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.
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.
|Goligorsky, M S; Hirschi, K (2016) Stress-Induced Premature Senescence of Endothelial and Endothelial Progenitor Cells. Adv Pharmacol 77:281-306|
|Ceneri, Nicolle; Zhao, Lina; Young, Bryan D et al. (2016) Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1Î² Production. Arterioscler Thromb Vasc Biol :|
|PochÃ©, Ross A; Zhang, Min; Rueda, Elda M et al. (2016) RONIN Is an Essential Transcriptional Regulator of Genes Required for Mitochondrial Function in the Developing Retina. Cell Rep 14:1684-97|
|Han, Liang; Kong, Derek K; Zheng, Ming-Qiang et al. (2016) Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging. ACS Nano 10:4209-18|
|Garros-Regulez, Laura; Aldaz, Paula; Arrizabalaga, Olatz et al. (2016) mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance. Expert Opin Ther Targets 20:393-405|
|Goldsmith, Sam; Lovell-Badge, Robin; Rizzoti, Karine (2016) SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary. Development 143:2376-88|
|Lopez-Ramirez, Miguel A; Calvo, Charles-FÃ©lix; Ristori, Emma et al. (2016) Isolation and Culture of Adult Zebrafish Brain-derived Neurospheres. J Vis Exp :53617|
|Slater, John H; Culver, James C; Long, Byron L et al. (2015) Recapitulation and Modulation of the Cellular Architecture of a User-Chosen Cell of Interest Using Cell-Derived, Biomimetic Patterning. ACS Nano 9:6128-38|
|Han, Jinah; Calvo, Charles-FÃ©lix; Kang, Tae Hyuk et al. (2015) Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans. Cell Rep 10:1158-72|
|Massensini, Andre R; Ghuman, Harmanvir; Saldin, Lindsey T et al. (2015) Concentration-dependent rheological properties of ECM hydrogel for intracerebral delivery to a stroke cavity. Acta Biomater 27:116-30|
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