An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway.
An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway.
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DOI：
10.1523/jneurosci.4491-12.2013
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发表时间：
2013-04-03
期刊：
影响因子：
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通讯作者：
Zlokovic BV
中科院分区：
文献类型：
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作者：
Guo H;Zhao Z;Yang Q;Wang M;Bell RD;Wang S;Chow N;Davis TP;Griffin JH;Goldman SA;Zlokovic BV
活化蛋白C（APC）是一种具有抗凝和细胞信号传导活性的蛋白酶。在中枢神经系统中，APC及其具有降低的抗凝活性但保留细胞信号传导活性的类似物，如3 K3 A-APC，发挥神经保护、血管保护和抗炎作用。鼠APC促进啮齿类动物缺血性和创伤性脑损伤后的室管膜下神经发生。人类APC是否可以影响人类中常驻祖细胞的神经元产生尚不清楚。在这里，我们表明，3 K3 A-APC，而不是S360 A-APC（APC的酶活性类似物），刺激神经元有丝分裂和分化从胎儿人神经干细胞和祖细胞（NPC）。3 K3 A-APC对细胞增殖和分化的影响与成纤维细胞生长因子和脑源性生长因子的作用相当。其对神经元分化的促进作用伴随着对星形胶质细胞分化的抑制。此外，3 K3 A-APC在神经元产生过程中发挥适度的抗凋亡作用。这些作用似乎是通过特异性蛋白酶激活（PAR）和鞘氨醇-1-磷酸（S1 PR）受体介导的，因为siRNA介导的PAR 1-4和S1 PR 1-5的抑制揭示了PAR 1、PAR 3和S1 PR 1是3 K3 A-APC的神经原性作用所需的。3 K3 A-APC激活S1 PR 1的下游靶点Akt，而S1 PR 1、PAR 1和PAR 3沉默则抑制了3 K3 A-APC的激活。用腺病毒转导具有激酶缺陷型Akt突变体的NPC消除了3 K3 A-APC对NPC的作用，证实了Akt激活在3 K3 A-APC介导的神经发生中的关键作用。因此，APC及其药理学类似物，通过影响PAR和S1 PR信号在居民神经祖细胞，可能是在人类中枢神经系统的发展和修复的有效调节剂。
Activated protein C (APC) is a protease with anticoagulant and cell-signaling activities. In the central nervous system, APC and its analogs with reduced anticoagulant activity but preserved cell signaling activities, such as 3K3A-APC, exert neuroprotective, vasculoprotective and anti-inflammatory effects. Murine APC promotes subependymal neurogenesis in rodents in vivo after ischemic and traumatic brain injury. Whether human APC can influence neuronal production from resident progenitor cells in humans is unknown. Here we show that 3K3A-APC, but not S360A-APC (an enzymatically inactive analog of APC), stimulated neuronal mitogenesis and differentiation from fetal human neural stem and progenitor cells (NPCs). 3K3A-APC’s effects on proliferation and differentiation were comparable to those respectively obtained with fibroblast growth factor and brain-derived growth factor. Its promoting effect on neuronal differentiation was accompanied by inhibition of astroglial differentiation. In addition, 3K3A-APC exerted modest anti-apoptotic effects during neuronal production. These effects appeared mediated through specific protease activated (PAR) and sphingosine-1-phosphate (S1PR) receptors, in that siRNA-mediated inhibition of PARs 1–4 and S1PRs 1–5 revealed that PAR1, PAR3 and S1PR1 are required for the neurogenic effects of 3K3A-APC. 3K3A-APC activated Akt, a downstream target of S1PR1, which was inhibited by S1PR1, PAR1 and PAR3 silencing. Adenoviral transduction of NPCs with a kinase-defective Akt mutant abolished the effects of 3K3A-APC on NPCs, confirming a key role of Akt activation in 3K3A-APC-mediated neurogenesis. Thus, APC and its pharmacological analogues, by influencing PAR and S1PR signals in resident neural progenitor cells, may be potent modulators of both development and repair in the human CNS.