Cardiovascular diseases are a leading cause of death. Blood vessel replacement is a common treatment for vascular diseases. However, autologous grafts are limited by the availability, the need for additional surgeries and the morbidity of the donor sites, and synthetic vascular grafts are limited to large-diameter blood vessels due to thrombosis and failure in small diameter grafts. The tissue engineering approach is promising and can improve the biocompatibility and the performance of vascular grafts, but the in vitro fabrication of cellular grafts takes weeks, is expensive, and is difficult to scale upfor clinical applications. A clinically viable strategy is in-situ tissue engineering, wherein an acellular, bioactive and bioabsorbable vascular graft can effectively recruit endogenous cells to self-regenerate the blood vessel. In the past few years, we have developed acellular, bioactive microfibrous vascular grafts that can be made available off-the-shelf. The grafts are anti-thrombogenic and can recruit endothelial progenitor cells (EPCs) for enhanced endothelialization and long-term patency; the grafts also recruit mesenchymal stem cells (MSCs) and bioabsorb to facilitate tissue remodeling and maturation. We have identified a novel type of MSCs that are Sox10+ and can differentiate into smooth muscle cells (SMCs) in vascular grafts. However, the mechanisms of MSC or SMC recruitment remains to be determined, and whether a MMP cleavage-resistant stromal cell-derived factor-1a (SDF-1a) and the porosity of vascular grafts can lead to better graft performance is not clear. Furthermore, validation of this novel approach in a large animal model is necessary for the translation towards clinical therapies. We hypothesize that: (1) A MMP cleavage-resistant form of SDF-1a, S-SDF-1(S4V), will increase its stability and further enhance the endothelialization and the remodeling of vascular grafts, (2) the increase in the porosity of vascular grafts will facilitate the recruitment/infiltration of MSCs and accelerate vascular graft remodeling, and (3) during the regeneration of vascular grafts, MSCs rather than mature SMCs are recruited for the remodeling. To test our hypothesis, three Specific Aims are proposed: (1) To investigate whether S- SDF-1(S4V) increase the recruitment of EPCs and MSCs and the remodeling of vascular grafts in the rat and mouse lineage tracing models; (2) To determine how the porosity of vascular grafts regulate the recruitment of MSCs and the remodeling of the grafts in the rat model; (3) To investigate the effects of S- SDF-1(S4V) and graft porosity on the recruitment of EPCs and MSCs and the endothelialization and the remodeling of vascular grafts in a swine model. The accomplishment of this project will advance our understanding on the roles of stem cells and progenitor cells in the regeneration of blood vessels, and will lead to the development of the next generation of vascular grafts that are available off-the-shelf, bioactive, and can recruit endogenous stem cells for in situ remodeling.
In this project, we will engineer the structure and chemistry of bioactive vascular grafts and investigate the roles of endogenous stem cells and progenitor cells in the regeneration of blood vessels in situ in both small animal and large animal models. The proposed studies will elucidate the mechanisms of tissue regeneration, and can lead to the development of a new generation of vascular grafts that have high patency, can self-regenerate and remodel, can be made available off-the-shelf, and are scalable for clinical applications.
