Filippo Thais R M, Galindo Layla T, Barnabe Gabriela F, Ariza Carolina B, Mello Luiz E, Juliano Maria A, Juliano Luiz, Porcionatto Marimélia A
Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.
Stem Cell Res. 2013 Sep;11(2):913-25. doi: 10.1016/j.scr.2013.06.003. Epub 2013 Jun 15.
Neural stem/progenitor cells (NSC) respond to injury after brain injuries secreting IL-1, IL-6, TNF-α, IL-4 and IL-10, as well as chemokine members of the CC and CXC ligand families. CXCL12 is one of the chemokines secreted at an injury site and is known to attract NSC-derived neuroblasts, cells that express CXCL12 receptor, CXCR4. Activation of CXCR4 by CXCL12 depends on two domains located at the N-terminal of the chemokine. In the present work we aimed to investigate if the N-terminal end of CXCL12, where CXCR4 binding and activation domains are located, was sufficient to induce NSC-derived neuroblast chemotaxis. Our data show that a synthetic peptide analogous to the first 21 amino acids of the N-terminal end of CXCL12, named PepC-C (KPVSLSYRCPCRFFESHIARA), is able to promote chemotaxis of neuroblasts in vivo, and stimulate chemotaxis and proliferation of CXCR4+ cells in vitro, without affecting NSC fate. We also show that PepC-C upregulates CXCL12 expression in vivo and in vitro. We suggest the N-terminal end of CXCL12 is responsible for a positive feedback loop to maintain a gradient of CXCL12 that attracts neuroblasts from the subventricular zone into an injury site.
神经干细胞/祖细胞（NSC）在脑损伤后会对损伤做出反应，分泌白细胞介素-1（IL-1）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白细胞介素-4（IL-4）和白细胞介素-10，以及CC和CXC配体家族的趋化因子成员。CXC趋化因子配体12（CXCL12）是在损伤部位分泌的趋化因子之一，已知它能吸引NSC来源的神经母细胞，即表达CXCL12受体CXCR4的细胞。CXCL12对CXCR4的激活取决于趋化因子N端的两个结构域。在本研究中，我们旨在探究CXCL12的N端（CXCR4结合和激活结构域所在之处）是否足以诱导NSC来源的神经母细胞趋化。我们的数据表明，一种类似于CXCL12 N端前21个氨基酸的合成肽，名为PepC-C（KPVSLSYRCPCRFFESHIARA），能够在体内促进神经母细胞的趋化，并在体外刺激CXCR4+细胞的趋化和增殖，而不影响NSC的命运。我们还表明，PepC-C在体内和体外均可上调CXCL12的表达。我们认为，CXCL12的N端负责一个正反馈回路，以维持CXCL12梯度，从而将来自脑室下区的神经母细胞吸引到损伤部位。
