be induced to differentiate into SMCs. The gene expression, acquirement of SMC contractile and electrophysiological characteristics and secretion of extracellular matrix (ECM, e.g collagen I, III and elastin) will be recorded separately. We expect that SMCs derived from Notch1mut-BAV-iPS are dysfunctional and SMC’s function will be normalized after the correction of Notch 1 mutation. Third, we will generate BAV patient’s specific vascular graft using Notch1mut-BAV-iPS, cNotch1mut-BAV-iPS and the control iPS cells. The SMCs and endothelial cells derived from iPS cells are planted into a two-layer vascular graft scaffold and cultured in a bioreactor. The tissue-engineered vascular graft is tested in vitro and in vivo. This study will help us understand the aneurysm formation BAV patients, develop new medication to retard the growth of the aneurysm and strategies of prophylactic surgical repair, and develop the patient specific vascular graft which is resistant to infection and has growth potential to treat the aneurysm.
Engineering vascular tissue with functional smooth muscle cells derived from human iPS cells and nanofibrous scaffolds
Published in Biomaterials, 2014
Patient-specific cardiovascular progenitor cells derived from integration-free induced pluripotent stem cells for vascular tissue regeneration
Published in Biomaterials, 2015