Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/99398
標題: 骨髓間質幹細胞治療由Akr1A1基因缺失所誘發酒精性肝損傷之功效評估
Evaluation of the therapeutic efficacy of bone marrow mesenchymal stem cells on alcoholic liver injury triggered by aldo-keto reductase 1A1 (Akr1A1) gene deficiency
作者: 陳婉如
Wan-Ru Chen
關鍵字: 醛還原酶;骨髓間質幹細胞;酒精;肝損傷;AKR1A1;Bone marrow mesenchymal stem cell;alcohol;liver injury
引用: Abdel-Misih, S. R. and M. Bloomston (2010). 'Liver anatomy.' Surg Clin North Am 90(4): 643-653. Addolorato, G., E. Capristo, M. Marini, P. Santini, U. Scognamiglio, M. Attilia, D. Messineo, G. Sasso, G. Gasbarrini and M. Ceccanti (2000). 'Body composition changes induced by chronic ethanol abuse: evaluation by dual energy X-ray absorptiometry.' Am J Gastroenterol 95(9): 2323-2327. Ahmadian Kia, N., A. R. Bahrami, M. Ebrahimi, M. M. Matin, Z. Neshati, M. R. Almohaddesin, N. Aghdami and H. R. Bidkhori (2011). 'Comparative analysis of chemokine receptor''s expression in mesenchymal stem cells derived from human bone marrow and adipose tissue.' J Mol Neurosci 44(3): 178-185. Akihara, R., T. Homma, J. Lee, K. Yamada, S. Miyata and J. Fujii (2016). 'Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress.' Biochem Biophys Res Commun 478(2): 765-771. Aleynik, A., K. M. Gernavage, Y. S. Mourad, L. S. Sherman, K. Liu, Y. A. Gubenko and P. Rameshwar (2014). 'Stem cell del ivery of therapies for brain disorders.' Clin Transl Med 3(1): 24. Alfaifi, M., Y. W. Eom, P. N. Newsome and S. K. Baik (2018). 'Mesenchymal stromal cell therapy for liver diseases.' J Hepatol 68(6): 1272-1285. Allan, D. and D. Lohnes (2000). 'Cloning and developmental expression of mouse aldehyde reductase (AKR1A4).' Mech Dev 94(1): 271-275. Almalki, S. G. and D. K. Agrawal (2016). 'Effects of matrix metalloproteinases on the fate of mesenchymal stem cells.' Stem Cell Res Ther 7(1): 129. Anderson, P., A. B. Carrillo-Gálvez, A. García-Pérez, M. Cobo and F. Martín (2013). 'CD105 (endoglin)-negative murine mesenchymal stromal cells define a new multipotent subpopulation with distinct differentiation and immunomodulatory capacities.' PLoS One 8(10): e76979. Angelos, M. G. and D. S. Kaufman (2015). 'Pluripotent stem cell applications for regenerative medicine.' Curr Opin Organ Transplant 20(6): 663-670. Arteel, G. E. (2010). 'Animal models of alcoholic liver disease.' Dig Dis 28(6): 729-736. Augello, A. and C. De Bari (2010). 'The regulation of differentiation in mesenchymal stem cells.' Hum Gene Ther 21(10): 1226-1238. Augello, A., R. Tasso, S. M. Negrini, R. Cancedda and G. Pennesi (2007). 'Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen‐induced arthritis.' Arthritis Rheum 56(4): 1175-1186. Bala, S., J. Petrasek, S. Mundkur, D. Catalano, I. Levin, J. Ward, H. Alao, K. Kodys and G. Szabo (2012). 'Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases.' Hepatology 56(5): 1946-1957. Barve, A., L. S. Marsano, D. Parajuli, M. Cave and C. J. McClain (2017). Alcoholic liver disease. Liver Disorders, Springer: 173-197. Becker, A. J., E. A. McCulloch and J. E. Till (1963). 'Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.' Nature 197:452-454 Bertola, A., S. Mathews, S. H. Ki, H. Wang and B. Gao (2013). 'Mouse model of chronic and binge ethanol feeding (the NIAAA model).' Nat Protoc 8(3): 627-637. Bianco, P., P. G. Robey and P. J. Simmons (2008). 'Mesenchymal stem cells: revisiting history, concepts, and assays.' Cell Stem Cell 2(4): 313-319. Bishi, D. K., S. Mathapati, K. M. Cherian, S. Guhathakurta and R. S. Verma (2014). 'In vitro hepatic trans-differentiation of human mesenchymal stem cells using sera from congestive/ischemic liver during cardiac failure.' PLoS One 9(3): e92397. Blegen, M. B., E. S. D. da Silva, R. Bock, N. Morisot, D. Ron and V. A. Alvarez (2018). 'Alcohol operant self-administration: Investigating how alcohol-seeking behaviors predict drinking in mice using two operant approaches.' Alcohol 67: 23-36. Botros, M. and K. A. Sikaris (2013). 'The de ritis ratio: the test of time.' Clin Biochem Rev 34(3): 117-130. Brien, S. E., P. E. Ronksley, B. J. Turner, K. J. Mukamal and W. A. Ghali (2011). 'Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies.' BMJ 342: d636. Brooks, P. J., M. A. Enoch, D. Goldman, T. K. Li and A. Yokoyama (2009). 'The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.' PLoS Med 6(3): e50. Campbell, K. H., J. McWhir, W. A. Ritchie and I. Wilmut (1996). 'Sheep cloned by nuclear transfer from a cultured cell line.' Nature 380(6569): 64-6. Caplan, A. I. (1991). 'Mesenchymal stem cells.' J Orthop Res 9(5): 641-650. Casini, A. (2000). 'Alcohol-induced fatty liver and inflammation: where do Kupffer cells act?' J Hepatol 32(6): 1026-1030. Cederbaum, A. (2017). 'Role of cytochrome P450 and oxidative stress in alcohol-induced liver injury.' Reactive Oxygen Species 4: 303-319 Chang, J. S., J. R. Hsiao and C. H. Chen (2017). 'ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective.' J Biomed Sci 24(1): 19. Chaudhry, K. K., G. Samak, P. K. Shukla, H. Mir, R. Gangwar, B. Manda, T. Isse, T. Kawamoto, M. Salaspuro, P. Kaihovaara, P. Dietrich, I. Dragatsis, L. E. Nagy and R. K. Rao (2015). 'ALDH2 deficiency promotes ethanol-induced gut barrier dysfunction and fatty liver in mice.' Alcohol Clin Exp Res 39(8): 1465-1475. Chen, H., Y. Tung, C. Tsai, C. Lai, Z.-L. Lai, H. Tsai, Y. Lin, C. Wang and C. Chen (2014). 'Kefir improves fatty liver syndrome by inhibiting the lipogenesis pathway in leptin-deficient ob/ob knockout mice.' Int J Obes 38(9): 1172-1179. Chen, S., L. Xu, N. Lin, W. Pan, K. Hu and R. Xu (2011). 'Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells.' Life Sci 89(25-26): 975-981. Chen, Y., S. Singh, A. Matsumoto, S. K. Manna, M. A. Abdelmegeed, S. Golla, R. C. Murphy, H. Dong, B. J. Song, F. J. Gonzalez, D. C. Thompson and V. Vasiliou (2016). 'Chronic glutathione depletion confers protection against alcohol-induced steatosis: Implication for redox activation of AMP-activated protein kinase pathway.' Sci Rep 6: 29743. Chow, C. Y. and L. T. Reiter (2017). 'Etiology of human genetic disease on the fly.' Trends Genet 33(6): 391-398. Cichoż-Lach, H. and A. Michalak (2014). 'Oxidative stress as a crucial factor in liver diseases.' World J Gastroenterol 20(25): 8082-8091. Cohen, J. I. and L. E. Nagy (2011). 'Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells.' J Dig Dis 12(1): 3-9. Corradetti, B., F. Taraballi, J. O. Martinez, S. Minardi, N. Basu, G. Bauza, M. Evangelopoulos, S. Powell, C. Corbo and E. Tasciotti (2017). 'Hyaluronic acid coatings as a simple and efficient approach to improve MSC homing toward the site of inflammation.' Sci Rep 7(1): 7991. Coughlin, R. P., A. Oldweiler, D. T. Mickelson and C. T. Moorman, 3rd (2017). 'Adipose-derived stem cell transplant technique for degenerative joint disease.' Arthrosc Tech 6(5): e1761-e1766. Couinaud, C. (1957). 'The Liver: Anatomical and surgical investigations.' J Chir (Paris) 71(5):408-427. Curtis, J. M., W. S. Hahn, E. K. Long, J. S. Burrill, E. A. Arriaga and D. A. Bernlohr (2012). 'Protein carbonylation and metabolic control systems.' Trends Endocrinol Metab 23(8): 399-406. Delorme, B., J. Ringe, N. Gallay, Y. Le Vern, D. Kerboeuf, C. Jorgensen, P. Rosset, L. Sensebe, P. Layrolle, T. Haupl and P. Charbord (2008). 'Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells.' Blood 111(5): 2631-2635. Derderian, S. C., P. P. Togarrati, C. King, P. W. Moradi, D. Reynaud, A. Czechowicz, I. L. Weissman and T. C. MacKenzie (2014). 'In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.' Blood 124(6): 973-980. Dienstag, J. L. and A. B. Cosimi (2012). 'Liver transplantation--a vision realized.' N Engl J Med 367(16): 1483-1485. Ding, W. X., M. Li, X. Chen, H. M. Ni, C. W. Lin, W. Gao, B. Lu, D. B. Stolz, D. L. Clemens and X. M. Yin (2010). 'Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.' Gastroenterology 139(5): 1740-1752. Dominici, M., K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F. Marini, D. Krause, R. Deans, A. Keating, D. Prockop and E. Horwitz (2006). 'Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.' Cytotherapy 8(4): 315-317. Dunn, W. and V. H. Shah (2016). 'Pathogenesis of alcoholic liver disease.' Clin Liver Dis 20(3): 445-456. Duraiyan, J., R. Govindarajan, K. Kaliyappan and M. Palanisamy (2012). 'Applications of immunohistochemistry.' J Pharm Bioallied Sci 4(Suppl 2): S307- S309. Ebrahimkhani, M. R., J. A. Neiman, M. S. Raredon, D. J. Hughes and L. G. Griffith (2014). 'Bioreactor technologies to support liver function in vitro.' Adv Drug Deliv Rev 69-70: 132-157. Ehninger, A. and A. Trumpp (2011). 'The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in.' J Exp Med 208(3): 421-428. El‐Kabbani, O., N. C. Green, G. Lin, M. Carson, S. Narayana, K. Moore, T. Flynn and L. DeLucas (1994). 'Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications.' Acta Crystallogr D Biol Crystallogr 50(6): 859-868. Eng, M. Y., S. E. Luczak and T. L. Wall (2007). 'ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review.' Alcohol Res Health 30(1): 22-27. Eseonu, O. I. and C. De Bari (2015). 'Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis.' Rheumatology (Oxford) 54(2): 210-218. Ezquer, F., J. Bahamonde, Y.-L. Huang and M. Ezquer (2017). 'Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy.' Stem Cell Res Ther 8(1): 20. Fengler, V. H., T. Macheiner, S. M. Kessler, B. Czepukojc, K. Gemperlein, R. Muller, A. K. Kiemer, C. Magnes, J. Haybaeck, C. Lackner and K. Sargsyan (2016). 'Susceptibility of different mouse wild type strains to develop diet-induced NAFLD/AFLD-associated liver disease.' PLoS One 11(5): e0155163. Fischer, A. H., K. A. Jacobson, J. Rose and R. Zeller (2008). 'Hematoxylin and eosin staining of tissue and cell sections.' CHH Protoc 2008(5): pdb. prot4986. Friedenstein, A., R. Chailakhyan and U. Gerasimov (1987). 'Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers.' Cell Tissue Kinet 20(3): 263-272. Gabbay, K. H., K. M. Bohren, R. Morello, T. Bertin, J. Liu and P. Vogel (2010). 'Ascorbate synthesis pathway: dual role of ascorbate in bone homeostasis.' J Biol Chem 285(25): 19510-19520. Galicia-Moreno, M. and G. Gutiérrez-Reyes (2014). 'The role of oxidative stress in the development of alcoholic liver disease.' Rev Gastroenterol Mex 79(2): 135-144. Gallatin, W. M., I. L. Weissman and E. C. Butcher (1983). 'A cell-surface molecule involved in organ-specific homing of lymphocytes.' Nature 304(5921): 30. Gallatin, W. M., I. L. Weissman and E. C. Butcher (2006). 'Pillars Article: A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature 1983. 304: 30–34.' J Immunol 177(1): 5-9. Gao, B. and R. Bataller (2011). 'Alcoholic liver disease: Pathogenesis and new therapeutic targets.' Gastroenterology 141(5): 1572-1585. Gao, F., S. M. Chiu, D. A. Motan, Z. Zhang, L. Chen, H. L. Ji, H. F. Tse, Q. L. Fu and Q. Lian (2016). 'Mesenchymal stem cells and immunomodulation: current status and future prospects.' Cell Death Dis 7: e2062. Gao, Y., Z. Zhou, T. Ren, S.-J. Kim, Y. He, W. Seo, A. Guillot, Y. Ding, R. Wu and S. Shao (2018). 'Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.' Gut pii: gutjnl-2018-316221. Garg, A. and P. N. Newsome (2013). 'Bone marrow mesenchymal stem cells and liver regeneration: believe the hypoxia!' Stem Cell Res Ther 4(5): 108. Gazdic, M., A. Arsenijevic, B. S. Markovic, A. Volarevic, I. Dimova, V. Djonov, N. Arsenijevic, M. Stojkovic and V. Volarevic (2017). 'Mesenchymal stem cell-dependent modulation of liver diseases.' Int J Biol Sci 13(9): 1109-1117. Ghaffari-Nazari, H. (2018). 'The known molecules involved in MSC homing and migration.' J Stem Cell Res Med 3(1). Gholamrezanezhad, A., S. Mirpour, M. Bagheri, M. Mohamadnejad, K. Alimoghaddam, L. Abdolahzadeh, M. Saghari and R. Malekzadeh (2011). 'In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis.' Nucl Med Biol 38(7): 961-967. Gnecchi, M., Z. Zhang, A. Ni and V. J. Dzau (2008). 'Paracrine mechanisms in adult stem cell signaling and therapy.' Circ Res 103(11): 1204-1219. Gong, W., M. Guo, Z. Han, Y. Wang, P. Yang, C. Xu, Q. Wang, L. Du, Q. Li, H. Zhao, F. Fan and Q. Liu (2016). 'Mesenchymal stem cells stimulate intestinal stem cells to repair radiation-induced intestinal injury.' Cell Death Dis 7(9): e2387. Gong, Z., R. Hu, Y. Shou, B. Qiao, C. Chen, F. Xu, X. He and X. Yan (2018). 'Radiation reaction induced spiral attractors in ultra-intense colliding laser beams.' Matt Radiat Extremes 1(6): 308-315. Gurdon, J. (1962). 'The transplantation of nuclei between two subspecies of Xenopus.' Dev Biol 5:68-83. Han, K. H., N. Hashimoto and M. Fukushima (2016). 'Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes.' World J Gastroenterol 22(1): 37-49. Hass, R., C. Kasper, S. Böhm and R. Jacobs (2011). 'Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC.' Cell Commun Signal 9(1): 12. Heino, T. J. and J. A. Määttä (2018). 'Bone marrow niche: Role of different cells in bone metastasis.' Cur Mol Bio Rep 4(2): 80-87. Heymann, F., J. Peusquens, I. Ludwig‐Portugall, M. Kohlhepp, C. Ergen, P. Niemietz, C. Martin, N. van Rooijen, J. C. Ochando and G. J. Randolph (2015). 'Liver inflammation abrogates immunological tolerance induced by Kupffer cells.' Hepatology 62(1): 279-291. Hinshelwood, A., G. McGarvie and E. M. Ellis (2003). 'Substrate specificity of mouse aldo–keto reductase AKR7A5.' Chem Biol Interact 143: 263-269. Hira, V. V. V., C. J. F. Van Noorden, H. E. Carraway, J. P. Maciejewski and R. J. Molenaar (2017). 'Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.' Biochim Biophys Acta Rev Cancer 1868(1): 183-198. Hocking, A. M. (2015). 'The role of chemokines in mesenchymal stem cell homing to wounds.' Adv Wound Care (New Rochelle) 4(11): 623-630. Homma, T., T. Shirato, R. Akihara, S. Kobayashi, J. Lee, K. I. Yamada, S. Miyata, M. Takahashi and J. Fujii (2018). 'Mice deficient in aldo-keto reductase 1a (Akr1a) are resistant to thioacetamide-induced liver injury.' Toxicol Lett 294: 37-43. Hsu, Y. C. and E. Fuchs (2012). 'A family business: stem cell progeny join the niche to regulate homeostasis.' Nat Rev Mol Cell Biol 13(2): 103-114. Huang, A. H. C., Y. K. Chen, L. M. Lin, T. Y. Shieh and A. W. S. Chan (2008). 'Isolation and characterization of dental pulp stem cells from a supernumerary tooth.' J Oral Pathol Med 37(9): 571-574. Huang, X.-J., Y.-K. Choi, H.-S. Im, O. Yarimaga, E. Yoon and H.-S. Kim (2006). 'Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques.' Sensors 6(7): 756-782. Huebert, R. C. and J. Rakela (2014). 'Cellular therapy for liver disease. ' Mayo Clin Proc 89(3):414-424  Hyndman, D., D. R. Bauman, V. V. Heredia and T. M. Penning (2003). 'The aldo-keto reductase superfamily homepage.' Chem Biol nteract 43-144: 621-631. Ip, J. E., Y. Wu, J. Huang, L. Zhang, R. E. Pratt and V. J. Dzau (2007). 'Mesenchymal stem cells use integrin β1 not CXC chemokine receptor 4 for myocardial migration and engraftment.' Mol Biol Cell 18(8): 2873-2882. Israel, Y., M. E. Quintanilla, E. Karahanian, M. Rivera-Meza and M. Herrera-Marschitz (2015). 'The 'first hit' toward alcohol reinforcement: role of ethanol metabolites.' Alcohol Clin Exp Res 39(5): 776-786. Ito, Y., S. Nakamura, N. Sugimoto, T. Shigemori, Y. Kato, M. Ohno, S. Sakuma, K. Ito, H. Kumon, H. Hirose, H. Okamoto, M. Nogawa, M. Iwasaki, S. Kihara, K. Fujio, T. Matsumoto, N. Higashi, K. Hashimoto, A. Sawaguchi, K. I. Harimoto, M. Nakagawa, T. Yamamoto, M. Handa, N. Watanabe, E. Nishi, F. Arai, S. Nishimura and K. Eto (2018). 'Turbulence activates platelet biogenesis to enable clinical scale ex vivo production.' Cell 174(3): 636-648 e618. Jang, Y. O., Y. J. Kim, S. K. Baik, M. Y. Kim, Y. W. Eom, M. Y. Cho, H. J. Park, S. Y. Park, B. R. Kim, J. W. Kim, H. Soo Kim, S. O. Kwon, E. H. Choi and Y. M. Kim (2014). 'Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study.' Liver Int 34(1): 33-41. Ji, C., C. Chan and N. Kaplowitz (2006). 'Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model.' J Hepatol 45(5): 717-724. Kasarala, G. and H. L. Tillmann (2016). 'Standard liver tests.' Clin Liver Dis 8(1): 13-18. Kassim, A. A. and D. Sharma (2017). 'Hematopoietic stem cell transplantation for sickle cell disease: the changing landscape.' Hematol Oncol Stem Cell Ther 10(4): 259-266. Kawaratani, H., T. Tsujimoto, A. Douhara, H. Takaya, K. Moriya, T. Namisaki, R. Noguchi, H. Yoshiji, M. Fujimoto and H. Fukui (2013). 'The effect of inflammatory cytokines in alcoholic liver disease.' Mediators Inflamm 2013:495156 Khanlarkhani, N., M. Baazm, F. Mohammadzadeh, A. Najafi, S. Mehdinejadiani and A. Sobhani (2016). 'Multipotent stem cell and reproduction.' J Stem Cells 11(4): 219-229. Kharaziha, P., P. M. Hellstrom, B. Noorinayer, F. Farzaneh, K. Aghajani, F. Jafari, M. Telkabadi, A. Atashi, M. Honardoost, M. R. Zali and M. Soleimani (2009). 'Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial.' Eur J Gastroenterol Hepatol 21(10): 1199-1205. Kitaori, T., H. Ito, E. M. Schwarz, R. Tsutsumi, H. Yoshitomi, S. Oishi, M. Nakano, N. Fujii, T. Nagasawa and T. Nakamura (2009). 'Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model.' Arthritis Rheum 60(3): 813-823. Koenig, G. and S. Seneff (2015). 'Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk.' Dis Markers 2015:818570 Kong, L., L.-Z. Zheng, L. Qin and K. K. Ho (2017). 'Role of mesenchymal stem cells in osteoarthritis treatment.' J Orthop Translat 9: 89-103. Kubo, N., S. Narumi, K. Hakamada and A. Nakane (2012). 'Efficacy of adipose tissue-derived mesenchymal stem cells for fulminant hepatitis in mice induced by concanavalin A.' J Gastroenterol Hepatol 27(1):165-172. Kurahashi, T., M. Kwon, T. Homma, Y. Saito, J. Lee, M. Takahashi, K. Yamada, S. Miyata and J. Fujii (2014). 'Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals.' Biochem Biophys Res Commun 452(1): 136-141. Lagasse, E., H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I. L. Weissman and M. Grompe (2000). 'Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.' Nat Med 6(11): 1229-1134. Lai, C. W., H. L. Chen, T. C. Tsai, T. W. Chu, S. H. Yang, K. Y. Chong and C. M. Chen (2016). 'Sexually dimorphic expression of eGFP transgene in the Akr1A1 locus of mouse liver regulated by sex hormone-relatedepigenetic remodeling.' Sci Rep 6: 24023. Lai, C.W., H.L. Chen, M.Y. Tu, W.Y. Lin, T. Röhrig, S.H. Yang, Y.W. Lan, K.Y. Chong and C.-M. Chen (2017). 'A novel osteoporosis model with ascorbic acid deficiency in Akr1A1 gene knockout mice.' Oncotarget 8(5): 7357-7369. Lala, V. and D. A. Minter (2018). 'Liver function tests.' In: StatPearls. Treasure Island (FL). Lanthier, N., N. Lin-Marq, L. Rubbia-Brandt, S. Clement, N. Goossens and L. Spahr (2017). 'Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns?' Stem Cell Res Ther 8(1): 88. Le Blanc, K., C. Götherström, O. Ringdén, M. Hassan, R. McMahon, E. Horwitz, G. Anneren, O. Axelsson, J. Nunn and U. Ewald (2005). 'Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta.' Transplantation 79(11): 1607-1614. Lee, D. K. and S. U. Song (2018). 'Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications.' Cell Immunol 326: 68-76. Leung, T. M., Y. Lu, W. Yan, J. A. Moron-Concepcion, S. C. Ward, X. Ge, L. Conde de la Rosa and N. Nieto (2012). 'Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.' Hepatology 55(5): 1596-1609. Levitt, D. G. and M. D. Levitt (2016). 'Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements.' Int J Gen Med 9: 229-255. Li, D. and E. M. Ellis (2012). 'Inducible protection of human astrocytoma 1321N1 cells against hydrogen peroxide and aldehyde toxicity by 7-hydroxycoumarin is associated with the upregulation of aldo-keto reductases.' Neurotoxicology 33(5): 1368-1374. Li, S., H. Y. Tan, N. Wang, Z. J. Zhang, L. Lao, C. W. Wong and Y. Feng (2015). 'The role of oxidative stress and antioxidants in liver diseases.' Int J Mol Sci 16(11): 26087-26124. Li, T., Y. Yan, B. Wang, H. Qian, X. Zhang, L. Shen, M. Wang, Y. Zhou, W. Zhu, W. Li and W. Xu (2013). 'Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis.' Stem Cells Dev 22(6): 845-854. Li, Y., Q. Zhang, X. Yin, W. Yang, Y. Du, P. Hou, J. Ge, C. Liu, W. Zhang, X. Zhang, Y. Wu, H. Li, K. Liu, C. Wu, Z. Song, Y. Zhao, Y. Shi and H. Deng (2011). 'Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules.' Cell Res 21(1): 196-204. Lieber, C. S. and L. M. DeCarli (1982). 'The feeding of alcohol in liquid diets: two decades of applications and 1982 update.' Alcohol Clin Exp Res 6(4): 523-531. Lin, J., L. Meng, Z. Yao, S. Chen, J. Yang, Z. Tang, N. Lin and R. Xu (2015). 'Use an alginate scaffold-bone marrow stromal cell (BMSC) complex for the treatment of acute liver failure in rats.' International journal of clinical and experimental medicine 8(8): 12593-12600. Liu, X., O.-P. R. Hamnvik, J. P. Chamberland, M. Petrou, H. Gong, C. A. Christophi, D. C. Christiani, S. N. Kales and C. S. Mantzoros (2014). 'Circulating alanine transaminase (ALT) and γ-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study.' Metabolism 63(6): 773-782. Long, M. W., J. L. Williams and K. G. Mann (1990). 'Expression of human bone-related proteins in the hematopoietic microenvironment.' J Clin Invest 86(5): 1387-1395. Louvet, A. and P. Mathurin (2015). 'Alcoholic liver disease: mechanisms of injury and targeted treatment.' Nat Rev Gastroenterol Hepatol 12(4): 231-242. Ma, H., C. D. Folmes, J. Wu, R. Morey, S. Mora-Castilla, A. Ocampo, L. Ma, J. Poulton, X. Wang, R. Ahmed, E. Kang, Y. Lee, T. Hayama, Y. Li, C. Van Dyken, N. M. Gutierrez, R. Tippner-Hedges, A. Koski, N. Mitalipov, P. Amato, D. P. Wolf, T. Huang, A. Terzic, L. C. Laurent, J. C. Izpisua Belmonte and S. Mitalipov (2015). 'Metabolic rescue in pluripotent cells from patients with mtDNA disease.' Nature 524(7564): 234-238. Mandal, C., D. Halder, K. H. Jung and Y. G. Chai (2017). 'In utero alcohol exposure and the alteration of histone marks in the developing fetus: An epigenetic phenomenon of maternal drinking.' Int J Biol Sci 13(9): 1100-1108. Mandrekar, P., A. Ambade, A. Lim, G. Szabo and D. Catalano (2011). 'An essential role for monocyte chemoattractant protein‐1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice.' Hepatology 54(6): 2185-2197. Mareschi, K., M. Novara, D. Rustichelli, I. Ferrero, D. Guido, E. Carbone, E. Medico, E. Madon, A. Vercelli and F. Fagioli (2006). 'Neural differentiation of human mesenchymal stem cells: Evidence for expression of neural markers and eag K+ channel types.' Exp Hematol 34(11): 1563-1572. Marshall, J. C., N. V. Christou and J. L. Meakins (1988). 'Immunomodulation by altered gastrointestinal tract flora: the effects of orally administered, killed Staphylococcus epidermidis, Candida, and Pseudomonas on systemic immune responses.' Arch Surg 123(12): 1465-1469. Martin, G. R. (1981). 'Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.' Proc Natl Acad Sci U S A 78(12): 7634-7638. Mathews, S., M. Xu, H. Wang, A. Bertola and B. Gao (2014). 'Animals models of gastrointestinal and liver diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges.' Am J Physiol Gastrointest Liver Physiol 306(10): G819-823. Mehlem, A., C. E. Hagberg, L. Muhl, U. Eriksson and A. Falkevall (2013). 'Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease.' Nat Protoc 8(6): 1149-1154. Mohamadnejad, M., K. Alimoghaddam, M. Mohyeddin-Bonab, M. Bagheri, M. Bashtar, H. Ghanaati, H. Baharvand, A. Ghavamzadeh and R. Malekzadeh (2007). 'Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis.' Arch Iran Med 10(4): 459-466. Mol, M., L. Regazzoni, A. Altomare, G. Degani, M. Carini, G. Vistoli and G. Aldini (2017). 'Enzymatic and non-enzymatic detoxification of 4-hydroxynonenal: methodological aspects and biological consequences.' Free Radic Biol Med 111: 328-344. Molina, P. E., J. D. Gardner, F. M. Souza-Smith and A. M. Whitaker (2014). 'Alcohol abuse: Critical pathophysiological processes and contribution to disease burden.' Physiology (Bethesda) 29(3): 203-215. Morrison, S. J. and J. Kimble (2006). 'Asymmetric and symmetric stem-cell divisions in development and cancer.' Nature 441(7097): 1068. Mukherjee, S. (2013). 'Alcoholism and its effects on the central nervous system.' Curr Neurovasc Res 10(3): 256-262. Musa, S., L. Z. Xin, V. Govindasamy, F. W. Fuen and N. H. A. Kasim (2014). 'Global search for right cell type as a treatment modality for cardiovascular disease.' Expert Opin Biol Ther 14(1): 63-73. Nanau, R. and M. Neuman (2015). 'Biomolecules and biomarkers used in diagnosis of alcohol drinking and in monitoring therapeutic interventions.' Biomolecules 5(3): 1339-1385. Nasef, A., N. Ashammakhi and L. Fouillard (2008). 'Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms.' Regen Med 3(4):531-546 Nasir, G. A., S. Mohsin, M. Khan, S. Shams, G. Ali, S. N. Khan and S. Riazuddin (2013). 'Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice.' J Transl Med 11(1): 78. Nemeth, K., A. Keane-Myers, J. M. Brown, D. D. Metcalfe, J. D. Gorham, V. G. Bundoc, M. G. Hodges, I. Jelinek, S. Madala and S. Karpati (2010). 'Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma.' Proc Nati Acad Sci U S A 107(12):5652-5657. Németh, K., A. Leelahavanichkul, P. S. Yuen, B. Mayer, A. Parmelee, K. Doi, P. G. Robey, K. Leelahavanichkul, B. H. Koller and J. M. Brown (2009). 'Bone marrow stromal cells attenuate sepsis via prostaglandin E 2–dependent reprogramming of host macrophages to increase their interleukin-10 production.' Nat Med 15(1): 42-49. Nitzsche, F., C. Muller, B. Lukomska, J. Jolkkonen, A. Deten and J. Boltze (2017). 'Concise review: MSC adhesion cascade-insights into homing and transendothelial migration.' Stem Cells 35(6): 1446-1460. Nurmi, K., J. Virkanen, K. Rajamaki, K. Niemi, P. T. Kovanen and K. K. Eklund (2013). 'Ethanol inhibits activation of NLRP3 and AIM2 inflammasomes in human macrophages--a novel anti-inflammatory action of alcohol.' PLoS One 8(11): e78537. Ohlstein, B., T. Kai, E. Decotto and A. Spradling (2004). 'The stem cell niche: theme and variations.' Curr Opin Cell Biol 16(6): 693-699. Osna, N. A. and K. K. Kharbanda (2016). 'Multi-organ alcohol-related damage: mechanisms and treatment.' Biomolecules 6(2) pii:E20. Palackal, N. T., M. E. Burczynski, R. G. Harvey and T. M. Penning (2001). 'Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1).' Chem Biol Int 130: 815-824. Park, J. C., J. M. Kim, I. H. Jung, J. C. Kim, S. H. Choi, K. S. Cho and C. S. Kim (2011). 'Isolation and characterization of human periodontal ligament (PDL) stem cells (PDLSCs) from the inflamed PDL tissue: in vitro and in vivo evaluations.' J Clin Periodontol 38(8): 721-731. Penning, T. M. (2015). 'The aldo-keto reductases (AKRs): Overview.' Chem Biol Interact 234: 236-246. Piva, M., G. Domenici, O. Iriondo, M. Rabano, B. M. Simoes, V. Comaills, I. Barredo, J. A. Lopez-Ruiz, I. Zabalza, R. Kypta and M. Vivanco (2014). 'Sox2 promotes tamoxifen resistance in breast cancer cells.' EMBO Mol Med 6(1): 66-79. Ponnaiyan, D. and V. Jegadeesan (2014). 'Comparison of phenotype and differentiation marker gene expression profiles in human dental pulp and bone marrow mesenchymal stem cells.' Eur J Dent 8(3): 307-313. Ponte, A. L., E. Marais, N. Gallay, A. Langonné, B. Delorme, O. Hérault, P. Charbord and J. Domenech (2007). 'The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities.' Stem Cells 25(7): 1737-1745. Pratt-Hyatt, M., A. J. Lickteig and C. D. Klaassen (2013). 'Tissue distribution, ontogeny, and chemical induction of aldo-keto reductases in mice.' Drug Metab Dispos 41(8):1480-1487. Rabani, V., M. Shahsavani, M. Gharavi, A. Piryaei, Z. Azhdari and H. Baharvand (2010). 'Mesenchymal stem cell infusion therapy in a carbon tetrachloride-induced liver fibrosis model affects matrix metalloproteinase expression.' Cell Biol Int 34(6): 601-605. Rajendram, R., R. Hunter, V. Preedy and T. Peters (2005). 'ALCOHOL| Absorption, Metabolism and Physiological Effects.' Encyclopedia of Human Nutrition 48-57. Rasineni, K. and C. A. Casey (2012). 'Molecular mechanism of alcoholic fatty liver.' Indian J Pharmacol 44(3): 299-303. Raynaud, C. M., M. Maleki, R. Lis, B. Ahmed, I. Al-Azwani, J. Malek, F. F. Safadi and A. Rafii (2012). 'Comprehensive characterization of mesenchymal stem cells from human placenta and fetal membrane and their response to osteoactivin stimulation.' Stem Cells Int 2012: 658356. Ress, C. and S. Kaser (2016). 'Mechanisms of intrahepatic triglyceride accumulation.' World J Gastroenterol 22(4): 1664-1673. Riekstina, U., I. Cakstina, V. Parfejevs, M. Hoogduijn, G. Jankovskis, I. Muiznieks, R. Muceniece and J. Ancans (2009). 'Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis.' Stem Cell Rev 5(4): 378-386. Ringden, O. and A. Keating (2011). Mesenchymal stromal cells as treatment for chronic GVHD. Bone Marrow Transplant 46(2):163-164 Ringe, J., S. Strassburg, K. Neumann, M. Endres, M. Notter, G. R. Burmester, C. Kaps and M. Sittinger (2007). 'Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2.' J Cell Biochem 101(1): 135-146. Rüster, B., S. Göttig, R. J. Ludwig, R. Bistrian, S. Müller, E. Seifried, J. Gille and R. Henschler (2006). 'Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells.' Blood 108(12): 3938-3944. Ryan, J., F. Barry, J. Murphy and B. P. Mahon (2007). 'Interferon‐γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.' Clin Exp Immunol 149(2): 353-363. Ryu, K. H., S. Y. Kim, Y. R. Kim, S. Y. Woo, S. H. Sung, H. S. Kim, S. C. Jung, I. Jo and J. W. Park (2014). 'Tonsil-derived mesenchymal stem cells alleviate concanavalin A-induced acute liver injury.' Exp Cell Res 326(1): 143-154. Sacchetti, B., A. Funari, S. Michienzi, S. Di Cesare, S. Piersanti, I. Saggio, E. Tagliafico, S. Ferrari, P. G. Robey, M. Riminucci and P. Bianco (2007). 'Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.' Cell 131(2): 324-336. Saigusa, S., K. Tanaka, Y. Toiyama, T. Yokoe, Y. Okugawa, Y. Ioue, C. Miki and M. Kusunoki (2009). 'Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy.' Ann Surg Oncol 16(12): 3488-3498. Sakamoto, Y., N. Kokudo, Y. Kawaguchi and K. Akita (2017). 'Clinical anatomy of the Liver: Review of the 19th meeting of the Japanese Research Society of Clinical Anatomy.' Liver Cancer 6(2): 146-160. Sasaki, M., R. Abe, Y. Fujita, S. Ando, D. Inokuma and H. Shimizu (2008). 'Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.' J Immunol 180(4): 2581-2587. Scherjon, S. A., C. Kleijburg-van der Keur, W. A. Noort, F. H. Claas, R. Willemze, W. E. Fibbe and H. H. Kanhai (2003). 'Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation.' Blood 102(4): 1548-1549. Schofield, R. (1978). 'The relationship between the spleen colony-forming cell and the haemopoietic stem cell.' Blood Cells 4(1-2): 7-25. Schrepfer, S., T. Deuse, H. Reichenspurner, M. Fischbein, R. Robbins and M. Pelletier (2007). Stem cell transplantation: the lung barrier. Transplant Proc 39(2):573-576 Shenoy, S., E. Angelucci, S. D. Arnold, K. S. Baker, M. Bhatia, D. Bresters, A. C. Dietz, J. De La Fuente, C. Duncan, J. Gaziev, A. A. King, M. A. Pulsipher, A. R. Smith and M. C. Walters (2017). 'Current results and future research priorities in late effects after hematopoieticstem cell transplantation for children with sickle cell disease and thalassemia: A consensus statement from the second pediatric blood and marrow transplant consortium international conference on late effects after pediatric hematopoietic stem cell transplantation.' Biol Blood Marrow Transplant 23(4): 552-561. Shi, Y., Y. Wang, Q. Li, K. Liu, J. Hou, C. Shao and Y. Wang (2018). 'Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.' Nat Rev Nephrol 14(8): 493-507. Shiota, G. and N. Itaba (2017). 'Progress in stem cell-based therapy for liver disease.' Hepatol Res 47(2): 127-141. Sid, B., J. Verrax and P. Calderon (2013). 'Role of oxidative stress in the pathogenesis of alcohol-induced liver disease.' Free Radic Res 47(11): 894-904. Singh, M., A. Kapoor and A. Bhatnagar (2015). 'Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls.' Chem Biol Interact 234: 261-273. Sneddon, J. B., Q. Tang, P. Stock, J. A. Bluestone, S. Roy, T. Desai and M. Hebrok (2018). 'Stem cell therapies for treating diabetes: progress and remaining challenges.' Cell Stem Cell 22(6): 810-823. Sobhani, A., N. Khanlarkhani, M. Baazm, F. Mohammadzadeh, A. Najafi, S. Mehdinejadiani and F. S. Aval (2017). 'Multipotent stem cell and current application.' Acta Med Iran 55(1): 6-23. Sohni, A. and C. M. Verfaillie (2013). 'Mesenchymal stem cells migration homing and tracking.' Stem Cells Int 2013: 130763. Sordi, V., M. L. Malosio, F. Marchesi, A. Mercalli, R. Melzi, T. Giordano, N. Belmonte, G. Ferrari, B. E. Leone and F. Bertuzzi (2005). 'Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.' Blood 106(2): 419-427. Spaggiari, G. M., A. Capobianco, S. Becchetti, M. C. Mingari and L. Moretta (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. Steiner, J. L. and C. H. Lang (2017). 'Alcohol, adipose tissue and lipid dysregulation.' Biomolecules 7(1) pii:E16. Steingen, C., F. Brenig, L. Baumgartner, J. Schmidt, A. Schmidt and W. Bloch (2008). 'Characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells.' J Mol Cell Cardiol 44(6): 1072-1084. Stoscheck, C. M. (1990). Quantitation of protein. Methods Enzymol 182: 50-68. Suk, K. T., M. Y. Kim and S. K. Baik (2014). 'Alcoholic liver disease: Treatment.' World J Gastroenterol 20(36): 12934-12944. Suk, K. T., J. H. Yoon, M. Y. Kim, C. W. Kim, J. K. Kim, H. Park, S. G. Hwang, D. J. Kim, B. S. Lee, S. H. Lee, H. S. Kim, J. Y. Jang, C. H. Lee, B. S. Kim, Y. O. Jang, M. Y. Cho, E. S. Jung, Y. M. Kim, S. H. Bae and S. K. Baik (2016). 'Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial.' Hepatology 64(6): 2185-2197. Szabo, G. (2015). 'Gut-liver axis in alcoholic liver disease.' Gastroenterology 148(1): 30-36. Tabera, S., J. A. Pérez-Simón, M. Díez-Campelo, L. I. Sánchez-Abarca, B. Blanco, A. López, A. Benito, E. Ocio, F. M. Sánchez-Guijo and C. Cañizo (2008). 'The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes.' Haematologica 93(9): 1301-1309. Takahashi, K., K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda and S. Yamanaka (2007). 'Induction of pluripotent stem cells from adult human fibroblasts by defined factors.' Cell 131(5): 861-872. Takahashi, M., S. Miyata, J. Fujii, Y. Inai, S. Ueyama, M. Araki, T. Soga, R. Fujinawa, C. Nishitani and S. Ariki (2012). 'In vivo role of aldehyde reductase.' Biochim Biophys Acta 1820(11): 1787-1796. Taléns-Visconti, R., A. Bonora, R. Jover, V. Mirabet, F. Carbonell, J. V. Castell and M. J. Gómez-Lechón (2006). 'Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells.' World J Gastroenterol 12(36): 5834-5845. Tevlin, R., E. Y. Seo, O. Marecic, A. McArdle, X. Tong, B. Zimdahl, A. Malkovskiy, R. Sinha, G. Gulati and X. Li (2017). 'Pharmacological rescue of diabetic skeletal stem cell niches.' Sci Transl Med 9(372): eaag2809. Theise, N. D., M. Nimmakayalu, R. Gardner, P. B. Illei, G. Morgan, L. Teperman, O. Henegariu and D. S. Krause (2000). 'Liver from bone marrow in humans.' Hepatology 32(1): 11-16. Thomson, J. A., J. Itskovitz-Eldor, S. S. Shapiro, M. A. Waknitz, J. J. Swiergiel, V. S. Marshall and J. M. Jones (1998). 'Embryonic stem cell lines derived from human blastocysts.' Science 282(5391): 1145-1147. Thursz, M., E. Forrest, P. Roderick, C. Day, A. Austin, J. O''Grady, S. Ryder, M. Allison, D. Gleeson, A. McCune, D. Patch, M. Wright, S. Masson, P. Richardson, L. Vale, J. Mellor, L. Stanton, M. Bowers, I. Ratcliffe, N. Downs, S. Kirkman, T. Homer and L. Ternent (2015). 'The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 x 2 factorial randomised controlled trial.' Health Technol Assess 19(102): 1-104. Tilg, H., A. R. Moschen and N. C. Kaneider (2011). 'Pathways of liver injury in alcoholic liver disease.' J Hepatol 55(5): 1159-1161. Torruellas, C., S. W. French and V. Medici (2014). 'Diagnosis of alcoholic liver disease.' World J Gastroenterol 20(33): 11684-11699. Tran, C. and M. S. Damaser (2015). 'Stem cells as drug delivery methods: application of stem cell secretome for regeneration.' Adv Drug Deliv Rev 82: 1-11. Trefts, E., M. Gannon and D. H. Wasserman (2017). 'The liver.' Curr Biol 27(21): R1147-R1151. Tsuchiya, M., C. Ji, O. Kosyk, S. Shymonyak, S. Melnyk, H. Kono, V. Tryndyak, L. Muskhelishvili, I. P. Pogribny, N. Kaplowitz and I. Rusyn (2012). 'Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice.' Hepatology 56(1): 130-139. Tsukamoto, H., K. Machida, A. Dynnyk and H. Mkrtchyan (2009). ''Second hit' models of alcoholic liver disease.' Semin Liver Dis 29(2): 178-187. Tung, Y.-T., T.-Y. Tang, H.-L. Chen, S.-H. Yang, K.-Y. Chong, W. T. Cheng and C.-M. Chen (2014). 'Lactoferrin protects against chemical-induced rat liver fibrosis by inhibiting stellate cell activation.' J Dairy Sci 97(6): 3281-3291. Ueno, A., R. Lazaro, P.-Y. Wang, R. Higashiyama, K. Machida and H. Tsukamoto (2012). 'Mouse intragastric infusion (iG) model.' Nat protoc 7(4): 771-781. Vaculik, C., C. Schuster, W. Bauer, N. Iram, K. Pfisterer, G. Kramer, A. Reinisch, D. Strunk and A. Elbe-Burger (2012). 'Human dermis harbors distinct mesenchymal stromal cell subsets.' J Invest Dermatol 132(3 Pt 1): 563-574. Varela, M. A., H. J. Curtis, A. G. Douglas, S. M. Hammond, A. J. O''Loughlin, M. J. Sobrido, J. Scholefield and M. J. Wood (2016). 'Transfer of genetic therapy across human populations: Molecular targets for increasing patient coverage in repeat expansion diseases.' Eur J Hum Genet 24(2): 271-276. Vierbuchen, T., A. Ostermeier, Z. P. Pang, Y. Kokubu, T. C. Südhof and M. Wernig (2010). 'Direct conversion of fibroblasts to functional neurons by defined factors.' Nature 463(7284): 1035-1041. Wang, Y., Y. Liu, I. Kirpich, Z. Ma, C. Wang, M. Zhang, J. Suttles, C. McClain and W. Feng (2013). 'Lactobacillus rhamnosus GG reduces hepatic TNFalpha production and inflammation in chronic alcohol-induced liver injury.' J Nutr Biochem 24(9): 1609-1615. Wang, Y., H. K. Seitz and X. D. Wang (2010). 'Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats.' Alcohol Clin Exp Res 34(3): 567-573. Wang, Z., X. Dou, S. Li, X. Zhang, X. Sun, Z. Zhou and Z. Song (2014). 'Nuclear factor (erythroid‐derived 2)‐like 2 activation‐induced hepatic very‐low‐density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice.' Hepatology 59(4): 1381-1392. Wang, Z.-G., X.-B. Dou, Z.-X. Zhou and Z.-Y. Song (2016). 'Adipose tissue-liver axis in alcoholic liver disease.' World J Gastrointest Pathophysiol 7(1): 17-26. Wei, X., X. Yang, Z. P. Han, F. F. Qu, L. Shao and Y. F. Shi (2013). 'Mesenchymal stem cells: a new trend for cell therapy.' Acta Pharmacol Sin 34(6): 747-754. Williams, R., K. Ashton, R. Aspinall, M. A. Bellis, J. Bosanquet, M. E. Cramp, N. Day, A. Dhawan, J. Dillon, J. Dyson, J. Ferguson, G. Foster, S. I. Gilmore, M. Glynn, J. A. Guthrie, M. Hudson, D. Kelly, A. Langford, P. Newsome, J. O''Grady, R. Pryke, S. Ryder, M. Samyn, N. Sheron and J. Verne (2015). 'Implementation of the lancet standing commission on liver disease in the UK.' Lancet 386(10008): 2098-2111. Wilmut, I., A. E. Schnieke, J. McWhir, A. J. Kind and K. H. Campbell (2007). 'Viable offspring derived from fetal and adult mammalian cells.' Cloning Stem Cells 9(1): 3-7. Xie, Z., O. A. Barski, J. Cai, A. Bhatnagar and S. M. Tipparaju (2011). 'Catalytic reduction of carbonyl groups in oxidized PAPC by Kvβ2 (AKR6).' Chem Biol Interact 191(1-3): 255-260. Xu, T., L. Zheng, L. Xu, L. Yin, Y. Qi, Y. Xu, X. Han and J. Peng (2014). 'Protective effects of dioscin against alcohol-induced liver injury.' Arch Toxicol 88(3): 739-753. Xu, X., L. Zheng, Q. Yuan, G. Zhen, J. L. Crane, X. Zhou and X. Cao (2018). 'Transforming growth factor-β in stem cells and tissue homeostasis.' Bone Res 6(1): 2. Yang, Y., D. C. Liu, Q. M. Wang, Q. Q. Long, S. Zhao, Z. Zhang, Y. Ma, Z. M. Wang, L. L. Chen and L. S. Wang (2016). 'Alcohol consumption and risk of coronary artery disease: A dose-response meta-analysis of prospective studies.' Nutrition 32(6): 637-644. Yin, H., F. Price and M. A. Rudnicki (2013). 'Satellite cells and the muscle stem cell niche.' Physiol Rev 93(1): 23-67. Yin, T. and L. Li (2006). 'The stem cell niches in bone.' J Clin Invest 116(5): 1195-1201. Yin, Y., X. Li, X. He, R. Wu, H. Sun and F. Chen (2017). 'Leveraging stem cell homing for therapeutic regeneration.' J Dent Res 96(6): 601-609. You, M., A. Jogasuria, C. Taylor and J. Wu (2015). 'Sirtuin 1 signaling and alcoholic fatty liver disease.' Hepatobiliary Surg Nutr 4(2): 88-100. Yu, F., J. Li, H. Chen, J. Fu, S. Ray, S. Huang, H. Zheng and W. Ai (2011). 'Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion.' Oncogene 30(18): 2161-2172. Yu, H. S., T. Oyama, T. Isse, K. Kitakawa, M. Ogawa, T. T. Pham and T. Kawamoto (2009). 'Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice.' Toxicol Mech Methods 19(9): 535-540. Yusa, K., S. T. Rashid, H. Strick-Marchand, I. Varela, P. Q. Liu, D. E. Paschon, E. Miranda, A. Ordonez, N. R. Hannan, F. J. Rouhani, S. Darche, G. Alexander, S. J. Marciniak, N. Fusaki, M. Hasegawa, M. C. Holmes, J. P. Di Santo, D. A. Lomas, A. Bradley and L. Vallier (2011). 'Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells.' Nature 478(7369): 391-394. Zakhari, S. (2015). 'Chronic alcohol drinking: Liver and pancreatic cancer?' Clin Res Hepatol Gastroenterol 39 Suppl 1: S86-91. Zhang, D. (2017). 'A clinical study of bone mesenchymal stem cells for the treatment of hepatic fibrosis induced by hepatolenticular degeneration.' Genet Mol Res 16(1). Zhang, H. and G. G. Meadows (2010). 'Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice.' Cancer Immunol Immunother 59(8): 1151-1159. Zhang, W., W. Zhong, Q. Sun, X. Sun and Z. Zhou (2018). 'Adipose-specific lipin1 overexpression in mice protects against alcohol-induced liver injury.' Sci Rep 8(1): 408. Zhang, X., M. Hirai, S. Cantero, R. Ciubotariu, L. Dobrila, A. Hirsh, K. Igura, H. Satoh, I. Yokomi, T. Nishimura, S. Yamaguchi, K. Yoshimura, P. Rubinstein and T. A. Takahashi (2011). 'Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue.' J Cell Biochem 112(4): 1206-1218. Zhang, Y., W. Cai, Q. Huang, Y. Gu, Y. Shi, J. Huang, F. Zhao, Q. Liu, X. Wei, M. Jin, C. Wu, Q. Xie, Y. Zhang, B. Wan and Y. Zhang (2014). 'Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells.' Hepatology 59(2): 671-682. Zhao, L., S. Chen, X. Shi, H. Cao and L. Li (2018). 'A pooled analysis of mesenchymal stem cell-based therapy for liver disease.' Stem Cell Res Ther 9(1): 72. Zhao, Y., X. Yin, H. Qin, F. Zhu, H. Liu, W. Yang, Q. Zhang, C. Xiang, P. Hou, Z. Song, Y. Liu, J. Yong, P. Zhang, J. Cai, M. Liu, H. Li, Y. Li, X. Qu, K. Cui, W. Zhang, T. Xiang, Y. Wu, Y. Zhao, C. Liu, C. Yu, K. Yuan, J. Lou, M. Ding and H. Deng (2008). 'Two supporting factors greatly improve the efficiency of human iPSC generation.' Cell Stem Cell 3(5): 475-479. Zhong, W., Y. Zhao, Y. Tang, X. Wei, X. Shi, W. Sun, X. Sun, X. Yin, X. Sun and S. Kim (2012). 'Chronic alcohol exposure stimulates adipose tissue lipolysis in mice: role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis.' Am J Pathol 180(3): 998-1007. Zhong, Z., V. K. Ramshesh, H. Rehman, Q. Liu, T. P. Theruvath, Y. Krishnasamy and J. J. Lemasters (2014). 'Acute ethanol causes hepatic mitochondrial depolarization in mice: role of ethanol metabolism.' PLoS One 9(3): e91308. Zhou, Z. and W. Zhong (2017). 'Targeting the gut barrier for the treatment of alcoholic liver disease.' Liver Res 1(4): 197-207. Zhu, Q., L. Zou, K. Jagavelu, D. A. Simonetto, R. C. Huebert, Z.-D. Jiang, H. L. DuPont and V. H. Shah (2012). 'Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice.' J Hepatol 56(4): 893-899. Zhu, X., B. He, X. Zhou and J. Ren (2013). 'Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis.' Cell Tissue Res 351(3): 477-486.
摘要: 
酒精性肝損傷起因於飲酒,長期大量飲酒容易形成酒精性脂肪肝、肝炎、肝纖維化甚至發展成不可逆的肝硬化,成為全球慢性肝病的主要致病因素,而酒精性肝損傷病程發展取決於酒精攝取量、持續時間、飲食以及個體遺傳變異性。AKR1A1屬於醛酮還原家族成員,由醛還原酶基因所編碼,是機體依賴NADPH的重要酵素,能將多種醛類還原成其相對應醇類物質,並參與細胞的解毒作用。當體內先天缺乏醛還原酶,等同於瓦解細胞抵抗毒害物質的能力,進而造成細胞毒性,AKR1A1作為體內醛還原解毒酵素,對於酒精引起肝臟疾病之關聯性仍待探究。因此本試驗第一部分將同時建立AKR1A1缺乏小鼠及其遺傳背景ICR小鼠酒精誘導肝損傷模式,探討AKR1A1缺乏對酒精性肝損傷之易感性。試驗中使用9週齡ICR及AKR1A1eGFP/eGFP小鼠,利用Lieber-Decarli流質飲食模式,分別餵食1-4 %酒精液態飼料及正常液態飼料使其適應一週,小鼠至10週齡即以5 %酒精濃度餵養,進行為期八週的實驗。結果顯示,酒精造成Akr1A1eGFP/eGFP小鼠出現肝功能異常、肝臟三酸甘油脂蓄積及肝細胞脂肪變性,並誘發酒精代謝途徑中CYP2E1蛋白表現,導致脂質過氧化物4-HNE產生,使肝細胞釋放促炎因子TNF-α 與IL-1β,並且出現死亡現象;然而酒精並未誘發ICR小鼠明顯肝損傷,且於蛋白層次中發現酒精餵養增加ICR小鼠肝臟AKR1A1的表現,顯示醛還原酶遺傳性缺陷大幅提高小鼠對酒精之敏感性。過去研究陸續支持間質幹細胞具有修復遺傳缺陷疾病之潛力,因此試驗第二部分欲藉由骨髓間質幹細胞移植,評估移植治療是否修復醛還原酶功能並進一步改善由醛還原酶缺乏所導致肝損傷病症。首先以尾靜脈注射移植骨髓間質幹細胞,於移植四週後犧牲小鼠。由螢光顯微鏡與幹細胞表面標記染色皆可發現部分骨髓間質幹細胞分布於肝臟,經IHC染色結果顯示細胞移植後Akr1A1eGFP/eGFP小鼠肝臟表現醛還原酶,接著觀察肝損傷修復情形,藉由蛋白層次證實骨髓間質幹細胞釋出旁分泌因子TGFβ、HGF參與肝細胞修復,且降低肝臟三酸甘油脂堆積、脂肪變性並回復肝功能,更提升抗氧化物質GSH含量並削弱CYP2E1代謝途徑,減少脂質過氧化產物MDA、4-HNE的生成,降低過氧化物質對肝臟的損害,有效抑制發炎反應,顯示醛還原酶的存在可提高小鼠對酒精性肝損傷的易感性。綜合上述結果,本試驗證實醛還原酶在酒精性肝損傷之重要性,有潛力作為研究酒精代謝疾病的動物模式。

Alcoholic liver disease (ALD) is caused by excessive alcohol consumption. The spectrum of alcohol-related liver injury varies from hepatic steatosis, steatohepatitis, alcoholic fibrosis to irreversible cirrhosis. Alcohol is emerging as the commonest cause of chronic liver disease worldwide. The severity and prognosis of alcohol-induced liver disease depends on the amount, duration of alcohol consumption, diet as well as genetic predisposition of an individual. AKR1A1 is a member of the aldo-keto reductase (AKR) superfamily, which is encoded by the AKR1A1 gene. The enzyme catalyze the reduction of various aldehydes to their corresponding alcohols in an NADPH-dependent manner and participate in the detoxification. Aldehyde reductase deficiency contribute to cell damage because of toxic substances stimulation AKR1A1 acts as an aldehyde-reducing and detoxifying enzyme in organism, the association of alcohol-induced liver disease remains to be explored. In this study, the first aim of the experiment will establish the model of alcohol-induced liver injury in AKR1A1 deficient mice and their genetic background ICR mice, revealing the susceptibility of AKR1A1 deficiency to alcoholic liver injury. The 9-week-old ICR and AKR1A1eGFP/eGFP mice were divided into four groups that was used to fed Lieber-Decarli diet containing 1-4% alcohol liquid diet or an isocaloric (Pair-fed) control diet adjusted by 1 weeks. The mice were fed 5 % alcohol for 8 weeks at 10-week-old. The results showed that alcohol caused abnormal liver function, hepatic triglyceride accumulation and steatosis in AKR1A1eGFP/eGFP mice. Alcohol consumption increases the CYP2E1 levels, leading to lipid peroxidation and lipid peroxidation products such as 4-hydroxynonenal , increasing pro-inflammatory cytokines TNF-α and IL-1β protein level and the risk of death. Interestingly, Alcohol did not cause liver injury significant in ICR mice. However, alcohol feeding increased hepatic AKR1A1 protein level. It shows that the genetic defect of aldehyde reductase susceptibility to alcohol. Over the years, growing number of studies have provided evidence in support the potential of mesenchymal stem cells to fixing genetic disorders. Therefore, the second aim of the experiment is to evaluate whether aldehyde reductase function repaired by bone marrow mesenchymal stem cells after cell transplantation to further improve liver injuury caused by aldehyde reductase deficiency. First, Bone marrow mesenchymal stem cells were transplanted by tail vein injection, and the mice were sacrificed four weeks after transplantation. Some mesenchymal stem cells were found in the liver by fluorescence microscopy and stem cell surface marker staining. IHC staining showed that the liver of AKR1A1eGFP/eGFP mice ecpressed aldehyde reductase after cell transplantation. Then observe the repair of liver damage, Hierarchy confirmed that mesenchymal stem cells release paracrine factors TGFβ and HGF involved in hepatocyte repair, and reduce hepatic triglyceride accumulation, steatosis and restore liver function, enhance antioxidant GSH content and decreased CYP2E1 protein levels, reduce lipid peroxidation products MDA, 4-HNE damage liver and effectively decreases the inflammation. It was shown that aldehyde reductase increases the susceptibility of mice to alcoholic liver injury. In conclusion, we confirmed the importance of aldehyde reductase in alcoholic liver injury and has potential as an animal model for studying alcohol related diseases.
URI: http://hdl.handle.net/11455/99398
Rights: 同意授權瀏覽/列印電子全文服務,2022-02-12起公開。
Appears in Collections:生命科學系所

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.