Central Nervous System (CNS) has been identified as an immunoprivileged site originally due to the lack of lymphatic vasculature. There are intricate vascular network without lymphatic vasculature in the brain and spinal cord during development and in adult. Using the spinal cord vasculature model, we focus on understanding mechanisms by which the spinal cord prevents lymphangiogenesis but not angiogenesis. We have found that supernatant from cultured embryonic spinal cord prevents the differentiation of lymphatic endothelial cells, as well as the migration of lymphatic but not blood endothelial cells. Now we are extensively working to identify neuronal or glial signal(s) that prevent the differentiation and migration of the lymphatic endothelial cells in the CNS. The findings also provide a rational for testing the signal(s) as potent inhibitors of adult and tumor-induced lymphangiogenesis. Stem cells are established in the niche, a unique and specialized microenvironment. Given the importance of the vascular niche for a variety of stem cells, understanding the paracrine signals for stem cell maintenance has become more important. Whole-mount staining approach of the subventricular zone (SVZ) in the lateral ventricle walls of adult brain has revealed that slowly-dividing SVZ cells (adult neural stem cells?) are closely interacted with the local vasculature. Our challenge is to utilize a systematic multi-faceted approach to identify and validate the vascular niche signals involved in maintenance, self-renewal, proliferation and differentiation of neural stem cells. We have also developed a whole-mount imaging approach to examine brain vascular network that associate with neurons and astrocytes as well as neural stem cells. We are now evaluating the physiological relevance of the candidate niche signals in vitro and in vivo.

Project Start
Project End
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Budget End
Support Year
1
Fiscal Year
2011
Total Cost
$431,243
Indirect Cost
Name
National Heart, Lung, and Blood Institute
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Type
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Sato, Yuya; Uchida, Yutaka; Hu, Jingqiong et al. (2017) Soluble APP functions as a vascular niche signal that controls adult neural stem cell number. Development 144:2730-2736
Arnold, Thomas D; Niaudet, Colin; Pang, Mei-Fong et al. (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking ?V?8-TGF? signaling in the brain. Development 141:4489-99
Okabe, Keisuke; Kobayashi, Sakiko; Yamada, Toru et al. (2014) Neurons limit angiogenesis by titrating VEGF in retina. Cell 159:584-96
Kim, Kee K; Nam, Joseph; Mukouyama, Yoh-Suke et al. (2013) Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development. J Cell Biol 200:443-58
Nam, Joseph; Onitsuka, Izumi; Hatch, John et al. (2013) Coronary veins determine the pattern of sympathetic innervation in the developing heart. Development 140:1475-85
Lee, Cheol; Hu, Jingqiong; Ralls, Sherry et al. (2012) The molecular profiles of neural stem cell niche in the adult subventricular zone. PLoS One 7:e50501
Li, Wenling; Mukouyama, Yoh-suke (2011) Whole-mount immunohistochemical analysis for embryonic limb skin vasculature: a model system to study vascular branching morphogenesis in embryo. J Vis Exp :
Cunningham, Kirk; Uchida, Yutaka; O'Donnell, Erin et al. (2011) Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations. Hum Mol Genet 20:3198-206
James, Jennifer M; Mukouyama, Yoh-suke (2011) Neuronal action on the developing blood vessel pattern. Semin Cell Dev Biol 22:1019-27