Blood vessels and nerves develop in parallel and their survival and function in postnatal tissues are interdependent;thus, when one system is damaged, the other degenerates. Ischemic stroke is one example in which vascular damage leads to neurological degeneration and functional deficits;stroke affects 1 in 59 adults annually of whom ~5 million are permanently disabled. While the initial damage from stroke produces neuronal cell loss, the process quickly evolves into loss of other cell types and extracellular matrix, resulting in a cavitational void. Our preliminary animal studies, in a model that mimics human stroke, suggest that transplantation of neural stem cells (NSC) alone may ameliorate functional deficits caused by stroke;however, we found no neural restoration since transplanted cells integrated only into areas that retained tissue architecture. Moreover, engrafted NSC did not persist, limiting repair. We will circumvent these current limitations of cell transplantation by bioengineering a microenvironment that will sustain NSC and enable their propagation ex vivo, as well as in vivo upon transplantation. We laid the experimental groundwork for our project in previous studies in which we established a 3D model of the NSC niche via imaging and quantitative analysis, and developed biomaterials suitable for engineering this microenvironment ex vivo. We also established proof of principle that transplantation of cell-matrix constructs into stroke models is feasible and reduces lesion size. In the proposed studies, we will continue to optimize the design of our engineered niches based on our biological studies of the regulation of neurogenesis and angiogenesis in the brain (Aim 1), and by sequential testing in vitro (Aim 2) and in vivo (Aim 3) in progressively more challenging and realistic models of stroke, which will enable us to move closer to developing neuro- vascular regenerative therapies for human patients. Although our initial clinical target will be stroke-injured tissues, the insights gained, and strategies developed, from our proposed studies will be broadly applicable to repair of other neurovascular injuries such as traumatic brain injury and multiple sclerosis.

Public Health Relevance

Blood vessels and nerves develop alongside each other and their survival and function are interdependent. So, when one tissue is damaged, the other degenerates, such as in response to stroke injury. We are studying how both systems function together in the adult brain, and are using this information to develop bioengineering strategies to promote parallel regeneration of blood vessels and nerves in injured patients.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (BNVT)
Program Officer
Hunziker, Rosemarie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Kicheva, Anna; Bollenbach, Tobias; Ribeiro, Ana et al. (2014) Coordination of progenitor specification and growth in mouse and chick spinal cord. Science 345:1254927
Hoffmann, Stephanie A; Hos, Deniz; Kuspert, Melanie et al. (2014) Stem cell factor Sox2 and its close relative Sox3 have differentiation functions in oligodendrocytes. Development 141:39-50
Hirschi, Karen K; Li, Song; Roy, Krishnendu (2014) Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng 16:277-94
Naumova, Anna V; Modo, Michel; Moore, Anna et al. (2014) Clinical imaging in regenerative medicine. Nat Biotechnol 32:804-18
Martin, Kathleen A; Hirschi, Karen K (2014) The magic touch: endothelial cells muscle-up adipose. Circ Res 115:752-4
Co?kun, S├╝leyman; Chao, Hsu; Vasavada, Hema et al. (2014) Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep 9:581-90