Loss of function to arteries or the microvasculature, due to diseases such as atherosclerosis, peripheral artery diseases or ischemia, contributes to high morbidity and high mortality in the U.S. An emerging solution is mesenchymal stem cell (MSC) therapy, which has the potential to regenerate blood vessels and revolutionize the treatment of vascular diseases. However, results from MSC-based vascular therapies have been inconsistent, and worse, some studies have reported vascular dysfunction. These therapeutic outcomes are, at least in part, attributable to an ill-defined cell environment, which ultimately regulates MSC fate during therapy. To achieve successful MSC-based vascular therapy, several unresolved issues must be addressed: (a) suboptimal MSC environments that result in a mixed cell populations with low vascular specificity or signaling;(b) lack of mechanistic understandings as to how multifactorial environments determine MSC fate in vivo;and (c) limited platform technologies available for the translation of in vitro cell differentiatio environments to in vivo vascular therapies. To address these knowledge gaps, the overall goal of this proposal is to establish a comprehensive platform that recapitulates the synergism of the physical and biochemical environments in normal vascular tissues in order to perpetuate highly specific and mature vascular differentiation of MSCs for vascular therapy. Our hypothesis is that vessel-mimetic mechanical and biochemical environments provide synergistic signaling to MSCs, perpetuating vascular regeneration under physiological conditions in vitro and in vivo. To pursue our hypothesis, we will take an innovative approach by developing 3D nanofibrous niches with independently modulated microenvironment factors, i.e. matrix rigidity, ligand and cytokine, to optimize vascular cell regeneration, and incorporating these distinct niches into a graft scaffold with spatiotemporal control for evaluation under physiological flow. This approach is built on our team's biomaterial capabilities of producing nanofibrous materials with controlled rigidity, anisotropy and spatiotemporal release of proteins, and ligand incorporation.
Three aims are proposed here:
AIM 1 focuses on MSC-matrix interaction mechanisms underlying the rational design of 3D synthetic niche matrices for vascular differentiation;
AIM 2 seeks to define synthetic niches that converge mechano-chemical signaling for optimal vascular regeneration;
and AIM 3 integrates and evaluates synthetic niches with vascular grafts to demonstrate feasibility and provide critical feedback for future design and clinical translation. This new interdisciplinary study, combining biomaterials, cell signaling, vascular mechanobiology and tissue engineering, if successful, will help to accomplish our long-term goal of designing application-specific vascular microphysiological systems that can predict, improve and optimize cell-based vascular therapy.
Statement Loss of functional artery or microvasculature for blood perfusion, due to diseases such as atherosclerosis, peripheral artery diseases and ischemia, to just name a few, accounts for high morbidity and mortality in the U.S. Stem cell therapy using mesenchymal stem cells is an emerging solution in clinic, but raises concerns about the therapy efficacy. This project aims to develop a biomaterial platform that can precisely define the physical, chemical, structural and biological microenvironments for mesenchymal stem cells, which may lead to highly efficacious vascular therapy in the future.
|Floren, Michael; Bonani, Walter; Dharmarajan, Anirudh et al. (2016) Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. Acta Biomater 31:156-66|
|Fan, Yonghong; Pan, Xiaxin; Wang, Ke et al. (2016) Influence of chirality on catalytic generation of nitric oxide and platelet behavior on selenocystine immobilized TiO2 films. Colloids Surf B Biointerfaces 145:122-9|
|Floren, Michael; Tan, Wei (2015) Three-dimensional, soft neotissue arrays as high throughput platforms for the interrogation of engineered tissue environments. Biomaterials 59:39-52|
|Guo, Dong-Jie; Liu, Rui; Cheng, Yu et al. (2015) Reverse adhesion of a gecko-inspired synthetic adhesive switched by an ion-exchange polymer-metal composite actuator. ACS Appl Mater Interfaces 7:5480-7|
|Elliott, Winston; Scott-Drechsel, Devon; Tan, Wei (2015) In Vitro Model of Physiological and Pathological Blood Flow with Application to Investigations of Vascular Cell Remodeling. J Vis Exp :e53224|
|Nagiah, Naveen; Johnson, Richard; Anderson, Roy et al. (2015) Highly Compliant Vascular Grafts with Gelatin-Sheathed Coaxially Structured Nanofibers. Langmuir 31:12993-3002|
|Elliott, Winston H; Bonani, Walter; Maniglio, Devid et al. (2015) Silk Hydrogels of Tunable Structure and Viscoelastic Properties Using Different Chronological Orders of Genipin and Physical Cross-Linking. ACS Appl Mater Interfaces 7:12099-108|
|Wingate, Kathryn; Floren, Michael; Tan, Yan et al. (2014) Synergism of matrix stiffness and vascular endothelial growth factor on mesenchymal stem cells for vascular endothelial regeneration. Tissue Eng Part A 20:2503-12|
|Madhavan, Krishna; Elliott, Winston H; Bonani, Walter et al. (2013) Mechanical and biocompatible characterizations of a readily available multilayer vascular graft. J Biomed Mater Res B Appl Biomater 101:506-19|