The subventricular zone response to ischemic lesions and granulocyte-colony stimulating factor (G-CSF)

SUBURO AM; CASTAÑEDA M; LOPEZ VICCHI M; IRIBARNE M; TORBIDONI V

El Castillo, Córdoba, Argentin

Congreso; Tango Lessons for Brain Cancer Research: Understanding Cellular Intricacy, Improvising New Therapies; 2007

McDonell Foundatioon

Neural precursor cells (NPCs) are multipotent cells with the ability to self-renew and to generate mature, differentiated daughter cells of all neural lineages. NPCs can shift their fate dynamically in response to environmental cues and share several properties with neoplastic cells of neuroectodermal origin, including migratory capacity, self-renewal potential, and gene expression profile. It has recently been shown that neural malignancy can be maintained or enhanced by the presence of “stem-like” cells within the tumors. However, it has also been demonstrated that endogenous NPCs show extensive tropism for glioma grafts and migrate from the subventricular zone to surround the tumour, improving survival time of glioma-bearing animals. The response of NPCs to ischemic lesions of the brain might provide clues for understanding those complex relationships. Thus, I will describe our findings on the subventricular zone (SVZ) of the lateral ventricle wall, after cortical devascularizing lesions with or without treatment with granulocyte colony stimulating factor (G-CSF).The SVZ contains NPCs that support neurogenesis and gliogenesis throughout adult life. These NPCs appear closely interdigitated with blood vessels, show the structural and molecular characteristics of astrocytes, and express glial fibrillary acidic protein (GFAP).Devascularizing lesions were selectively made on cortical areas M1, M2 and S1 and were followed by a motor deficit that partially remitted in 2-3 weeks. However, mice treated with G-CSF during the first 5 days post-ischemia showed an almost complete behavioral recovery.After devascularizing lesions, a significant increase of GFAP-immunoreactive cells was observed in the ipsilateral SVZ. At the same time, cells expressing the cell surface antigen prominin-1 (CD133) appeared beneath the corpus callosum, in what appeared to be a lateral migratory stream of differentiating cells. A large proportion of prominin-1-positive cells were closely associated with vascular endothelia. Prominin-1 is a fairly promiscuous marker that exists on both normal and neoplastic stem-like cells of neural and non-neural cell lineages. However, it could barely be detected in normal SVZs.Treatment with G-CSF apparently enlarged the population of GFAP-immunoreactive cells of the SVZ and modified the distribution pattern of prominin-1-expressing cells.Besides their well known role in granulocyte production, G-CSF and G-CSF receptors are present in normal and neoplastic brain cells. Available evidence suggests that coexpression of both molecules in high grade gliomas would reflect autocrine upregulation of tumor growth and invasion. The implication of G-CSF in neoplastic growth regulation would argue against its use in cancer therapy. However, G-CSF- enhancement of endogenous NPCs proliferation and differentiation could perhaps restrict tumoral growth.