Adelita Taís, Stilhano Roberta Sessa, Han Sang Won, Justo Giselle Zenker, Porcionatto Marimelia
Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 04039, Brazil.
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 04044, Brazil.
Stem Cell Res. 2017 Jul;22:61-69. doi: 10.1016/j.scr.2017.05.013. Epub 2017 Jun 4.
The subventricular zone (SVZ) of the adult mammalian brain hosts full potential neural stem cells (NSCs). NSCs are able to respond to extracellular signals in the brain, amplifying the pool of progenitor cells and giving rise to neuroblasts that show ability to migrate towards an injury site. These signals can come from vascular system, cerebrospinal fluid, glial cells, or projections of neurons in adjoining regions. CXCL12, a chemokine secreted after brain injury, reaches the SVZ in a gradient manner and drives neuroblasts towards the lesion area. Among many other molecules, matrix metalloproteinase 2 and 9 (MMP-2/9) are also released during brain injury. MMP-2/9 can cleave CXCL12 generating a new molecule, CXCL12(5-67), and its effects on NSCs viability is not well described. Here we produced recombinant CXCL12 and CXCL12(5-67) and evaluated their effect in murine adult NSCs migration and survival in vitro. We showed CXCL12(5-67) does not promote NSCs migration, but does induce cell death. The NSC death induced by CXCL12(5-67) involves caspases 9 and 3/7 activation, implying the intrinsic apoptotic pathway in this phenomenon. Our evidences in vitro make CXCL12(5-67) and its receptor potential candidates for brain injuries and neurodegeneration studies.
成年哺乳动物大脑的脑室下区（SVZ）含有具有全部潜能的神经干细胞（NSC）。神经干细胞能够对大脑中的细胞外信号作出反应，扩增祖细胞池并产生具有向损伤部位迁移能力的神经母细胞。这些信号可来自血管系统、脑脊液、神经胶质细胞或相邻区域神经元的投射。CXCL12是脑损伤后分泌的一种趋化因子，以梯度方式到达SVZ并驱使神经母细胞向损伤区域迁移。在许多其他分子中，基质金属蛋白酶2和9（MMP - 2/9）在脑损伤时也会释放。MMP - 2/9可切割CXCL12产生一种新分子CXCL12(5 - 67)，其对神经干细胞活力的影响尚未得到充分描述。在此，我们制备了重组CXCL12和CXCL12(5 - 67)，并评估了它们对成年小鼠神经干细胞体外迁移和存活的影响。我们发现CXCL12(5 - 67)不促进神经干细胞迁移，但会诱导细胞死亡。CXCL12(5 - 67)诱导的神经干细胞死亡涉及半胱天冬酶9和3/7的激活，这表明该现象中存在内源性凋亡途径。我们的体外研究证据使CXCL12(5 - 67)及其受体成为脑损伤和神经退行性变研究的潜在候选对象。
