We have recently proven that the adult hematopoietic stem cell (HSC) is able to produce functional hemangioblast acitivity. Using an animal model of adult retinal neovascularization, we performed a series of experiments that showed the adult HSC can contribute to both blood and blood vessel repair in response to ischemic injury. Bone marrow recipients were durably reconstituted with donor HSC from transgenic mice that constitutively express Gfp. Ischemia was induced in one retina per animal. The recruitment of bone marrow-derived progeny to the retinas was detected by confocal microscopy. This showed that newly differentiated vascular tufts were composed of Gfp+HSC derived endothelial cells. Stromal cell-derived factor 1 (SDF-1) has been shown to play an important role in HSC movement and homing and in the recruitment of endothelial cells. In this proposal we seek to utilize this unique model to address the following hypotheses:
Aim 1. Hypothesis: SDF-1 is required to induce HSC-derived hemangioblast activity. 1a. Determine if the administration of SDF-1 blocking antibodies can stop HSC-derived hemangioblast activity and block the formation of retinal neovascularization in our ischemia model, 1b. Define alternative methods to block SDF-1 activity, such as developing an anti-SDF-1 antibody, usingCXCR4 antagonists, and using siRNA.
Aim 2. Hypothesis: Administration of exogenous SDF-1 protein will enhance hemangioblast activity. 2a. Determine if the administration of additional exogenous SDF-1 protein into our ischemia model will enhance the development of neovascularization in our iscbemia model. 2b. Determine if the administration of exogenous SDF-1 protein is sufficient for the promotion of HSC-derived hemangioblast activity.
|Butler, Jason M; Guthrie, Steven M; Koc, Mehmet et al. (2005) SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest 115:86-93|