Cardiovascular diseases are a leading cause of death in California and the United States. It is generally accepted that vascular diseases such as atherosclerosis and restenosis are caused by the dysfunction of endothelial cells (ECs), inflammatory responses, and the de-differentiation and proliferation of smooth muscle cells (SMCs). However, our recent findings suggest that the activation and differentiation of a novel type of vascular stem cells (VSCs) in the blood vessel wall rather than the de-differentiation of SMCs result in the proliferative/synthetic SMCs in neointima, suggesting that vascular diseases are stem cell diseases. In addition, VSCs can be identified and isolated in atherosclerotic lesions of human coronary arteries, but the role of human VSCs in the development of vascular diseases remains to be elucidated. We propose to use a tissue engineering approach to reconstitute an in vitro three-dimensional (3D) model of human vascular diseases based on our findings on VSCs. This human VSC-based in vitro 3D model will not only shed light on the microenvironmental regulation of VSC activation and differentiation, but also provide an enabling technology for high throughput screening of new drugs by targeting VSCs for the therapies.
Statement of Benefit to California:
Cardiovascular diseases are a leading cause of death in California, in the United States and in the world. In the past few decades, the therapies have been developed to target smooth muscle cells in the blood vessels. Here we propose a new stem cell model of vascular diseases and suggest that vascular stem cells rather than smooth muscle cells play an important role in disease development and thus vascular stem cells should be the target of therapies. The results of this project will have transformative impact on the development of novel therapies for vascular diseases, and will benefit the health care in California and beyond. This 3D in vitro model of vascular diseases will not only be valuable for the investigation of the disease mechanisms but also be a enabling technology for the high throughput screening of new drugs for therapies.
The goal of this proposal is to develop a new model of human vascular diseases, such as atherosclerosis, in order to address gaps in the field. The proposal builds on prior work by the applicant in which a novel type of multipotent vascular stem cell (VSC) was identified in an animal model. The work proposed here will utilize a three-dimensional (3D) system in order to mimic the forces involved in the circulation of blood and to study the biology of VSCs, including their contribution to the development of vascular diseases. In Aim 1, the applicants propose to characterize human VSCs isolated from healthy and diseased arteries and to develop the in vitro 3D model. Aim 2 will investigate the effects of blood vessel cells, flow patterns and signaling on the proliferation of VSCs. The goal of Aim 3 is to understand what factors influence VSC differentiation and how that may contribute to the development of atherosclerosis.
Significance and Innovation
- The proposed studies are significant because they can potentially change the way we understand vascular remodeling. If such VSCs do exist in humans, they could lead to improved understanding of vascular pathology.
- The proposed studies are innovative in that they intend to characterize a previously unidentified VSC population with multilineage potential.
Feasibility and Experimental Design
- Although the applicants provide some evidence toward the isolation of human VSCs, some reviewers did not find that data compelling, and questioned whether the required cell type would be available for the proposed studies.
- There is no evidence that the applicant has isolated VSCs from human diseased arteries; this may represent a particular challenge.
- Reviewers expressed concern that the bioreactor the project depends on has not yet been developed. Furthermore, a bioreactor approach will never fully recapitulate the dynamic microenvironment of the remodeling vasculature and will lack the inflammatory cells, which are part of this process.
Principal Investigator (PI) and Research Team
- The PI is an outstanding established investigator with an excellent track record.
- Sufficient experience is present within the research team to perform the proposed studies.
- The research facilities and environment are excellent.
Responsiveness to the RFA
- The proposal is responsive to the RFA in that it studies human vascular stem cells in vitro.