維生素對小鼠骨髓間質幹細胞的分化及免疫調節特性之影響

Effects of vitamins on the differentiation and immune regulatory properties of mouse bone marrow mesenchymal stem cells

10.6342/NTU201703440

王資婷

間質幹細胞 ； 維生素A ； 維生素D ； 葉酸 ； 脂肪細胞分化 ； Mesenchymal stem cells ； vitamin A ； vitamin D ； folic acid ； adipocyte differentiation

臺灣大學生化科技學系學位論文

2017年

碩士

林璧鳳

繁體中文

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.

1. Abbas, M. A. (2017). Physiological functions of Vitamin D in adipose tissue. J Steroid Biochem Mol Biol 165(Pt B): 369-381.
   連結：
2. Abe, I., Shirato, K., Hashizume, Y., Mitsuhashi, R., Kobayashi, A., Shiono, C., Sato, S., Tachiyashiki, K. and Imaizumi, K. (2013). Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats. Environ Health Prev Med 18(1): 78-84.
   連結：
3. Aggarwal, S. and Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4): 1815-1822.
   連結：
4. Ahima, R. S. (2008). Revisiting leptin's role in obesity and weight loss. J Clin Invest 118(7): 2380-2383.
   連結：
5. Augello, A., Tasso, R., Negrini, S. M., Amateis, A., Indiveri, F., Cancedda, R. and Pennesi, G. (2005). Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35(5): 1482-1490.
   連結：
6. Baeke, F., Takiishi, T., Korf, H., Gysemans, C. and Mathieu, C. (2010). Vitamin D: modulator of the immune system. Curr Opin Pharmacol 10(4): 482-496.
   連結：
7. Barry, F., Boynton, R. E., Liu, B. and Murphy, J. M. (2001). Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. Exp Cell Res 268(2): 189-200.
   連結：
8. Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., Moseley, A. and Hoffman, R. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30(1): 42-48.
   連結：
9. Basoli, V., Santaniello, S., Cruciani, S., Ginesu, G. C., Cossu, M. L., Delitala, A. P., Serra, P. A., Ventura, C. and Maioli, M. (2017). Melatonin and vitamin D interfere with the adipogenic fate of adipose-derived stem cells. Int J Mol Sci 18(5).
   連結：
10. Beresford, J. N., Gallagher, J. A. and Russell, R. G. (1986). 1,25-Dihydroxyvitamin D3 and human bone-derived cells in vitro: effects on alkaline phosphatase, type I collagen and proliferation. Endocrinology 119(4): 1776-1785.
    連結：
11. Bhaskar, B., Mekala, N., Baadhe, R. and Rao, P. (2014). Role of signaling pathways in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 9(6): 508-512.
    連結：
12. Boot, M. J., Steegers-Theunissen, R. P., Poelmann, R. E., Van Iperen, L., Lindemans, J. and Gittenberger-de Groot, A. C. (2003). Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro.
    連結：
13. Bosetti, M., Boccafoschi, F., Leigheb, M., Bianchi, A. E. and Cannas, M. (2012). Chondrogenic induction of human mesenchymal stem cells using combined growth factors for cartilage tissue engineering. J Tissue Eng Regen Med 6(3): 205-213.
    連結：
14. Braun, J., Kurtz, A., Barutcu, N., Bodo, J., Thiel, A. and Dong, J. (2013). Concerted regulation of CD34 and CD105 accompanies mesenchymal stromal cell derivation from human adventitial stromal cell. Stem Cells Dev 22(5): 815-827.
    連結：
15. Brunel, M., Herr, F. and Durrbach, A. (2016). Immunosuppressive Properties of Mesenchymal Stem Cells. Curr Transplantation Reports 3(4): 348-357.
    連結：
16. Caplan, A. I. (1991). Mesenchymal stem cells. J Orthop Res 9(5): 641-650.
    連結：
17. Cassani, B., Villablanca, E. J., De Calisto, J., Wang, S. and Mora, J. R. (2012). Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med 33(1): 63-76.
    連結：
18. Chang, E. and Kim, Y. (2016). Vitamin D decreases adipocyte lipid storage and increases NAD-SIRT1 pathway in 3T3-L1 adipocytes. Nutrition 32(6): 702-708.
    連結：
19. Chen, L. B., Jiang, X. B. and Yang, L. (2004). Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J Gastroenterol 10(20): 3016-3020.
    連結：
20. Chen, S., Sims, G. P., Chen, X. X., Gu, Y. Y., Chen, S. and Lipsky, P. E. (2007). Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179(3): 1634-1647.
    連結：
21. Chen, X., McClurg, A., Zhou, G. Q., McCaigue, M., Armstrong, M. A. and Li, G. (2007). Chondrogenic differentiation alters the immunosuppressive property of bone marrow-derived mesenchymal stem cells, and the effect is partially due to the upregulated expression of B7 molecules. Stem Cells 25(2): 364-370.
    連結：
22. Choi, H., Lee, R. H., Bazhanov, N., Oh, J. Y. and Prockop, D. J. (2011). Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 118(2): 330-338.
    連結：
23. Comoli, P., Ginevri, F., Maccario, R., Avanzini, M. A., Marconi, M., Groff, A., Cometa, A., Cioni, M., Porretti, L., Barberi, W., Frassoni, F. and Locatelli, F. (2008). Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant 23(4): 1196-1202.
    連結：
24. Courtemanche, C., Elson-Schwab, I., Mashiyama, S. T., Kerry, N. and Ames, B. N. (2004). Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro. J Immunol 173(5): 3186-3192.
    連結：
25. Deeb, K. K., Trump, D. L. and Johnson, C. S. (2007). Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7(9): 684-700.
    連結：
26. DeLuca, G. C., Kimball, S. M., Kolasinski, J., Ramagopalan, S. V. and Ebers, G. C. (2013). Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 39(5): 458-484.
    連結：
27. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. and Pulendran, B. (2007). Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8(10): 1086-1094.
    連結：
28. Dimarino, A. M., Caplan, A. I. and Bonfield, T. L. (2013). Mesenchymal stem cells in tissue repair. Front Immunol 4: 201.
    連結：
29. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D. and Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4): 315-317.
    連結：
30. Duester, G. (2008). Retinoic acid synthesis and signaling during early organogenesis. Cell 134(6): 921-931.
    連結：
31. Duffy, M. M., Ritter, T., Ceredig, R. and Griffin, M. D. (2011). Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2(4): 34.
    連結：
32. English, K. and Mahon, B. P. (2011). Allogeneic mesenchymal stem cells: agents of immune modulation. J Cell Biochem 112(8): 1963-1968.
    連結：
33. Fantuzzi, G. (2005). Adipose tissue, adipokines, and inflammation.
    連結：
34. J Allergy Clin Immunol 115(5): 911-919; quiz 920.
    連結：
35. Frey, S. K. and Vogel, S. (2011). Vitamin A metabolism and adipose tissue biology. Nutrients 3(1): 27-39.
    連結：
36. Friedenstein, A. J., Chailakhyan, R. K., Latsinik, N. V., Panasyuk, A. F. and Keiliss-Borok, I. V. (1974). Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17(4): 331-340.
    連結：
37. Friedman, M. S., Long, M. W. and Hankenson, K. D. (2006). Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. J Cell Biochem 98(3): 538-554.
    連結：
38. Gallego, O., Belyaeva, O. V., Porte, S., Ruiz, F. X., Stetsenko, A. V., Shabrova, E. V., Kostereva, N. V., Farres, J., Pares, X. and Kedishvili, N. Y. (2006). Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoids. Biochem J 399(1): 101-109.
    連結：
39. Geng, S., Zhou, S. and Glowacki, J. (2011). Effects of 25-hydroxyvitamin D3 on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1alpha-hydroxylase. J Bone Miner Res 26(5): 1145-1153.
    連結：
40. Ghannam, S., Pene, J., Moquet-Torcy, G., Jorgensen, C. and Yssel, H. (2010). Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 185(1): 302-312.
    連結：
41. Gombart, A. F. (2009). The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 4(9): 1151-1165.
    連結：
42. Gudas, L. J. and Wagner, J. A. (2011). Retinoids regulate stem cell differentiation.
    連結：
43. J Cell Physiol 226(2): 322-330.
    連結：
44. Haddad, R. and Saldanha-Araujo, F. (2014). Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far? Biomed Res Int 216806.
    連結：
45. Hisada, K., Hata, K., Ichida, F., Matsubara, T., Orimo, H., Nakano, T., Yatani, H., Nishimura, R. and Yoneda, T. (2013). Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes.
    連結：
46. J Bone Miner Metab 31(1): 53-63.
    連結：
47. Ho, A. D., Wagner, W. and Franke, W. (2008). Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy 10(4): 320-330.
    連結：
48. Hoogduijn, M. J. (2015). Are mesenchymal stromal cells immune cells?
    連結：
49. Arthritis Res Ther 17: 88.
    連結：
50. Iwata, M., Hirakiyama, A., Eshima, Y., Kagechika, H., Kato, C. and Song, S. Y. (2004). Retinoic acid imprints gut-homing specificity on T cells. Immunity 21(4): 527-538.
    連結：
51. Jacobs, S. A., Roobrouck, V. D., Verfaillie, C. M. and Van Gool, S. W. (2013). Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 91(1): 32-39.
    連結：
52. Ji, Y. and Studzinski, G. P. (2004). Retinoblastoma protein and CCAAT/enhancer- binding protein beta are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. Cancer Res 64(1): 370-377.
    連結：
53. Jin, H. J., Bae, Y. K., Kim, M., Kwon, S. J., Jeon, H. B., Choi, S. J., Kim, S. W., Yang, Y. S., Oh, W. and Chang, J. W. (2013). Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci 14(9): 17986-18001.
    連結：
54. Katagiri, T., Yamaguchi, A., Ikeda, T., Yoshiki, S., Wozney, J. M., Rosen, V., Wang, E. A., Tanaka, H., Omura, S. and Suda, T. (1990). The non-osteogenic mouse pluripotent cell line, C3H10T1/2, is induced to differentiate into osteoblastic cells by recombinant human bone morphogenetic protein-2.
    連結：
55. Biochem Biophys Res Commun 172(1): 295-299.
    連結：
56. Kelly, K. B., Kennelly, J. P., Ordonez, M., Nelson, R., Leonard, K., Stabler, S., Gomez-Munoz, A., Field, C. J. and Jacobs, R. L. (2016). Excess folic acid increases lipid Storage, weight gain, and adipose tissue inflammation in high fat diet-fed rats. Nutrients 8(10).
    連結：
57. Kharaziha, P., Hellstrom, P. M., Noorinayer, B., Farzaneh, F., Aghajani, K., Jafari, F., Telkabadi, M., Atashi, A., Honardoost, M., Zali, M. R. and Soleimani, M. (2009). Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial.
    連結：
58. Eur J Gastroenterol Hepatol 21(10): 1199-1205.
    連結：
59. Kinoshita, M., Kayama, H., Kusu, T., Yamaguchi, T., Kunisawa, J., Kiyono, H., Sakaguchi, S. and Takeda, K. (2012). Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J Immunol 189(6): 2869-2878.
    連結：
60. Kogawa, M., Findlay, D. M., Anderson, P. H., Ormsby, R., Vincent, C., Morris, H. A. and Atkins, G. J. (2010). Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption. Endocrinology 151(10): 4613-4625.
    連結：
61. Le Blanc, K. and Mougiakakos, D. (2012). Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12(5): 383-396.
    連結：
62. Le Blanc, K. and Ringden, O. (2007). Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262(5): 509-525.
    連結：
63. Lee, J. K., Jin, H. K., Endo, S., Schuchman, E. H., Carter, J. E. and Bae, J. S. (2010). Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 28(2): 329-343.
    連結：
64. Li, D., Wang, P., Li, Y., Xie, Z., Wang, L., Su, H., Deng, W., Wu, Y. and Shen, H. (2015). All-trans retinoic acid improves the effects of bone marrow-derived mesenchymal stem cells on the treatment of Ankylosing Spondylitis: an in vitro study. Stem Cells Int 2015: 484528.
    連結：
65. Li, P., Li, S. H., Wu, J., Zang, W. F., Dhingra, S., Sun, L., Weisel, R. D. and Li, R. K. (2013). Interleukin-6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege. J Cell Mol Med 17(9): 1136-1145.
    連結：
66. Lin, H. L., Chen, C. J., Tsai, W. C., Yen, J. H. and Liu, H. W. (2006). In vitro folate deficiency induces apoptosis by a p53, Fas (Apo-1, CD95) independent, bcl-2 related mechanism in phytohaemagglutinin-stimulated human peripheral blood lymphocytes. Br J Nutr 95(5): 870-878.
    連結：
67. Liu, P., Oyajobi, B. O., Russell, R. G. and Scutt, A. (1999). Regulation of Osteogenic Differentiation of Human Bone Marrow Stromal Cells: Interaction Between Transforming Growth Factor-β and 1,25(OH)2 Vitamin D3. Calcif Tissue Int 65(2): 173-180.
    連結：
68. Liu, Z. J., Zhuge, Y. and Velazquez, O. C. (2009). Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem 106(6): 984-991.
    連結：
69. Luz-Crawford, P., Jorgensen, C. and Djouad, F. (2017). Mesenchymal Stem Cells Direct the Immunological Fate of Macrophages. Results Probl Cell Differ 62: 61-72.
    連結：
70. Luz-Crawford, P., Kurte, M., Bravo-Alegría, J., Contreras, R., Nova-Lamperti, E., Tejedor, G., Noël, D., Jorgensen, C., Figueroa, F., Djouad, F. and Carrión, F. (2013). Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells.
    連結：
71. Stem Cell Res Ther 4(3): 65.
    連結：
72. Mackay, A. M., Beck, S. C., Murphy, J. M., Barry, F. P., Chichester, C. O. and Pittenger, M. F. (1998). Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng 4(4): 415-428.
    連結：
73. Maggini, J., Mirkin, G., Bognanni, I., Holmberg, J., Piazzon, I. M., Nepomnaschy, I., Costa, H., Canones, C., Raiden, S., Vermeulen, M. and Geffner, J. R. (2010). Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One 5(2): e9252.
    連結：
74. Malladi, P., Xu, Y., Yang, G. P. and Longaker, M. T. (2006). Functions of vitamin D, retinoic acid, and dexamethasone in mouse adipose-derived mesenchymal cells. Tissue Eng 12(7): 2031-2040.
    連結：
75. Manicassamy, S., Ravindran, R., Deng, J., Oluoch, H., Denning, T. L., Kasturi, S. P., Rosenthal, K. M., Evavold, B. D. and Pulendran, B. (2009). Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med 15(4): 401-409.
    連結：
76. Meijer, K., de Vries, M., Al-Lahham, S., Bruinenberg, M., Weening, D., Dijkstra, M., Kloosterhuis, N., van der Leij, R. J., van der Want, H., Kroesen, B. J., Vonk, R. and Rezaee, F. (2011). Human primary adipocytes exhibit immune cell function: adipocytes prime inflammation independent of macrophages. PLoS One 6(3): e17154.
    連結：
77. Meisel, R., Zibert, A., Laryea, M., Gobel, U., Daubener, W. and Dilloo, D. (2004). Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103(12): 4619-4621.
    連結：
78. Mezey, E., Key, S., Vogelsang, G., Szalayova, I., Lange, G. D. and Crain, B. (2003). Transplanted bone marrow generates new neurons in human brains.
    連結：
79. Proc Natl Acad Sci U S A 100(3): 1354-1369.
    連結：
80. Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M. and Cheroutre, H. (2007). Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835): 256-260.
    連結：
81. Mundra, V., Gerling, I. C. and Mahato, R. I. (2013). Mesenchymal stem cell-based therapy. Mol Pharm 10(1): 77-89.
    連結：
82. Munir, H., Ward, L. S. C., Sheriff, L., Kemble, S., Nayar, S., Barone, F., Nash, G. B. and McGettrick, H. M. (2017). Adipogenic differentiation of mesenchymal stem cells alters their immunomodulatory properties in a tissue-specific manner.
    連結：
83. Pellis, L., Dommels, Y., Venema, D., Polanen, A., Lips, E., Baykus, H., Kok, F., Kampman, E. and Keijer, J. (2008). High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells.
    連結：
84. Br J Nutr 99(4): 703-708.
    連結：
85. Polymeri, A., Giannobile, W. V. and Kaigler, D. (2016). Bone Marrow Stromal Stem Cells in Tissue Engineering and Regenerative Medicine. Horm Metab Res 48(11): 700-713.
    連結：
86. Posa, F., Di Benedetto, A., Colaianni, G., Cavalcanti-Adam, E. A., Brunetti, G., Porro, C., Trotta, T., Grano, M. and Mori, G. (2016). Vitamin D effects on osteoblastic differentiation of mesenchymal stem cells from dental tissues. Stem Cells Int 2016: 9150819.
    連結：
87. Pricola, K. L., Kuhn, N. Z., Haleem-Smith, H., Song, Y. and Tuan, R. S. (2009). Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem 108(3): 577-588.
    連結：
88. Purton, L. E., Dworkin, S., Olsen, G. H., Walkley, C. R., Fabb, S. A., Collins, S. J. and Chambon, P. (2006). RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med 203(5): 1283-1293.
    連結：
89. Rasmusson, I., Le Blanc, K., Sundberg, B. and Ringden, O. (2007). Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol 65(4): 336-343.
    連結：
90. Rasmusson, I., Ringden, O., Sundberg, B. and Le Blanc, K. (2003). Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76(8): 1208-1213.
    連結：
91. Raverdeau, M. and Mills, K. H. (2014). Modulation of T cell and innate immune responses by retinoic Acid. J Immunol 192(7): 2953-2958.
    連結：
92. Ryan, A. E., Lohan, P., O'Flynn, L., Treacy, O., Chen, X., Coleman, C., Shaw, G., Murphy, M., Barry, F., Griffin, M. D. and Ritter, T. (2014). Chondrogenic differentiation increases antidonor immune response to allogeneic mesenchymal stem cell transplantation. Mol Ther 22(3): 655-667.
    連結：
93. Samuel, S. and Sitrin, M. D. (2008). Vitamin D's role in cell proliferation and differentiation. Nutr Rev 66(10 Suppl 2): S116-124.
    連結：
94. Sawaengsri, H., Wang, J., Reginaldo, C., Steluti, J., Wu, D., Meydani, S. N., Selhub, J. and Paul, L. (2016). High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem 30: 102-107.
    連結：
95. Scaglione, F. and Panzavolta, G. (2014). Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenbiotica 44(5): 480-488.
    連結：
96. Schwarz, E. J., Reginato, M. J., Shao, D., Krakow, S. L. and Lazar, M. A. (1997). Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription. Mol Cell Biol 17(3): 1552-1561.
    連結：
97. Skillington, J., Choy, L. and Derynck, R. (2002). Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 159(1): 135-146.
    連結：
98. Sotiropoulou, P. A. and Papamichail, M. (2007). Immune properties of mesenchymal stem cells. Methods Mol Biol 407: 225-243.
    連結：
99. Sotiropoulou, P. A., Perez, S. A., Gritzapis, A. D., Baxevanis, C. N. and Papamichail, M. (2006). Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24(1): 74-85.
    連結：
100. Spaggiari, G. M., Abdelrazik, H., Becchetti, F. and Moretta, L. (2009). MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113(26): 6576-6583.
     連結：
101. Spaggiari, G. M., Capobianco, A., Becchetti, S., Mingari, M. C. and Moretta, L. (2006). Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107(4): 1484-1490.
     連結：
102. Takahashi, J., Palmer, T. D. and Gage, F. H. (1999). Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J Neurobiol 38(1): 65-81.
     連結：
103. Tse, W. T., Pendleton, J. D., Beyer, W. M., Egalka, M. C. and Guinan, E. C. (2003). Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75(3): 389-397.
     連結：
104. Uccelli, A., Moretta, L. and Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nat Rev Immunol 8(9): 726-736.
     連結：
105. Valle, Y. L., Almalki, S. G. and Agrawal, D. K. (2016). Vitamin D machinery and metabolism in porcine adipose-derived mesenchymal stem cells. Stem Cell Res Ther 7(1): 118.
     連結：
106. Wagner, W., Horn, P., Castoldi, M., Diehlmann, A., Bork, S., Saffrich, R., Benes, V., Blake, J., Pfister, S., Eckstein, V. and Ho, A. D. (2008). Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One 3(5): e2213.
     連結：
107. Wang, M. K., Sun, H. Q., Xiang, Y. C., Jiang, F., Su, Y. P. and Zou, Z. M. (2012). Different roles of TGF-beta in the multi-lineage differentiation of stem cells. World J Stem Cells 4(5): 28-34.
     連結：
108. Wei, X., Yang, X., Han, Z. P., Qu, F. F., Shao, L. and Shi, Y. F. (2013). Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 34(6): 747-754.
     連結：
109. Wood, R. J. (2008). Vitamin D and adipogenesis: new molecular insights. Nutr Rev 66(1): 40-46.
     連結：
110. Wu, C. H., Huang, T. C. and Lin, B. F. (2017). Folate deficiency affects dendritic cell function and subsequent T helper cell differentiation. J Nutr Biochem 41: 65-72.
     連結：
111. Yasmeen, R., Jeyakumar, S. M., Reichert, B., Yang, F. and Ziouzenkova, O. (2012). The contribution of vitamin A to autocrine regulation of fat depots. Biochim Biophys Acta 1821(1): 190-197.
     連結：
112. Yokota, A., Takeuchi, H., Maeda, N., Ohoka, Y., Kato, C., Song, S. Y. and Iwata, M. (2009). GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity. Int Immunol 21(4): 361-377.
     連結：
113. Yu, M., Li, W., Luo, S., Zhang, Y., Liu, H., Gao, Y., Wang, X., Wilson, J. X. and Huang, G. (2014). Folic acid stimulation of neural stem cell proliferation is associated with altered methylation profile of PI3K/Akt/CREB. J Nutr Biochem 25(4): 496-502.
     連結：
114. Yu, X., Liu, R., Zhao, G., Zheng, M., Chen, J. and Wen, J. (2014). Folate supplementation modifies CCAAT/enhancer-binding protein alpha methylation to mediate differentiation of preadipocytes in chickens. Poult Sci 93(10): 2596-2603.
     連結：
115. Zappia, E., Casazza, S., Pedemonte, E., Benvenuto, F., Bonanni, I., Gerdoni, E., Giunti, D., Ceravolo, A., Cazzanti, F., Frassoni, F., Mancardi, G. and Uccelli, A. (2005). Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106(5): 1755-1761.
     連結：
116. Zhang, S., Chen, X., Hu, Y., Wu, J., Cao, Q., Chen, S. and Gao, Y. (2016). All-trans retinoic acid modulates Wnt3A-induced osteogenic differentiation of mesenchymal stem cells via activating the PI3K/AKT/GSK3beta signalling pathway. Mol Cell Endocrinol 422: 243-253.
     連結：
117. Zhang, X., Liu, H., Cong, G., Tian, Z., Ren, D., Wilson, J. X. and Huang, G. (2008). Effects of folate on notch signaling and cell proliferation in neural stem cells of neonatal rats in vitro. J Nutr Sci Vitaminol (Tokyo) 54(5): 353-356.
     連結：
118. Zhou, S., LeBoff, M. S. and Glowacki, J. (2010). Vitamin D metabolism and action in human bone marrow stromal cells. Endocrinology 151(1): 14-22.
     連結：
119. Zhu, G. H., Huang, J., Bi, Y., Su, Y., Tang, Y., He, B. C., He, Y., Luo, J., Wang, Y., Chen, L., Zuo, G. W., Jiang, W., Luo, Q., Shen, J., Liu, B., Zhang, W. L., Shi, Q., Zhang, B. Q., Kang, Q., Zhu, J., Tian, J., Luu, H. H., Haydon, R. C., Chen, Y. and He, T. C. (2009). Activation of RXR and RAR signaling promotes myogenic differentiation of myoblastic C2C12 cells. Differentiation 78(4): 195-204.
     連結：
120. Bellner, L., Nichols, A., Pandey, V., Vanella, L., Gilliam, C., Gupte, R. and Abraham, N. (2015). Effect of Vitamin B12 and nutrients on adipogenesis-adipogenic markers in 3T3 cells. FASEB J 29(1 Supplement): 996.2.
121. Dev Dyn 227(2): 301-308.
122. Chiesa, S., Morbelli, S., Morando, S., Massollo, M., Marini, C., Bertoni, A., Frassoni, F., Bartolomé, S. T., Sambuceti, G., Traggiai, E. and Uccelli, A. (2011). Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A 108(42): 17384-17389.
123. Gouffon, J. S., Johnstone, M. and Zemel, M. B. (2011). Folate Modulation of Adipocyte Promoter Methylation and Lipolysis. Faseb Journal 25(1 Supplement ): 597.6.
124. Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A., Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F., Romagnani, P., Maggi, E., Romagnani, S. and Annunziato, F. (2006). Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24(2): 386-398.
125. Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., Ochoa, M. T., Schauber, J., Wu, K., Meinken, C., Kamen, D. L., Wagner, M., Bals, R., Steinmeyer, A., Zugel, U., Gallo, R. L., Eisenberg, D., Hewison, M., Hollis, B. W., Adams, J. S., Bloom, B. R. and Modlin, R. L. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311(5768): 1770-1773.
126. Mora, J. R., Iwata, M., Eksteen, B., Song, S. Y., Junt, T., Senman, B., Otipoby, K. L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D. H. and von Andrian, U. H. (2006). Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314(5802): 1157-1160.
127. Stem Cells 35(6): 1636-1646.
128. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S. M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D. M., Leri, A. and Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature 410(6829): 701-705.
129. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S. and Marshak, D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284(5411): 143-147.
130. Sadeghi, L., Kamali-Sarvestani, E., Azarpira, N., Shariati, M. and Karimi, M. H. (2014). Immunomodulatory effects of mice mesenchymal stem cells on maturation and activation of dendritic cells. Iran J Immunol 11(3): 177-188.
131. Sung, J. H., Yang, H. M., Park, J. B., Choi, G. S., Joh, J. W., Kwon, C. H., Chun, J. M., Lee, S. K. and Kim, S. J. (2008). Isolation and characterization of mouse mesenchymal stem cells. Transplant Proc 40(8): 2649-2654.