臺灣博碩士論文加值系統

高等動物的CNS受傷後，會誘發一連串的膠細胞增殖反應（gliotic reaction）。其最明顯的特徵是星形膠細胞增大，與胞內中間絲蛋白glial fibrillary acidic protein （GFAP）的大量增加。先前之研究發現一個280 kD的中間絲附屬蛋白（intermediate filament associate protein, IFAP）— IFAP-70/280kD，它在體內的表現只侷限於輻射膠細胞與星形膠細胞之先趨細胞內，並不見於成熟的星形膠細胞。因此，此IFAP可用以標示分化初期之星形膠細胞。我們最近的實驗也發現，在CNS受傷以後，傷口周圍的部分反應型星形膠細胞，會有IFAP-70/280kD 之再表現。此IFAP之再表現，顯示這類反應型膠細胞可能發生de-differentiation。依據IFAP-70/280kD之再表現與否，可將反應型星形膠細胞，區分為兩個次族群（subtype）：一類帶有IFAP，出現在傷口附近，可能與gliotic scar的形成有關；而另一類則不會再表現IFAP，出現在離傷口較遠處，可能參與受傷CNS的保護機制，與gliotic scar的形成無關。但關於上述兩型之星形膠細胞的性狀與實際功能仍不清楚。一般而言，成熟星形膠細胞已退出細胞週期，並不會進行有絲分裂。然而CNS受傷後，卻可以明顯地發現星形膠細胞數目增加。但是相關研究中，卻一直存在著兩派歧異的說法。一者認為，成熟的星形膠細胞並不會再行有絲分裂，這些增生的反應型星形膠細胞是源自subventricular zone的神經幹細胞，然後再向上遷徙到大腦皮質的傷口周圍。另一者則認為，CNS受傷後，傷口周圍的星形膠細胞會重新進入細胞週期，並行有絲分裂，這些增生的細胞便是來自原地的星形膠細胞。本實驗採用大腦針刺受傷模式，利用BrdU標示傷後增生之細胞，輔以GFAP及IFAP之免疫螢光染色。觀察發現，在帶有IFAP之次族群中，可見BrdU之標示；而不再表現IFAP之次族群則無BrdU之染色。換言之，BrdU+之反應型星形膠細胞必為IFAP+染色，但反之則不然。在傷後5天，傷口周圍區（距傷口邊緣50 — 800μm）之IFAP+反應型星形膠細胞數量達最高；然而此類細胞在傷口區（距傷口邊緣0 — 50μm）則到受傷8天才達最高值。BrdU在傷口區之染色則是持續增加至受傷後14天。可見藉由IFAP所標示之反應型星形膠細胞，在大腦受傷時，可能會隨著時間，而逐漸移向傷口。同時其發生de-differentiation之目的，可能便在重新獲得增生的能力，與其參與膠細胞疤形成之需求有關。

It is well known that traumatic injuries of the CNS induced a gliotic reaction characterized by reactive astrocytes, which is hypertrophy, process thickened, and enhanced expression of glial fibrillary acidic protein (GFAP). Recently, we have demonstrated that the injuries of CNS would induce a re-expression of an embryonic intermediate filament associate protein, IFAP-70/280kD. According to this IFAP, reactive astrocytes activated by stab-wound injury can be divided into two subtypes: persistent IFAP+/GFAP+ cells which are close to the wound in the area of glial scar, and transient IFAP—/GFAP+ cells which are farther from the wound. In this study, we use BrdU to examine the proliferation of these two subtypes of reactive astrocytes induced by stab injury of the rat cerebrum. Triple/double-label immunofluorescence microscopy was performed using antibodies to IFAP-70/280K, GFAP, and BrdU. The results showed that BrdU+ reactive astrocytes (GFAP+) were always co-labeled with IFAP+. It, however, is not necessary that IFAP+ reactive astrocytes will be BrdU+. There was no BrdU+ signal observed in IFAP— reactive astrocytes. By 5 days post-lesion, IFAP+ reactive astrocytes peaked in the neighboring area (50 — 800μm away from the wound edge), but were still elevating in the adjacent area to the wound (0 — 50μm away from the wound edge). By 8 days post-lesion, IFAP+ reactive astrocytes achieved the highest percentage in the adjacent area. And the BrdU-containing reactive astrocytes existed more closely to the wound. By 20 days post-lesion, following the formation of the gliotic scar at the stab-wound, there remianed a few IFAP+/GFAP+ cells persisted. The BrdU-containing reactive astrocytes were only observed in the scar. These results indicated that many IFAP+/GFAP+ reactive astrocytes close to the wound, in contrast to the IFAP—/GFAP+ ones farther from the wound, regain their proliferative potential to increase in number around a wound following stab injury of the brain, and participated in the formation of the gliotic scar.

摘要 ．．．．．．．．．．．．．．．．．．．．．．．．．．．i
目次 ．．．．．．．．．．．．．．．．．．．．．．．．．．．iii
緒論 ．．．．．．．．．．．．．．．．．．．．．．．．．．．1
前言 ．．．．．．．．．．．．．．．．．．．．．．．．．．．1
中樞神經系統的發育 ．．．．．．．．．．．．．．．．．．2
星形膠細胞的發育 ．．．．．．．．．．．．．．．．．．．．3
輻射膠細胞與星形膠細胞之功能 ．．．．．．．．．．．．．．4
膠細胞增殖反應 ．．．．．．．．．．．．．．．．．．．．．5
星形膠細胞在膠細胞增殖反應中的作用 ．．．．．．．．．．．6
反應型星形膠細胞之增生 ．．．．．．．．．．．．．．．．．9
中間絲蛋白（IF）與中間絲附屬蛋白（IFAP） ．．．．．．．．．10
GFAP與Vimentin ．．．．．．．．．．．．．．．．．．．11
Nestin ．．．．．．．．．．．．．．．．．．．．．．．．12
IFAP-70/280kD ．．．．．．．．．．．．．．．．．．．．13
實驗目的 ．．．．．．．．．．．．．．．．．．．．．．．14
實驗材料 ．．．．．．．．．．．．．．．．．．．．．．．．．15
實驗動物 ．．．．．．．．．．．．．．．．．．．．．．．15
抗體 ．．．．．．．．．．．．．．．．．．．．．．．．．15
特殊藥品 ．．．．．．．．．．．．．．．．．．．．．．．15
實驗方法 ．．．．．．．．．．．．．．．．．．．．．．．．．15
腦部手術 ．．．．．．．．．．．．．．．．．．．．．．．15
偽腦部手術（Sham-Operation） ．．．．．．．．．．．．．．16
標本處理：冷凍組織切片 ．．．．．．．．．．．．．．．．16
IFAP-70/280kD與GFAP之單一或雙重免疫螢光染色 ．．．．．．17
BrdU、IFAP-70/280kD與GFAP之多重免疫螢光染色 ．．．．．．17
兩階段免疫螢光染色 ．．．．．．．．．．．．．．．．．．17
細胞計數 ．．．．．．．．．．．．．．．．．．．．．．．18
實驗結果 ．．．．．．．．．．．．．．．．．．．．．．．．．19
正常及偽手術大白鼠之大腦中GFAP、IFAP-70/280kD與BrdU之免疫螢光染色 ．．．．．．．．．．．．．．．．．．．．．．20
受傷大腦皮質反應型星形膠細胞之變化 ．．．．．．．．．．21
1 Day Post-Lesion ．．．．．．．．．．．．．．．．．．．．．22
1.5 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．22
2 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．23
3 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．24
5 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．24
8 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．25
14 Days Post-Lesion ．．．．．．．．．．．．．．．．．．．．26
20 and 30 Days Post-Lesion ．．．．．．．．．．．．．．．．．26
腦室下區在大腦受傷後之反應 ．．．．．．．．．．．．．．．27
討論 ．．．．．．．．．．．．．．．．．．．．．．．．．．．28
IFAP-70/280kD在反應型星形膠細胞之再表現 ．．．．．．．．．28
反應型星形膠細胞之增生情形與可能來源 ．．．．．．．．．30
IFAP-70/280kD與膠細胞疤之形成 ．．．．．．．．．．．．．．．33
影響星形膠細胞增生及IFAP-70/280kD再表現之可能因子 ．．．34
結語 ．．．．．．．．．．．．．．．．．．．．．．．．．．．35
參考資料 ．．．．．．．．．．．．．．．．．．．．．．．．．37
圖表及說明 ．．．．．．．．．．．．．．．．．．．．．．．．45

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