間葉幹細胞分泌之基質金屬蛋白酶-9在其免疫調節功能之角色

骨髓間葉幹細胞(Mesenchymal stem cells, MSCs)為多潛能性幹細胞，具有自我更新、繁殖及分化成不同細胞的能力。因著眾多試管內及體內試驗證明間葉幹細胞具有優秀的免疫調節功能，將間葉幹細胞應用在治療免疫發炎反應失調疾病被視為相當有潛力的替代療法。然而將間葉幹細胞推展至臨床使用的過程並不順利。儘管有些人體試驗結果十分成功，但有些人體臨床試驗則顯示間葉幹細胞對發炎並無抑制功能。因此，為了間葉幹細胞的實用化，進一步探討並優化其免疫調節功能實屬必要。近年來發現間葉幹細胞的免疫調節功能部分會被周邊發炎環境所調控。過去，本實驗室發現間葉幹細胞會分泌高量的基質金屬蛋白酶-9(Matrix metalloproteinase 9, MMP-9)這個在許多發炎疾病中皆會被高度表現的蛋白。本論文延續過去的基礎，進一步探討發炎因子刺激是否會促使間葉幹細胞表現更高量的MMP-9，以及MMP-9是否會影響間葉幹細胞表現細胞激素(Cytokine)與趨化激素(Chemokine)的功能。我們發現相較於干擾素γ (Interferon-γ, IFN-γ)刺激，經脂多醣(Lipopolysaccharide, LPS)及腫瘤壞死因子α (Tumor-necrosis factor α, TNF-α)刺激後的間葉幹細胞會表現較高量的MMP-9。並且抑制MMP-9會降低間葉幹細胞表現介白素-6(Interleukin-6, IL-6)及干擾素誘導蛋白-10(C-X-C motif chemokine 10/Interferon-γ-induced protein 10, CXCL10/IP-10)的能力。另外，抑制T細胞增生及誘導調節性T細胞(Regulatory T cell, Treg)產生為間葉幹細胞抑制免疫反應的兩大利器。本論文亦探討經過不同發炎因子刺激後的間葉幹細胞是否會因著分泌MMP-9表現量之不同而改變其抑制T細胞增生及誘導調節性T細胞的能力。實驗結果證實MMP-9確有改變間葉幹細胞對T細胞的免疫調節功能。而抑制MMP-9會經由降低IFN-γ與介白素-1β (Interleukin-1β, IL-1β)及增加CD44在T細胞的表現量，因而增加間葉幹細胞對T 細胞的抑制功能及誘導調節性T細胞產生的能力。

關鍵字

間葉幹細胞；基質金屬蛋白酶-9

並列摘要

Bone marrow-derived mesenchymal stem cells (MSC) possess pluripotent and self-renewal properties. Importantly, MSC exhibit potent immunomodulatory abilities both in vitro and in vivo. Based on these findings, transplantation of MSC is considered as a promising therapy for several inflammatory diseases. However, several clinical trials have demonstrated conflicting results. To realize the potential of MSC therapy, it is necessary to investigate the approaches to optimize MSC immunomodulation. Recently, several studies indicate that the immunomodulatory abilities of MSC are partially changed by inflammatory stimuli. In our previous study, MMP-9 was highly expressed by MSC. Based on these information, this study aimed to examine that inflammatory mediators stimulation would change the MMP-9 expression in MSC or not. Then, we also investigated the role of MSCs-derived MMP-9 in the cytokines and chemkines production process. The results showed that lipopolysaccharide (LPS)-primed and Tumor-necrosis factor α (TNF-α)-primed MSC (MSC1 and MSCα) expressed higher MMP-9 than interferon-γ (IFN-γ)-primed MSC (MSCγ). Furthermore, blockade MMP-9 significantly reduced the levels of Interleukin-6 (IL-6) and C-X-C motif chemokine 10/Interferon-γ-induced protein 10 (CXCL10/IP-10) in MSCs. Suppression of T cells proliferation and induction of regulatory T cells (Treg) are two important mechanism underlying the MSC immunomodulation. We also investigated the influences of MMP-9 on these two important functions of MSC. In this section, we found that inhibition of MMP-9 significantly improved the ability of MSC1 and MSCα to suppress T cells proliferation and induce Treg.

並列關鍵字

Mesenchymal stem cell ； matrix metalloproteinase 9

參考文獻

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3. Tse, W.T., et al., Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation, 2003. 75(3): p. 389-97.

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間葉幹細胞分泌之基質金屬蛋白酶-9在其免疫調節功能之角色

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