臺灣博碩士論文加值系統

(1) 胎腦內小神經膠細胞於正常發育時之免疫表型 本實驗利用幾種相關單株抗體以觀察胎腦隨年齡增長時 (從懷孕第10天到20天)，小神經膠細胞內各種抗原的表現情形；所使用的單株抗體有認識主要組織相容性抗原 I (MHC class I, OX-18) 和抗原II (MHC class II, OX-6)，白血球一般抗原(OX-1)，CD4接受器(OX-35)，第3型補體受器(OX-42)，還有未知其功能的巨噬細胞抗原(ED1和ED2)。所有測試的抗原中，最早在胚胎第12天時，只有標誌ED1和ED2的小神經膠細胞出現。第14天，除了帶MHC class I抗原 (OX-18) 的細胞未偵測到外，其餘所有測的抗原均在變形性小神經膠細胞內被偵測到，而被標誌的細胞主要分布在發育中的白質。從第16天起，在紋狀體外側的大腦間質區 (the intermediate zone lateral to the striatum, IZS) 的小神經膠細胞中偵測到所有測試抗原。此後，有些標誌細胞伸出細胞突起 (例如：在胚胎第20天ED1, ED2, OX-6 和 OX-18標誌的細胞)，有些表現較弱的免疫活性 (例如：在胚胎第18天OX-6, OX-18, OX-35和OX-42標誌的細胞)。我們推測鼠胎腦內小神經膠細胞有免疫異質表型，而這種表現可能是因應發育時腦內局部環境的特殊需要所致。(2) 以凝集素標誌法探討胎腦內小神經膠細胞於正常發育時之超微結構本實驗利用可標誌小神經膠細胞膜上乳醣基(-D-galactose)的凝集素-GSA I-B4 (Griffonia simplicifolia B4 isolectin) 織化學法，並經由光學及電子顯微鏡來觀察鼠腦內小神經膠細胞在胚胎發育早期(胚胎第11天~15天)的分化情形。GSA I-B4標誌細胞早在胚胎第11天時便出現在神經上皮內。從胚胎第11天到15天，這些被GSA I-B4標誌細胞的數目相當少。GSA I-B4標誌細胞的分布由靠近神經上皮基底膜處向腦室逐漸減少。根據細胞的核質比以及細胞質內超微構造的特徵，在胚胎第11、12天的胎腦內，顯示有二種型式的GSA I-B4標誌細胞，即原始型/胚胎型巨噬細胞和吞噬細胞二種。隨著胎腦的發育，在胚胎第14天開始出現具有高度液泡狀的典型變形性小神經膠細胞，屬GSA I-B4標誌的第三型細胞。此時，仍可觀察到先前出現的原始型/胚胎型巨噬細胞及吞噬細胞。本研究顯示並沒有中間型細胞介於這三種不同型式的GSA I-B4標誌細胞。而小神經膠細胞在胚胎發育早期呈現多種形態的特性推測可能與其功能的多樣異質性有關。(3) 胎腦內小神經膠細胞經糖性皮質固醇處理後之免疫表型及增生情形在本實驗中，將懷孕第10天的母鼠經腹腔注射糖性皮質固醇 (dexamethasone, DEX)，觀察從胚胎第16天到第20天時，胎腦內小神經膠細胞其免疫分子 (ED1 和 OX-42) 受DEX的影響情形，並與對照組作比較。結果發現: 這些免疫標誌的小神經膠細胞其外形及分布情形並不因藥物的處理而有所改變，但其數量上卻隨著所使用抗體的不同，而有不同的變化情形；因此計量紋狀體外側大腦間質區 (the intermediate zone lateral to the striatum, IZS) 的小神經膠細胞，結果顯示，受ED1和 OX-42標誌之小神經膠細胞密度，在胚胎第16天時與對照組比較，無明顯差異；在胚胎第18天時，細胞密度與對照組的比較都有明顯下降的趨勢，然而，OX-42標誌細胞密度在第20天卻有明顯增加的現象。另外，利用對小神經膠細胞膜上α-D-galactosy glycoprotein具專一性的凝集素-GSA I-B4來觀察小神經膠細胞在鼠腦內經糖性皮質固醇處理後的情形。結果發現在胚胎第16天時，GSA I-B4標誌的小神經膠細胞密度與同年齡對照組比較有意義的增加，至胚胎第18天時與同年齡對照組比較是減少，之後則無明顯差異。而利用雙重染色 (BrdU &OX-42 or GSA I-B4) 的方式來標誌增生中的小神經膠細胞，更發現經由DEX處理後，在胚胎第16天雙重標誌的小神經膠細胞有明顯增加的現象，因此推測這個現象可能是小神經膠細胞分裂增殖的結果。至於胚胎第18天時，經糖性皮質固醇處理後，OX-42和ED1標誌小神經膠細胞密度表現戲劇性的減少，推測可能是糖性皮質固醇的抑制作用使得抗原表現調降所致。總括言之，我們認為經由母體處理DEX，對胎腦不同發育階段內小神經膠細胞表面抗原的呈現會有不同的影響程度。這項訊息或許可以提供經由母體處理糖性皮質固醇以治療出生前胎兒特殊疾病之利用。(4) 以凝集素標誌法探討糖性皮質固醇對胎腦內小神經膠細胞超微結構之影響在本實驗中，將糖性皮質固醇(dexamethasone, DEX) 經由腹腔注射入懷孕第10天的母鼠，觀察從胚胎第16天到第20天時，胎腦中IZS處小神經膠細胞的超微結構及其凝集素標誌受DEX影響的情形，並與對照組作比較。本研究結果發現，經此藥物處理後，在胚胎第16天的標誌細胞大部分含有許多大型液泡及較多的高爾基氏體。這些大而圓的液泡有時佔據整個細胞質。從胚胎第18天起，在對照組與藥物處理組，GSA I-B4標誌細胞的細胞質內大都含有大量的大型液泡或者是溶菌體。不同的是，在DEX處理組內具發達液泡的標誌細胞，其細胞質內的粗糙內質網具長而多條平行排列在細胞核旁。有些具溶菌體堆積的標誌細胞，其溶菌體有GSA I-B4的標誌情形出現。而無論藥物的處理與否，標誌細胞內的高爾基氏體則從未有GSA I-B4的標誌。本研究顯示糖性皮質固醇對小神經膠細胞的超微結構及其凝集素的標誌呈現多方面的影響程度。因此我們推測這些小神經膠細胞因處在各種不同的活化及分化發育階段而造成其受DEX的影響有不同的反應或程度。(5) 胎鼠腦內小神經膠細胞在正常發育及糖性皮質固醇處理後與細胞凋亡的關係本章利用組織化學及免疫細胞化學技術，以探討胎腦內小神經膠細胞在正常發育及糖性皮質固醇處理下，與凋亡細胞的關係，其中以TUNEL(Terminal transferase mediated dUTP Nick End-Labelling)方法標誌凋亡細胞，凝集素GSA I-B4來標誌小神經膠細胞。實驗結果發現，在正常發育的胎腦內，凋亡細胞主要聚集在大腦背側的正中線處，並向頭吻兩端伸展；而小神經膠細胞也分布在凋亡細胞聚集處，同時有些小神經膠細胞含有凋亡體。至於凋亡的小神經膠細胞在正常發育的胎腦內則幾乎沒有觀察到。另外，在紋狀體外側的大腦間質區(IZS, intermediate zone lateral to the striatum)，自胚胎第16天起有小神經膠細胞的聚集，然而此處只有零星的凋亡細胞散佈，同時幾乎偵測不到含有凋亡體的小神經膠細胞或凋亡的小神經膠細胞。在懷孕第10天的母鼠體內注射糖性皮質固醇(dexamethasone, DEX)後，凋亡細胞在各個發育階段的分布及數目大致上並沒有顯著變化，然而小神經膠細胞族群數量在各個發育階段有不一致的變化；在胚胎第16天的IZS及第20天的海馬連合(hippocampal commissure)及緊鄰胼胝體上方的扣帶回皮質(cingulate cortex immediately dorsal to the corpus callosum)有顯著增加，在胚胎第18天的IZS有顯著減少。至於小神經膠細胞的凋亡及含有凋亡體的分布情形及數量並沒有明顯改變。基於以上的實驗結果，推測隨著胚胎的發育或經藥物處理時，小神經膠細胞族群的變化不是利用規劃性細胞死亡的方式來調控的。同時，無論藥物處理與否，胚胎發育時期的小神經膠細胞可能不負責清除大部分的凋亡細胞。另外，糖性皮質固醇對胚胎發育時期腦內各種細胞的作用可能有一致性作用----促進這些細胞分化而不誘導其凋亡。

(1) The present study examined the expression of different antigens in amoeboid microglial cells (AMC) in fetal rat brain extending from 12 to 20 days postconception (E10 to E20) using a panel of monoclonal antibodies against the major histocompatibility complex (MHC) class I (OX-18) and class II (OX-6) antigens, leukocyte common antigen (OX-1), CD4 receptor (OX-35), complement type 3 receptor (OX-42) or macrophage antigens of unknown function (ED1 and ED2). Of the above-mentioned antigens, ED1 and ED2-labelled AMC were first observed in the neuroepithelia as early as embryonic day 12 (E12); other antigens were not detected at this stage. At E14, except for MHC class I antigen, all other antigens were expressed by AMC distributed preponderantly in the developing white matter. At E16, AMC in the intermediate zone lateral to the striatum were endowed with all of the above-mentioned antigens including MHC class I. At E18, the immunoreactivities of AMC stained with OX-6, OX-18, OX-35 and OX-42 antibodies were noticeably reduced when compared with those ones at E16. At E20, amoeboid microglial cells exhibited full complement of antigen expression similar to those cells at E16; some of the labelled cells emitted a variable number of cytoplasmic processes. It is suggested that the successive and differential expression of various macrophage related antigens on AMC in fetal brain is related to the specific requirement of the local environment in different stages of developmental brain.(2) The development of microglia in embryonic rat brain extending from 11 to 15 days of gestation (E11~E15) was studied, based on light and electron microscopic identifications of microglia using peroxidase-coupled isolectin B4 of Griffonia simplicifolia (GSA I-B4) against alpha-D-galactose groups on the cell membrane. GSA I-B4-positive cells were observed in the neuroepithelia as early as embryonic day 11 (E11). Relatively low densities of GSA I-B4 positive cells resided in the brain from E11 to E15. The density of GSA I-B4 positive cells within the wall of the neuroepithelia was the greatest along the neuroepithelial basement membrane and declined progressively toward the ventricular lumen. At E11 and E12, ultrastructural examinations showed that there were two morphological types of GSA I-B4 positive cells, primitive/fetal macrophage and phagocyte, based on the differences of nucleus/cytoplasm ratio and the configuration of their cytoplasma. With aging, the typical amoeboid microglia with highly vacuolated structures were observed as early as E14. At the same time, GSA I-B4 positive cells mentioned above still coincided with the typical amoeboid microglia. The present study showed that there were no transitional forms appeared between the three types of GSA I-B4 positive cells. These results of the multiple forms of microglia existing in the early embryo were suggested to be related to the heterogeneity of microglial function.(3) The present study examined the effect of maternal administration of dexamethasone (DEX) on amoeboid microglial cells (AMC) in fetal rats extending from 16 to 20 days postconception (E16 to E20). After an intraperitoneal injection of DEX into pregnant rats at E10, the external morphology and distribution of immunolabelled AMC as detected with OX-42 and ED1 monoclonal antibodies remained unaltered when compared with those of the controls. The major effect of dexamethasone was on microglial cell population. Thus, the numbers of immunolabelled AMC with OX-42 or ED1 in the intermediate zone lateral to the striatum (IZS) of DEX-treated fetuses which remained relatively unchanged at E16 were significantly reduced at E18. However, OX-42 labelled cells showed an unexpected increase in number at E20 following DEX treatment. Microglial response to DEX was also analyzed in sections stained with the isolectin, GSA I-B4, which specifically binds alpha-D-galactosyl glycoproteins on microglia. The number of GSA I-B4 labelled AMC was significantly increased at E16, declined at E18 and remained constant thereafter in DEX-treated rats when compared with that of the controls. A major finding after DEX treatment was the wider occurrence of AMC double labelled with anti-BrdU antibody and GSA I-B4 or OX-42 at E16 compared with those in the controls suggesting that the initial increase of GSA I-B4 labelled AMC may be attributed to their proliferation. The drastic reduction of OX-42 and ED1 positive microglial cells notably at E18 may be due to the downregulation of surface antigens as a result of possible suppressive action of dexamethasone. On the basis of present findings, it is concluded that the antigenic expressions of fetal AMC may be modulated by DEX administrated maternally. Such however appeared to be extremely selective as reflected by the varied expression for certain immune molecules at different stages of brain development. This information would be useful in potential use of glucocorticoids in prenatal therapy of brain pathology via maternal circulation.(4) The present study described the effect of maternal administration of dexamethasone (DEX) on amoeboid microglial cells (AMC) in fetal rat brain extending from 16 to 20 days postconception (E16 to E20). After an intraperitoneal injection of DEX into pregnant rat at E10, the ultrastructure and lectin-labelling pattern of AMC in the intermediate zone lateral to the striatum (IZS) were examined. At E16, AMC in DEX-treated rats showed numerous large vacuoles and more Golgi complex. Large vacuoles in the cytoplasm of AMC were round in shape and occupied massive volume of the cytoplasm after DEX treatment. From E18 onward, the cytoplasm of most lectin-labelled AMC in saline-treated rats contained well-developed vacuoles or lysosomal granules as those in DEX-treated ones. Highly vacuolated AMC in DEX-treated brain were also characterized in the long strand of rER arranged in parallel and close to their nucleus. Some AMC with abundant lysosomes in DEX treated rats exhibited heavy staining with isolectin at their lysosomes. No lectin labelling at the Glogi apparatus of AMC was found both in DEX-treated and control brains.Present results demonstrated a multiple effect of DEX on the ultrastructure and lectin-labelled pattern of AMC. It was speculated that the differential responses of AMC to DEX may be dependent on the phase of cell activation and/or differentiation at different stages of brain development as previous findings (Wang et al., 1998).(5) Using histochemical and immunocytochemical techniques, we were to determine the possible involvement of apoptosis in regulating the microglial distribution in fetal rat brain after dexamethasone (DEX) treatment. Apoptotic cells were detected by using terminal transferase mediated dUTP nick end-labelling (TUNEL) method while microglial cells were labelled with the isolectin Griffonia simplicifolia (GSA I-B4). In normal fetal brain, apoptotic cells occurred mainly in the dorsal midline along its rostro-caudal axis of the brain, where lectin-labelled microglia were also distributed; some of them had contained several apoptotic bodies. Only rare apoptotic microglia was detected in these areas. On the other hand, there were a few apoptotic cells in the intermediate zone lateral to the striatum (IZS) where lectin-labelled microglia were common from embryonic day 16 (E16) onwards. At the same time, microglia engulfing apoptotic bodies or apoptotic microglia were almost not detected in the IZS. After an intraperitoneal injection of DEX into pregnant rats at E10, there was no noticeable change in the distribution of apoptotic cells at all stages examined but an accumulation of lectin-labelled microglia was observed in IZS at E16, in hippocampal commissure (Hip Com) and cingulate cortex immediately dorsal to the corpus callosum (CCDCC) at E20 and a decrease in IZS at E18. The number and distribution of apoptotic microglia or microglia engulfing apoptotic cells were also not affected in areas where apoptotic cells consistently existed. On the basis of present findings, it was suggested that the variation of microglial population with developmental growth may not be regulated by a form of programmed cell death as those in DEX-treated fetuses, and the microglia may not be the major scavenger of apoptotic cells in the normal fetal brains or those of DEX-treated ones. On the other hand, the effect of DEX on microglia or other neural cells in fetal brain may be related consistently to enhance the cell differentiation rather than induce cell apoptosis.

目錄第一章、緒論 ------------------------------------ 1 I. 引言 ------------------------------------------2 II. 小神經膠細胞的起源 --------------------------- 3 A. 軟腦膜起源 --------------------------- 3 B. 周皮細胞起源 --------------------------- 3 C. 神經外胚層起源 --------------------------- 4 D. 大單核白血球起源 --------------------------- 4 E. 其他 --------------------------- 5III. 小神經膠細胞的種類 ------------------------------ 6 A. 分枝性小神經膠細胞 --------------------------- 6 B. 變形性小神經膠細胞 --------------------------- 8 C. 活化的小神經膠細胞 --------------------------- 10 D. 再活化的小神經膠細胞 ------------------------- 11 IV. 小神經膠細胞的細胞生物學 ------------------------ 12 A. 小神經膠細胞的細胞化學標誌情形 --------------- 12 B. 小神經膠細胞的抗原呈現 ----------------------- 15 C. 吞噬作用 ------------------------------------- 16 V. 小神經膠細胞的演化與替換 ------------------------ 16 A. 變形性小神經膠細胞分化成分枝性小神經膠細胞的轉變 ---------------------- 16 B. 分枝性小神經膠細胞轉變成活化的腦巨噬細胞------ 17 C. 小神經膠細胞的增殖 --------------------------- 18 D. 小神經膠細胞的就地死亡 ----------------------- 19 VI. 小神經膠細胞的神經生物學 ------------------------ 20 A. 小神經膠細胞和中樞神經系統的發育 ------------ 20 B. 小神經膠細胞和中樞神經系統的再生 ------------ 21VII. 研究目的 ---------------------------------------- 22 VIII. 參考文獻 --------------------------------------- 23第二章、胎腦內小神經膠細胞於正常發育時之免疫表型摘要 ------------------------------------------------- 38[英文摘要] ------------------------------------------- 39 I.背景 --------------------------------------------- 40 II.研究方法及進行步驟 ------------------------------- 42III.結果 --------------------------------------------- 44 IV.討論 --------------------------------------------- 45 V.參考文獻 ----------------------------------------- 48 VI.圖表及圖片說明 ----------------------------------- 51第三章、以凝集素標誌法探討胎鼠腦內小神經膠細胞於正常發育 之超微結構 -------------------------------------- 58摘要 ------------------------------------------------- 59[英文摘要] ------------------------------------------- 60 I.背景 --------------------------------------------- 61 II.研究方法及進行步驟 ------------------------------- 63III.結果 --------------------------------------------- 65 IV.討論 --------------------------------------------- 68 V.參考文獻 ----------------------------------------- 70 VI.圖表及圖片說明 ----------------------------------- 72第四章、胎腦內小神經膠細胞經糖性皮質固醇處理後之免疫表型 及增生情形 --------------------------------------- 83摘要 ------------------------------------------------- 84[英文摘要] ------------------------------------------- 85 I.背景 --------------------------------------------- 86 II.研究方法及進行步驟 ------------------------------- 87III.結果 --------------------------------------------- 91 IV.討論 --------------------------------------------- 93 V.參考文獻 ----------------------------------------- 97 VI.圖表及圖片說明 ----------------------------------- 100第五章、以凝集素標誌法探討糖性皮質固醇對胎腦內小神經膠細胞 超微結構之影響 ----------------------------------- 107摘要 ------------------------------------------------- 108[英文摘要] ------------------------------------------- 109 I.背景 --------------------------------------------- 110 II.研究方法及進行步驟 ------------------------------- 111III.結果 --------------------------------------------- 112 IV.討論 --------------------------------------------- 113 V.參考文獻 ----------------------------------------- 116 VI.圖表及圖片說明 ----------------------------------- 119第六章、胎鼠腦內小神經膠細胞在正常發育及糖性皮質固醇處理後 與細胞凋亡的關係 --------------------------------- 127摘要 ------------------------------------------------- 128[英文摘要] ------------------------------------------- 129 I.背景 -------------------------------------------- 130 II.研究方法及進行步驟 ------------------------------- 132III.結果 --------------------------------------------- 134 IV.討論 --------------------------------------------- 137 V.參考文獻 ----------------------------------------- 141 VI.圖表及圖片說明 ----------------------------------- 145第七章、綜合結論 ------------------------------------- 153

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