Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor
Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor
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DOI：
10.1523/jneurosci.19-14-06006.1999
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发表时间：
1999-07-15
影响因子：
5.3
通讯作者：
DiCicco-Bloom, E
中科院分区：
文献类型：
--
作者：
Wagner, JP;Black, IB;DiCicco-Bloom, E
越来越多的证据表明，细胞外因子对体内神经遗传前体具有增殖作用。最近，我们发现全身水平的碱性成纤维细胞生长因子（bFGF）调节新生儿脑内的神经发生，该因子明显穿过血脑屏障（BBB）刺激有丝分裂。为了确定外周bFGF是否影响成年期的增殖，我们重点研究了神经发生持续到成熟的区域，海马和前脑室下区（SVZ）。在出生后第1天（P1）大鼠，皮下注射（5 ng/gm体重）8小时后，bFGF使海马和SVZ匀浆中[H-3]胸腺嘧啶的结合增加70%，并引起齿状回和SVZ背外侧有丝分裂核的两倍增加。与体内刺激的25%的增殖海马细胞在培养物中表达神经元特征相似，bfgf诱导的有丝分裂可能反映了神经发生的增加。bFGF的作用并不局限于围产期；外周因子刺激老年动物海马DNA合成（P7-P21），表明bFGF应答细胞持续存在，外周bFGF活性持续到发育晚期。为了开始确定潜在的机制，在P28大鼠中进行了药代动力学研究；bFGF从血浆迅速转移到脑脊液，两个室的水平平行上升，表明外周因子在成熟时穿过血脑屏障。因此，我们在成人中测试了bFGF；外周bFGF使SVZ和嗅道有丝分裂核的数量增加了三倍，这些区域表现出持续的神经发生。我们的观察结果表明，bFGF通过一种独特的内分泌样途径调节正在进行的神经发生，可能协调神经元数量和身体生长，并可能为治疗发育和成年期受损的大脑提供新的方法。
Mounting evidence indicates that extracellular factors exert proliferative effects on neurogenetic precursors in vivo. Recently we found that systemic levels of basic fibroblast growth factor (bFGF) regulate neurogenesis in the brain of newborn vats, with factors apparently crossing the blood-brain barrier (BBB) to stimulate mitosis. To determine whether peripheral bFGF affects proliferation during adulthood, we focused on regions in which neurogenesis persists into maturity, the hippocampus and the forebrain subventricular zone (SVZ). In postnatal day 1 (P1) rats, 8 hr after subcutaneous injection (5 ng/gm body weight), bFGF increased [H-3]thymidine incorporation 70% in hippocampal and SVZ homogenates and elicited twofold increases in mitotic nuclei in the dentate gyrus and the dorsolateral SVZ, detected by bromodeoxyuridine immunohistochemistry. Because similar to 25% of proliferating hippocampal cells stimulated in vivo expressed neuronal traits in culture, bFGF-induced mitosis may reflect increased neurogenesis. bFGF effects were not restricted to the perinatal period; hippocampal DNA synthesis was stimulated by peripheral factor in older animals (P7-P21), indicating the persistence of bFGF-responsive cells and activity of peripheral bFGF into late development. To begin defining underlying mechanisms, pharmacokinetic studies were performed in P28 rats; bFGF transferred from plasma to CSF rapidly, levels rising in both compartments in parallel, indicating that peripheral factor crosses the BBB during maturity. Consequently, we tested bFGF in adults; peripheral bFGF increased the number of mitotic nuclei threefold in the SVZ and olfactory tract, regions exhibiting persistent neurogenesis. Our observations suggest that bFGF regulates ongoing neurogenesis via a unique, endocrine-like pathway, potentially coordinating neuron number and body growth, and potentially providing new approaches for treating damaged brain during development and adulthood.