臺灣博碩士論文加值系統

間質幹細胞 (Mesenchymal stem cells, MSC) 具有多元的分化能力，且能調節免疫反應，協助組織修復，目前已被應用於細胞療法。在特定誘發條件下，MSC會分化為脂肪、軟骨及成骨細胞。有文獻發現當MSC分化為脂肪細胞後，免疫調節能力會減弱，顯示MSC的分化與免疫調節能力有關。維生素A與D也被發現會影響MSC的分化，是否也影響MSC的免疫調節能力尚未可知。因此，本研究目的欲探討維生素對MSC分化及免疫調節能力的影響。實驗方法為從BALB/c小鼠骨髓分離出MSC，分析表面抗原不具CD11b、CD34、CD90.2、CD45R (B220)，且呈現CD29、CD44、CD73、Sca1、CD105等，並分別用不同分化劑培養基誘發生成脂肪細胞、軟骨細胞或成骨細胞，以鑑定所得MSC之分化能力。同時也驗證可抑制T細胞的增生，是具免疫調控能力的MSC。確認每批所培養細胞具MSC特性後，分別將MSC培養於含不同濃度維生素A、維生素D或葉酸的培養基，於第3、7、14天，分析維生素對MSC分化為脂肪細胞的影響，同時也檢測發炎相關基因的表現量；以及與分離自脾臟的CD4+ T細胞共培養後，測定T細胞增生能力，分析維生素對MSC免疫調節能力的影響。實驗結果顯示，培養7天時，維生素A會抑制MSC表現PPARγ、C/EBPα、Ap2、Glut4等基因，且有助於MSC的增殖；維生素D在0.1 nM濃度下則會抑制MSC表現C/EBPα及Ap2，但不利於MSC的增殖；葉酸也有助於MSC的增殖，僅在100 μM 濃度下會抑制C/EBPα的基因，在20 µM 濃度下皆不影響MSC上述基因的表現。在免疫調節能力方面，此3種維生素皆不改變MSC抑制T細胞增生的能力，維生素A及葉酸培養7天時會抑制Tnfα、Tgfb的表現量，且維生素A培養14天時會促進Il-6的表現。綜合以上，在含維生素A微環境MSC會增殖，也較不易趨向分化為脂肪細胞；在含維生素D微環境中雖較不利於MSC增殖，但也會抑制脂肪相關基因的表現量；在含葉酸微環境中MSC也可增殖，且處於較未分化狀態。此添加維生素對MSC增殖與調控分化過程的研究成果，可做為開發MSC體外量產技術之參考。

Mesenchymal stem cells (MSCs) are multipotent stem cells which have regenerative and immunoregulatory properties. These features make MSCs being applied in cellular therapy an attractive approach. MSCs can differentiate into osteocytes, chondrocytes and adipocytes under certain culture condition. Recent studies have demonstrated that MSC might lose immunoregulatory properties during the adipogenic differentiation, suggesting its relationships with immunity. Vitamin A and D have been known to regulate the differentiation of MSCs, and might have effects on the immunoregulatory properties of MSCs. Hence, the aim of this study is to investigate the effects of vitamins on differentiation and immunoregulatory properties of MSCs. First, MSCs were isolated from 4-week-old BALB/c bone marrow, characterized by specific surface markers, differentiation tendency to adipocytes, chondrocytes and osteocytes under appropriate condition, and the immunoregulatory properties to supress T cells proliferation. After confirming all the above properties of MSCs, MSCs were cultrured in medium containing different concentrations of all trans-retinoic acid, 1α,25-(OH)2D3 and folic acid. Differentiation and immunoregulatory properties were determined on days 3, 7 and 14. These results showed that after a 7-day culture, vitamin A reduced the gene exprsesion of PPARγ, C/EBPα, Ap2, Glut4, and promoted the proliferation of MSCs. Vitamin D under 0.1 nM reduced the gene exprsesion of C/EBPα, Ap2, but also inhibited the proliferation of MSCs. Folic acid promoted the proliferation of MSCs and under 100 μM could reduce the expression of C/EBPα. On the other hand, all of these vitamins did not alter the inhibitory effect of MSC subsets on CD4+ T cell proliferation. Vitamin A and folic acid reduced the gene expression of Tnfα, Tgfb after a 7-day culture. Besides, Vitamin A enhanced the expression of Il-6 after a 14-day culture. In conclusion, Vitamin A could promote the proliferation of MSCs and inhibited the adipogenesis of MSCs. Vitamin D could inhibit the expression of adipocyte-related gene, but also inhibit the proliferation of MSCs. Folic acid could also promote the proliferation of MSCs, and maintain MSCs in an undifferentiated state. This research suggested that addition of vitamins at certain concentration might alter MSC proliferation and differentiation, which provides information for the expansion of MSCs.

摘要 i
Abstract ii
圖目錄 v
表目錄 vi
縮寫對照表 vii
第一章、緒論 1
第一節、文獻回顧 1
一、間質幹細胞 (Mesenchymal stem cells) 1
二、維生素A 6
三、維生素D 8
四、葉酸 10
第二節、研究動機與架構 12
第二章、材料與方法 13
第一節、間質幹細胞的分離及培養 13
第二節、間質幹細胞的鑑別 14
一、表型分析 14
二、分化能力 15
三、T細胞增生反應 16
第三節、維生素對間質幹細胞存活率及增生的影響 17
第四節、維生素對間質幹細胞分化特性之影響 18
一、實驗設計 18
二、油紅染色分析油滴生成量 19
三、Real time PCR分析間質幹細胞分化過程相關基因表現量 19
第五節維生素對間質幹細胞免疫調節特性之影響 21
一、實驗設計 21
二、Real time PCR分析間質幹細胞免疫調節相關基因表現量 22
三、T細胞增生反應 22
第六節、統計分析 22
第三章、結果 23
第一節、間質幹細胞的特性 23
一、表型分析 23
二、分化能力 24
三、對T細胞增生反應的影響 25
第二節、維生素對間質幹細胞存活率及增生之影響 26
第三節、維生素對間質幹細胞分化之影響 27
一、維生素A 28
二、維生素D 29
三、葉酸 31
第四節、維生素對間質幹細胞免疫調節特性之影響 33
一、維生素A 33
二、維生素D 35
三、葉酸 37
第四章、討論 39
第一節、維生素對間質幹細胞增生之影響 39
第二節、維生素對間質幹細胞分化之影響 39
一、維生素A 39
二、維生素D 41
三、葉酸 42
第三節、維生素對間質幹細胞免疫調節特性之影響 43
第四節、間質幹細胞的分化與免疫調節特性之相關性 43
第五節、結論 44
第五章、參考文獻 45

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