臺灣博碩士論文加值系統

間葉幹細胞(Mesenchymal stem cells)為多能性的幹細胞,不但具有分化成 不同細胞的潛力也可藉由旁分泌機制(paracrine effect)產生多種的細胞因子及趨 化因子(chemokine),這些旁分泌機制能刺激多樣的受體調解的生存途徑,藉此 誘導幹細胞歸巢、分化、或調解在受傷區域的抗發炎作用進而去促進組織再生。
肝臟再生的機制目前尚未很明確,但有先前研究指出肝臟再生不只是跟肝臟 細胞的擴增有關,也跟非實質細胞例如:肝臟竇內皮細胞(Liver sinusoidal endothelial cell)、庫佛氏細胞(Kupffer cell)及肝臟星狀細胞(Stellate cell)分泌一 些細胞因子(cytokine)及生長因子(growth factor)有關,特別是肝臟竇內皮細胞已 知可提供肝臟生長因子(HGF)及WNT2來促進肝臟再生,因此我們猜測間葉幹細 胞與非實質細胞的內分泌及旁分泌作用在肝臟再生機制中扮演著重要的角色。
本實驗主要研究間葉幹細胞跟肝臟竇內皮細胞共同促進肝臟再生的能力,我 們發現肝臟竇內皮細胞與間葉幹細胞共培養促進肝臟表現再生有絲分裂原例如: 白細胞介素 6 (IL-6)、腫瘤壞死因子 α(TNF-α)、轉化生長因子 β(TGF-β)、肝臟 生長因子(HGF)及WNT2的基因表現,而將間葉幹細胞與肝臟竇內皮細胞共同培 養後培養液中的細胞激素,肝臟生長因子及 WNT2 也明顯增加,另外先前有文 獻指出肝臟的再生與肝臟竇內皮祖細胞有關,而我們還發現間葉幹細胞與肝臟竇 內皮細胞共培養後會增加肝臟竇內皮祖細胞族群的表現。
根據以上結果,本研究推測間葉幹細胞及肝臟竇內皮細胞相互作用共同促進 肝臟有絲分裂原的基因表現及增加肝臟生長因子及 WNT2 來刺激肝臟細胞增生, 進一步去促進肝臟再生。

Non-parenchymal cells including liver sinusoidal endothelial cell (LSECs), kupffer cell and stellate cell, especially LSECs, have been known to respond to the microenvironment and promote liver regeneration through mediating the secretion levels of cellular secretomes such as hepatocyte growth factor (HGF), Wnt2, transforming growth factors (TGFs), tumour necrosis factor (TNF-α) and interleukin 6 (IL-6). Mesenchymal stem cells (MSCs) not only have multi-differentiation potential but also contribute to tissue regeneration both in vivo and vitro by paracrine signaling and our previous results have shown that MSCs can rescue carbon tetrachloride (CCl4)-induced liver injuries in mice. In this study, we have demonstrated that expression levels of mitogenic genes, WNT2 and HGF in LSEC were significant increased after co-cultured with MSCs and MSC condition medium which are important in liver. In addition, we found that MSC/LSEC co-cultured condition medium can not only promote the proliferation rate of primary hepatocytes but also increase the productions of albumin compare to hepatocyte growth medium. Although the detail mechanism of how MSCs increase the mitogenic marker expressions in LSECs is not clear, our data suggested that MSC can be used as a potential cell-based therapeutic resource in cooperation with LSEC which promotes liver regeneration.

Abstract ................................................................................................... VI
中文摘要 ................................................................................................. VII List of abbreviations................................................................................ VIII 1. Introduction .............................................................................................1
1.1. Liver regeneration .........................................................................1
1.2. Liver sinusoidal endothelial cells ................................................2
1.3. Definitions and applications of stem cells ..................................2
1.4. Mesenchymal stem cells ...............................................................3
1.5. Hepatic differentiation of mesenchymal stem cells....................5
1.6. 3D culture system ..........................................................................6
2. Materials and methods ..........................................................................7
2.1. Cultivation of bone marrow MSCs ...............................................7
2.2. Hepatic differentiation of MSCs in culture dish..........................8
2.3. Isolation and cultivation of primary hepatocytes .......................8
2.4. Isolation and cultivation of primary LSECs .................................9
2.5. Cultivation of LSEC cell line .......................................................11
2.6. Extraction and quantity of total RNA .........................................12
2.7. Reverse transcription (RT) ..........................................................13
2.8. Quantitative real time polymerase chain reaction (qPCR) .......13
2.9. Flow cytometry analysis .............................................................14
2.10. Indirect co-culture MSCs with LSECs ......................................14
2.11. Wnt2 Enzyme-linked immunosorbent assay (ELISA) .............15
2.12. HGF Enzyme-linked immunosorbent assay (ELISA) ..............16
I
2.13. VEGF-A Enzyme-linked immunosorbent assay (ELISA) ........17
2.14. Urea production assay ..............................................................18
2.15. Immunofluorescent staining .....................................................18
2.16. Self-form a functional liver organoid .......................................19
2.17. Statistical analysis .....................................................................20
3.Results ...................................................................................................21 3.1. Expression of liver regeneration-associated gene in LSEC after VEGF treatment, cultured in MSC CM or co-cultured with MSCs .....21 3.2. Liver regeneration-associated growth factors secretion level from LSECs, primary LSECs and both with VEGF treatment and LSECs co-cultured with MSCs .............................................................22
3.3. The effect of MSC CM, LSEC CM and MSC/LSEC co-cultured CM in vitro primary hepatocytes model ..............................................23
3.4. The expression of VEGF in MSCs, LSECs and MSC/LSEC co-cultured .............................................................................................25
3.5. The CD133+ LSEC progenitor population in MSCs and MSCs co-cultured with LSECs ........................................................................25
3.6. Generation of liver organoids from MDHs.................................26
4.Discussion ............................................................................................27 5. Conclusion ...........................................................................................34 6.References.............................................................................................35 Tables......................................................................................................46
Table 1. Table 2. Table 3.
Sequence of qPCR primers for LSECs...............................46
Sequence of qPCR primers for MDHs ................................47
Sequence of qPCR primers for MSCs ................................48
Table 4. The cytokine array of mouse MSCs conditioned medium49 Figures ...........................................................................................................50 Figure 1. Comparison of liver regeneration-associated gene expression in LSECs with/without VEGF treatment...........................51
Figure 2. Comparison of liver regeneration-associated gene expression in LSECs after co-cultured with MSCs ............................53
Figure 3. Comparison of liver regeneration-associated gene expression in LSECs cultured with/without MSC CM ........................55
Figure 4 . Comparison of liver regeneration-associated gene expression in primary LSECs with/without VEGF treatment.............57
Figure 5. Comparison of Wnt2 secretion level of LSECs and primary LSECs with/without VEGF treatment and LSECs co-cultured with MSCs .......................................................................................................58
Figure 6. Comparison of HGF secretion level of LSECs and primary LSECs with/without VEGF treatment and LSECs co-cultured with MSCs .......................................................................................................59
Figure 7. To elucidate the effect of MSC CM, LSEC CM and MSC/LSEC co-cultured CM on primary hepatocytes growth rate.....60
Figure 8. Comparison of cell cycle mediator gene expression in primary hepatocytes after cultured in MSC CM, LSEC CM and MSC/LSEC co-culture CM .....................................................................62
Figure 9. Hepatic specific gene expression after cultured in MSC condition medium, LSEC condition medium and MSC/LSEC co-cultured condition medium .............................................................66
Figure 10. Effects of condition medium with ALBUMIN expression on
primary hepatocytes..............................................................................67 Figure 11. Effects of condition medium with ALBUMIN expression on primary hepatocytes..............................................................................68 Figure 12. Effects of condition medium with urea production on primary hepatocytes..............................................................................69
Figure 13. Stat3 expression in hepatocytes after MSC/LSEC co-culture CM treatment. ......................................................................70
Figure 14. Nfκb expression in hepatocytes after MSC/LSEC co-culture CM treatment. ......................................................................71
Figure 15. Ap1 expression in hepatocytes after MSC/LSEC co-culture CM treatment. ......................................................................72
Figure 16. Comparison of the Vegf-a gene expression in LSECs and MSCs after co-cultured .........................................................................73
Figure 17. Comparison of VEGF-A secretion level of LSECs and primary LSECs with/without VEGF treatment and LSECs co-cultured with MSCs...........................................................................................74
Figure 18. Comparison of LSEC progenitor cell gene expression in MSCs after co-cultured with LSECs.....................................................75
Figure 19. LSEC progenitor cell population increased after MSCs co-cultured with LSECs ........................................................................76 Figure 20. Endothelial progenitor markers expression in mMSCs after co-cultured with LSECs................................................................77
Figure 21. mMSCs differentiated into hepatocyte-like cells after 28 days with 2-step induction medium.....................................................79
Figure 22. MSCs, LSECs and hepatocytes can self-formed live
organoid-like structure..........................................................................80
Figure 23. Compared the hepatic gene expression of MDHs and liver organoids. ..............................................................................................82

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