利用細胞外間質塗佈表面培養的間充質幹細胞治療急性移植物抗宿主疾病

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李欣庭(Hsin-Ting Lee) 查詢紙本館藏

畢業系所

化學工程與材料工程學系

論文名稱

利用細胞外間質塗佈表面培養的間充質幹細胞治療急性移植物抗宿主疾病
(Treatment of GVHD using MSCs cultured on ECM-coating surface)

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★ 羊水間葉幹細胞培養於接枝細胞外間質寡肽與環狀肽具有最佳表面硬度的生醫材料,其增殖能力及多能性之研究	★ 人類體細胞從組成誘導型多能性幹細胞培養在無飼養層上

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至系統瀏覽論文 (2024-8-20以後開放)

摘要(中)

移植物對抗宿主反應(GVHD)是一種在異體移植過後常見的排斥反應，特別是在骨髓移植手術後最常發生。在許多研究中指出人類間充質幹細胞(hMSCs)擁有免疫抑制作，所以近期有越來越多研究關於利用hMSCs治療免疫相關疾病，其中一種就是GVHD。在移植手術中利用hMSCs，像是骨隨幹細胞(BMSCs)或是脂肪幹細胞(ADSCs)，有相當顯著的保護能力可以有效保護移植的外來組織以防GVHD的發生。在此研究中，我們主要想要建立一套測試方式來檢測當我們利用不同種類的hMSCs去保護外來組織時是否也能有效的抑制GVHD的發生。我們探討(1)哪一種hMSCs可以更有效的抑制GVHD的發生。在本研究中我們選用人類羊水幹細胞(hAFSCs)、hADSCs和人類誘導多能幹細胞(hiPSCs, HPS0077)分化MSCs；(2)哪一種細胞生長環境(生物材料)能更有利於hMSCs 防止GVHD發生。為了要在與骨髓移植時相近的情況來模擬GVHD，我們先用hMSCs做成骨分化來得到成骨細胞。接下來我們將不同種類的hMSCs分別都與異體單核球共同培養，然後做活死細胞檢測，得知各種hMSCs都具有抗免疫反應。接下來我們更深入探討不同的細胞外基質(ECM)的細胞培養環境 (層粘連蛋白laminin-521, laminin-511, 人類重組-玻璃粘連蛋白rVN, 纖連蛋白fibronectin, 第一型膠原蛋白collagen type I and matrigel) 對於成骨細胞經過異體單核球共同培養後死亡率的減少以及對於hMSCs對於成骨細胞起的保護作用的差異。希望在未來hMSCs用來防止免疫系統作用的這種機制，特別是我們實驗室自己用hiPSCs分化出的MSCs有高度機會能夠應用於免疫相關疾病的治療。

摘要(英)

Graft versus host disease (GVHD) is a condition that occurs after allogeneic transplants in patients, especially after bone marrow transplantation. Mesenchymal stem cells (MSC) have been increasingly examined for the treatment of immune-related diseases such as GVHD due to their immunosuppressive properties. The transplantation of human MSCs (hMSCs) such as bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) has shown great effects to protect transplanted tissues or cells from GVHD. In this study, I aimed to establish the evaluation of GVHD effect on the insertion of various kind of hMSCs. I evaluated (1) which hMSCs were effective to suppress GVHD. The following hMSCs were selected in this study: human amniotic fluid stem cells (hAFSCs), hADSCs and human pluripotent stem cells (hiPSCs, HPS0077)-derived MSCs. I also investigated (2) which cell culture environment (biomaterials) supports GVHD treatment by hMSCs. The osteogenic differentiation from hMSCs was performed to obtain osteoblasts, which mimic the bone cells environment of the most happened GVHD situation. Then, hADSCs, hAFSCs and hiPSCs-derived MSCs were treated with allogenic mononuclear cells and subsequently, the live and dead staining of hMSCs were performed after allogenic mononuclear cell treatment. It is found that hADSCs, hAFSCs, and hiPSCs-derived MSCs had the ability to suppress the inflammation reaction by allogenic mononuclear cells. The effect to suppress the reaction by hMSCs is stronger in the following order: hAFSCs > hADSCs > hiPSCs-derived MSCs. We further evaluated the effect of ECM (extracellular matrix) proteins (laminin-521, laminin-511, recombinant vitronectin, fibronectin, collagen type I and Matrigel) on the decrease of dead cells of osteoblasts on ECM protein-coated dishes by treatment of allogenic mononuclear cells, where several kinds of hMSCs were co-cultured with the osteoblasts. The osteoblasts cultured on Matrigel-coated dishes showed more alive cells than those cultured on other ECM-coated dishes by treatment of allogenic mononuclear cells. For the MSCs which were used to prevent the immune attack, hAFSCs cultured on collagen showed more strongly immune tolerance. In the future, these immunosuppressive effects of hMSC, especially hiPSC-derived MSCs have high possibility to apply in other immune-related diseases.

關鍵字(中)

★ 急性移植物抗宿主疾病
★ 免疫抑制
★ 間質幹細胞
★ 共同培養
★ 單核細胞

關鍵字(英)

★ GVHD
★ immuno-suppression
★ mesenchymal stem cells
★ co-culture
★ mononuclear cells

論文目次

Chapter 1. Introduction 1
1-1 Graft-versus-host Disease (GVHD) 1
1-2 Stem Cells 3
1-2-1 Mesenchymal stem cells (MSCs) 5
1-2-2 Multipotency of MSCs 5
1-2-3 MSCs modulation in the immune system 6
1-2-4 Limitations and future of MSC usage in clinics 8
1-3 Extracellular Matrix (ECM) 10
1-3-1 Matrigel 11
1-3-2 Collagen 12
1-3-3 Laminin 13
1-3-4 Recombinant vitronectin 14
1-4 Peripheral Blood Mononuclear Cells (PBMCs) 15
1-5 Goal of this research 17
Chapter 2. Materials and methods 19
2-1 Materials 19
2-1-1 Cell source 19
I. Adipose tissue 19
II. Amniotic fluid 19
2-1-2 Culture medium 20
I. Human adipose derived stem cells (hADSCs) 20
II. Human amniotic fluid stem cells (hAFSCs) 20
2-1-3 Dissociation and passaging agent 21
2-1-4 Commercial cell cultivation dish 21
2-1-5 Surface coating ECM 21
2-1-6 Osteoblast differentiation 22
I. Commercial differentiation medium 22
II. Homemade differentiation medium 22
III. Evaluation of osteoblasts 22
2-1-7 Isolation of mononuclear cells 23
2-1-8 Live and Dead staining 23
2-1-9 Cytokine ELISA test 23
2-2 Experimental instruments 24
2-3 Experimental methods 24
2-3-1 Preparation and cultivation of human Adipose derived stem cells (hADSCs) 24
I. Extraction of hADSCs 24
II. hADSCs cultivation and passage 26
2-3-2 Preparation and cultivation of humam amniotic fluid stem cells (hAFSCs) 27
I. Extraction of hAFSCs 27
II. hAFSCs cultivation and passage 28
2-3-3 Cell counting 29
2-3-4 Preparation of ECM-coating dishes 30
2-3-5 Osteogenic differentiation and characterization 31
I. Osteogenic differentiation 31
II. Alkaline phosphate activity (ALP activity) 32
III. Alizarin red S staining 32
IV. von Kossa staining 33
2-3-6 Isolation of mononuclear cells 33
2-3-7 Co-culture of cells 34
I. Co-culture of hMSCs with osteoblasts 34
II. Mononuclear treatment of the cells 35
2-3-8 Live and Dead staining 35
2-3-9 Cytokine ELISA test 35
Chapter 3. Result and Discussion 38
3-1 Osteogenic differentiation 38
3-1-1 hAFSCs differentiation into osteoblasts on different ECM in several media 38
3-1-2 Development of hAFSCs induction into osteoblasts using homemade differentiation medium 40
3-1-3 Development of osteogenic differentiation process and medium ingredients 43
3-1-4 hADSCs differentiation into osteoblasts using homemade induction medium and commercial induction medium 44
3-1-5 hADSCs differentiation into osteoblasts on several ECM protein-coating surface 47
3-2 Immune privilege characteristics and suppression of hMSCs 49
3-2-1 hADSC-derived osteoblasts on ECM protein coating dishes treated by allogenic mononuclear cells 50
3-2-2 Immune tolerance of different MSCs on different ECM protein coating dishes 52
I. Immune tolerance comparison of hAFSCs single, hAFSC mix2, hiPSC (mix-4)-derived MSCs, and hADSC 52
II. Immune tolerance comparison of hAFSCs with hiPSC (mix-4)-derived MSCs 54
III. Comparison of doubling time of alive cells cultured on several ECM protein coating dishes after treatment of mononuclear cells 57
3-2-3 Co-culture of MSCs with ADSC-derived osteoblasts 59
Chapter 4. Conclusion 61
Reference 62
Appendix 69

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指導教授

樋口亞紺(Akon Higuchi)

審核日期

2022-8-24

推文