修回日期: 2010-07-08
接受日期: 2010-07-12
在线出版日期: 2010-08-08
骨髓间充质干细胞是一种来源于骨髓基质的具有多向分化能力的干细胞, 在特定条件下, 可以分化为骨细胞、软骨细胞、脂肪细胞、神经元样细胞及肝细胞等. 近年研究表明, 骨髓间充质干细胞能抑制和减轻肝纤维化, 并且具有免疫抑制和诱导免疫耐受的作用. 因此, 在细胞移植治疗终末期肝病方面具有广阔的临床应用前景.
引文著录: 徐静, 陈光. 骨髓间充质干细胞逆转肝纤维化的研究进展. 世界华人消化杂志 2010; 18(22): 2291-2295
Revised: July 8, 2010
Accepted: July 12, 2010
Published online: August 8, 2010
Bone marrow mesenchymal stem cells (BMSCs) are a group of stem cells capable of multilineage differentiation. Under given conditions, BMSCs can differentiate into a variety of cells, such as osteoblasts, chondrocytes, adipocytes, neuron-like cells and hepatocytes. In recent years, numerous studies have shown that BMSCs can not only inhibit and reduce liver fibrosis but also induce immunosuppression and immune tolerance. Therefore, transplantation of BMSCs can be used to treat end-stage liver disease.
- Citation: Xu J, Chen G. Advances in research of the reversal of liver fibrosis by transplantation of bone marrow mesenchymal stem cells. Shijie Huaren Xiaohua Zazhi 2010; 18(22): 2291-2295
- URL: https://www.wjgnet.com/1009-3079/full/v18/i22/2291.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i22.2291
肝硬化在我国发病率很高, 是由各种慢性肝损伤引起的, 其最主要的病理学特征是进行性肝纤维化. 多年以来人们一直都认为肝纤维化及肝硬化过程是不可逆的, 肝移植是治疗终末期肝硬化的唯一方法[1], 但由于肝源紧张、操作复杂、费用昂贵及移植后免疫排斥反应等, 使得这一治疗方法很难得到推广[2,3]. 近年来, 研究表明肝纤维化过程是可以逆转的[4-11], 且骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)移植在逆转肝纤维化方面的作用已经得到证实, 有望为肝纤维化、肝硬化的治疗带来新手段. 间充质干细胞(mesenchymal stem cells, MSCs)是一类具有自我更新能力和多向分化潜能的干细胞, 由于骨髓来源的MSCs易于取材, 未涉及伦理, 而广泛应用于肝纤维化逆转的实验研究, 我们就BMSCs移植在肝纤维化逆转中取得的相关进展作一综述.
肝纤维化以细胞外基质(extracellular matrix, ECM)的过量积聚为特征, 如Ⅰ、Ⅲ、Ⅳ、Ⅴ型胶原、层粘连蛋白和弹性蛋白. 在纤维化的肝脏中, ECM不仅产生的量增多, 而且构成也发生改变, Ⅰ型胶原占据主导地位. 肝星状细胞(hepatic stellate cell, HSC)是Ⅰ型胶原的主要来源, 肝损伤时, 处于静止状态的HSC迅速活化, 转化为肌成纤维样细胞并表达细胞骨架蛋白α-SMA及结合蛋白, 这些细胞具有很强的增生能力, 并且能够产生大量Ⅰ型胶原[12]. 除了HSC以外, 其他一些细胞也参与胶原的合成, 如门静脉周围的以及骨髓源性的成纤维细胞和纤维细胞[12,13]. 凋亡的肝细胞、肝内定居的Kupffer细胞以及炎症细胞也促使肝纤维化的发生, 他们通过释放活性氧簇及产生促纤维化细胞因子(如TNF-α、成纤维细胞生长因子和TGF-β1等)促使HSC的活化和Ⅰ型胶原的产生. 活化的HSC上调黏附分子的表达和释放促炎症反应细胞因子(如IL-6、IL-8、单核细胞趋化蛋白-1等), 进一步促使炎症细胞在损伤肝脏的聚集. 另外, HSC产生金属蛋白酶组织抑制剂(tissue inhibitor of metalloproteinases, TIMP), TIMP能抑制基质金属蛋白酶(matrix metalloproteinase, MMP), 而MMP的作用是降解ECM, 因此活化的HSC大量增殖, 使胶原和其他ECM的合成与降解失衡[14], 从而导致胶原在肝脏的沉积, 胶原的进行性积聚会引起肝脏结构和功能的紊乱, 并最终发展成肝硬化.
近年一些对肝纤维化动物模型的实验研究表明, 肝纤维化可以被逆转[12,15]. 祛除引起肝损伤的因素, 如病毒、酒精、缺血和药物等, 不仅能抑制肝纤维化的发展, 而且能使其消退[16]. 总之, 肝纤维化的消退与促纤维化及促炎症反应细胞因子水平的下降和活化HSC的凋亡有关[17,18].
MSCs是来源于中胚层的一类具有多向分化能力的干细胞, 大量体外实验证明, 在不同诱导条件下, MSCs不仅可以向多种中胚层来源的组织细胞分化, 如成骨细胞、软骨细胞、脂肪细胞、心肌细胞等, 还可以向外胚层和内胚层来源的神经元样细胞和肝细胞样细胞分化[19]. Lange等[20]研究证明, MSCs在体内外均可分化为肝实质细胞, 而MSCs所处微环境对其分化为肝细胞起着重要作用. Sato等[21]将人MSCs种植到慢性丙烯醇损伤的大鼠肝脏, 免疫组织化学观察到在MSCs移植的受体鼠肝内有人肝细胞特有的甲胎蛋白(alpha-fetoprotein, AFP)、ALB、CK19、CK18及AGPR的表达, 逆转录-聚合酶链反应发现有AFP和ALB的mRNA表达, 表明人MSCs能在适当微环境下诱导分化为肝细胞. 国内有学者[22]将人MSCs植入肝切除大鼠体内, 发现大鼠术后肝组织内有人AFP及特异性序列Alu-sx的表达, 提示人MSCs在大鼠体内不但已经向肝细胞分化, 并且发挥一定功能.
MSCs不仅具有多向分化潜能, 还具有低免疫原性、免疫抑制及诱导免疫耐受的作用. 有报道表明[23,24], MSCs表达组织相容性复合物Ⅰ而缺乏组织相容性复合物Ⅱ, 免疫原性较弱. Uccelli等[25]研究发现, BMSCs表面只表达少量HLA-Ⅰ类抗原, 不表达HLA-Ⅱ类抗原, 这种表达模式并不会随着细胞的分化成熟而明显改变, 同时激活T淋巴细胞所必需的协同刺激分子, 这些特性减少了BMSCs移植以后免疫排斥反应和相关并发症的发生. 此外, BMSCs可以通过旁分泌作用抑制B淋巴细胞和T淋巴细胞的增殖, 激活T淋巴细胞的凋亡从而起到免疫抑制作用[26,27]. Bartholomew等[28]给狒狒静脉注射BMSCs, 发现这样可使异体移植的皮瓣存活期明显延长, 证明BMSCs具有诱导免疫耐受作用. MSCs的多向分化潜能及免疫学特性, 再加上取材方便, 易于分离、培养、纯化和扩增, 为其移植治疗肝纤维化提供了很大可能性.
骨髓组织中至少存在造血干细胞及MSCs两种不同类型的干细胞, 为证实哪种细胞在逆转肝纤维化方面起作用, Yamamoto等[29]利用Live-8抗体将骨髓干细胞分为Live-8阳性细胞及Live-8阴性细胞两个亚群, 其中阳性细胞是造血干细胞, 而阴性细胞是非造血干细胞, 因为Live-8抗体是一种单克隆抗体, 他可以通过特定的细胞表面标志物来识别骨髓造血干细胞. Sakaida等[30]研究表明, 将骨髓干细胞植入CCl4诱导的肝纤维化小鼠体内, 发现Live-8阴性亚群的骨髓干细胞能够增强表达MMP, 使肝纤维化明显减轻, 而Live-8阳性细胞在对肝纤维化不起任何作用. 另外, Terai等[31]通过GFP/CCl4模型研究发现, Live-8阴性细胞能更有效的植入纤维化的肝组织中并且向肝细胞分化, 表明Live-8阴性亚群的骨髓干细胞(非造血干细胞, 可能是MSCs)能够逆转肝纤维化.
Fang等[32]研究发现, MSCs移植可以通过减少炎症反应、胶原沉积和组织重塑来修复损伤的心肝肺, 这表明, MSCs不仅能修复急性损伤的组织, 而且具有减轻慢性纤维化的作用. Abdel Aziz等[33]将雄鼠MSCs注入到CCl4诱导的肝纤维化雌鼠尾静脉中, 通过对雌鼠肝组织的组织病理学特征、肝功指标[丙氨酸氨基转移酶(alanine aminotransferase, ALT)和血清白蛋白(albumin, ALB)]、Ⅰ型胶原基因的表达以及羟基脯氨酸含量的检测, 证实MSCs具有抑制肝纤维化过程的作用. Oyagi等[34]将MSCs与肝细胞生长因子(hepatocyte growth factor, HGF)一起培养后, 植入CCl4诱导的肝损伤小鼠体内, 结果发现, 小鼠的ALB恢复正常, 转氨酶活性及肝纤维化明显受到抑制, 而将没和HGF一起培养的MSCs植入肝损伤的小鼠体内, 不会出现上述结果. 该实验发现, HGF可以诱导MSCs分化成肝细胞样细胞, 并具有部分肝细胞的功能, 还可以增加MSCs植入受体小鼠肝内的数量.
Terai等[35]报道, 9例肝硬化患者从周围静脉输注自体骨髓细胞, 移植24 wk后, ALB、总蛋白水平及Chlid-Pugh分级均明显改善(P<0.05), 且未观察到任何不良反应. 近年, 国内有学者[36]利用自体骨髓干细胞肝内移植治疗36例失代偿期肝硬化患者, 结果发现, 移植术后2、3 mo, ALT、TB和PT均较术前明显改善(P<0.05), 而ALB直到术后3 mo才明显好转(P<0.05). 移植术后2 mo, 腹水减轻的占70.8%(17/24), 乏力好转的占83.9%(26/31), 食欲改善的占90.3%(28/31). 移植术中和术后, 未见明显不良反应和并发症发生. 可见自体BMSCs移植可以作为肝硬化肝纤维化治疗的一种新方法.
MSCs逆转肝纤维化的具体机制尚不明确, 可能与以下几个方面有关: (1)MSCs分化成肝细胞, 修复损伤的肝组织: 在肝纤维化特别是肝硬化时, 有大量肝细胞坏死, 因此补充正常功能的肝细胞可以修复损伤的肝组织. 许多研究表明, MSCs在体内外均可分化为肝细胞[32,37-39]. (2)MSCs抑制HSC的活化, 促使HSC的凋亡, 减少ECM的生成: HSC是ECM的主要来源, 肝损伤时, HSC的活化是肝硬化肝纤维化发生发展的中心环节. Zhao等[40]研究发现, 在体外将MSCs与HSC共培养能够增加G0期HSC数量, 减少S期HSC数量. 由此推断, MSCs能抑制HSC的活化. Shi等[41]研究发现, MSCs能诱导HSC凋亡, MSCs诱导HSC凋亡的效应依赖于两者间的比值以及MSCs分泌的各种可溶性细胞因子的表达. MSCs诱导HSC凋亡是通过分泌各种细胞因子(例如NGF、HGF等)激活JNK途径实现的. 另外研究还发现通过抗体中和阻断MSCs分泌的TGF-β1,可以增强MSCs促HSC凋亡的效应. 这是因为TGF-β1能够促纤维化形成, 在刺激HSC活化和增生中具有重要作用, 其抑制凋亡的效应部分是由Fas配体表达减少介导的[30], 他还能抑制HGF的表达[42]. (3)MSCs分泌细胞因子/生长因子: MSCs能够分泌多种细胞因子及生长因子, 如HGF、NGF、TGF-β、ILs、TNF-α等[41,43-45]. Oyagi等[34]研究发现, MSCs和CCl4诱导的损伤肝细胞一起培养时, 分泌的HGF明显增多, 表明MSCs可能从损伤的肝细胞中接受某些信号, 受信号调节分泌HGF. HGF不仅能诱导MSCs分化成肝细胞, 还抑制TGF-β1产生, 阻止肝细胞凋亡及肝脏纤维化[46-48]. 另有报道称, 活化的HSC分泌的IL-6, 能够诱导MSCs分泌IL-10, 表明MSCs在肝脏的微环境中能够对HSC做出动态反应. 此外, MSCs还分泌TNF-α, 阻断MSCs分泌IL-10, TNF-α还阻断了MSCs抑制HSC增生和胶原合成[45]. (4)MSCs表达MMP, 降解ECM: MMP有较强的降解ECM作用[49], 研究表明骨髓干细胞植入CCl4诱导的肝硬化小鼠体内, 可使小鼠的肝功改善, 死亡率降低, 这与骨髓干细胞增强表达MMPs, 特别是MMP-9, 降解胶原纤维, 肝纤维化减轻有关[39]. (5)MSCs分化为肝卵原细胞, 促进肝修复再生: 研究表明[50], 在肝严重受损时, 肝细胞增殖受阻, 肝卵原细胞能增殖分化为肝细胞, 是肝修复的主要手段. Oh等[51]通过2-AAF/部分肝切除诱导的肝再生大鼠模型发现, 部分肝卵原细胞来源于骨髓干细胞, 并且能够分化成肝细胞.
MSCs能够分化为肝细胞, 抑制和减轻肝纤维化, 并且不发生同种异体移植排斥反应, 在治疗肝硬化肝纤维化方面具有广阔的应用前景. 但是直到目前为止, MSCs广泛应用于临床还有许多问题亟待解决: MSCs体内数量少, 体外分离、纯化及扩增方法还不够完善; MSCs特异性表面标志分子不确定; MSCs逆转肝纤维化的分子机制尚不清楚; MSCs移植后是否会产生无法控制的细胞分化增殖, 是否具有致瘤性. 相信随着这些难题的解决, MSCs移植有望成为治疗肝纤维化的理想方法.
肝硬化在我国发病率很高, 因条件所限, 肝移植很难得到推广. 骨髓间充质干细胞能分化成肝细胞, 并且具有抗纤维化及免疫抑制作用, 有望为终末期肝病治疗带来新的手段.
王钦红, 副教授, 美国杜克大学医学院肿瘤生物系
骨髓间充质干细胞逆转肝纤维化的分子机制是当前研究的热点.
有关骨髓间充质干细胞逆转肝纤维化的机制还不清楚, 目前研究主要集中在MSCs抑制HSC活化、促进HSC凋亡以及分泌各种细胞因子、抑制炎症反应方面.
本文立题新颖, 读者可以进一步深入了解骨髓间充质干细胞在逆转肝纤维化中的作用, 为肝纤维化、肝硬化患者的基础和临床的研究提供新的思路, 具有较大的意义.
编辑:李军亮 电编:何基才
| 1. | Bonis PA, Friedman SL, Kaplan MM. Is liver fibrosis reversible? N Engl J Med. 2001;344:452-454. [PubMed] [DOI] |
| 2. | Noble-Jamieson G, Valente J, Barnes ND, Friend PJ, Jamieson NV, Rasmussen A, Calne RY. Liver transplantation for hepatic cirrhosis in cystic fibrosis. Arch Dis Child. 1994;71:349-352. [PubMed] [DOI] |
| 3. | Ben-Ari Z, Pappo O, Zemel R, Mor E, Tur-Kaspa R. Association of lamivudine resistance in recurrent hepatitis B after liver transplantation with advanced hepatic fibrosis. Transplantation. 1999;68:232-236. [PubMed] [DOI] |
| 4. | Kumar M, Sarin SK. Is cirrhosis of the liver reversible? Indian J Pediatr. 2007;74:393-399. [PubMed] [DOI] |
| 5. | Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology. 2002;122:1525-1528. [PubMed] [DOI] |
| 6. | Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling MH, Albrecht J. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303-1313. [PubMed] [DOI] |
| 7. | Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med. 1997;127:981-985. [PubMed] |
| 8. | Wanless IR. Use of corticosteroid therapy in autoimmune hepatitis resulting in the resolution of cirrhosis. J Clin Gastroenterol. 2001;32:371-372. [PubMed] [DOI] |
| 9. | Kaplan MM, DeLellis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med. 1997;126:682-688. [PubMed] |
| 10. | Kweon YO, Goodman ZD, Dienstag JL, Schiff ER, Brown NA, Burchardt E, Schoonhoven R, Brenner DA, Fried MW. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001;35:749-755. [PubMed] [DOI] |
| 11. | Hammel P, Couvelard A, O'Toole D, Ratouis A, Sauvanet A, Fléjou JF, Degott C, Belghiti J, Bernades P, Valla D. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med. 2001;344:418-423. [PubMed] [DOI] |
| 12. | Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209-218. [PubMed] |
| 13. | Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis. 2001;21:437-451. [PubMed] [DOI] |
| 14. | Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005;10:927-939. [PubMed] [DOI] |
| 15. | Friedman SL, Bansal MB. Reversal of hepatic fibrosis -- fact or fantasy? Hepatology. 2006;43:S82-S88. [PubMed] [DOI] |
| 16. | Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol. 2006;21 Suppl 3:S84-S87. [PubMed] [DOI] |
| 17. | Breitkopf K, Haas S, Wiercinska E, Singer MV, Dooley S. Anti-TGF-beta strategies for the treatment of chronic liver disease. Alcohol Clin Exp Res. 2005;29:121S-131S. [PubMed] [DOI] |
| 18. | Ueberham E, Löw R, Ueberham U, Schönig K, Bujard H, Gebhardt R. Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology. 2003;37:1067-1078. [PubMed] [DOI] |
| 19. | Kassem M, Abdallah BM. Human bone-marrow-derived mesenchymal stem cells: biological characteristics and potential role in therapy of degenerative diseases. Cell Tissue Res. 2008;331:157-163. [PubMed] [DOI] |
| 20. | Lange C, Bassler P, Lioznov MV, Bruns H, Kluth D, Zander AR, Fiegel HC. Hepatocytic gene expression in cultured rat mesenchymal stem cells. Transplant Proc. 2005;37:276-279. [PubMed] [DOI] |
| 21. | Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106:756-763. [PubMed] [DOI] |
| 23. | Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg. 2002;74:19-24; discussion 24. [PubMed] [DOI] |
| 24. | Fändrich F, Lin X, Chai GX, Schulze M, Ganten D, Bader M, Holle J, Huang DS, Parwaresch R, Zavazava N. Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nat Med. 2002;8:171-178. [PubMed] [DOI] |
| 25. | Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36:2566-2573. [PubMed] [DOI] |
| 26. | Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC. Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia. 2005;19:1597-1604. [PubMed] [DOI] |
| 27. | Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367-372. [PubMed] [DOI] |
| 28. | Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-48. [PubMed] [DOI] |
| 29. | Yamamoto N, Terai S, Ohata S, Watanabe T, Omori K, Shinoda K, Miyamoto K, Katada T, Sakaida I, Nishina H. A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver. Biochem Biophys Res Commun. 2004;313:1110-1108. [PubMed] [DOI] |
| 30. | Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40:1304-1311. [PubMed] [DOI] |
| 31. | Terai S, Sakaida I, Nishina H, Okita K. Lesson from the GFP/CCl4 model--translational research project: the development of cell therapy using autologous bone marrow cells in patients with liver cirrhosis. J Hepatobiliary Pancreat Surg. 2005;12:203-207. [PubMed] [DOI] |
| 32. | Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation. 2004;78:83-88. [PubMed] [DOI] |
| 33. | Abdel Aziz MT, Atta HM, Mahfouz S, Fouad HH, Roshdy NK, Ahmed HH, Rashed LA, Sabry D, Hassouna AA, Hasan NM. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Clin Biochem. 2007;40:893-899. [PubMed] [DOI] |
| 34. | Oyagi S, Hirose M, Kojima M, Okuyama M, Kawase M, Nakamura T, Ohgushi H, Yagi K. Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol. 2006;44:742-748. [PubMed] [DOI] |
| 35. | Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292-2298. [PubMed] [DOI] |
| 36. | 朱 康顺, 单 鸿, 何 可可, 李 征然, 关 守海, 黄 明声, 钱 结胜, 庞 鹏飞, 姜 在波. 自体骨髓干细胞肝内移植治疗失代偿期 肝硬化的初步临床观察. 中国医学影像学技术. 2007;23:1863-1865. |
| 37. | Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004;40:1275-1284. [PubMed] [DOI] |
| 38. | Sakaida I, Terai S, Nishina H, Okita K. Development of cell therapy using autologous bone marrow cells for liver cirrhosis. Med Mol Morphol. 2005;38:197-202. [PubMed] [DOI] |
| 39. | Hung SC, Chen NJ, Hsieh SL, Li H, Ma HL, Lo WH. Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells. 2002;20:249-258. [PubMed] [DOI] |
| 40. | Zhao DC, Lei JX, Chen R, Yu WH, Zhang XM, Li SN, Xiang P. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol. 2005;11:3431-3440. [PubMed] |
| 41. | Shi L, Li G, Wang J, Sun B, Yang L, Wang G, Wang D, Mu L, Chen H, Jin L. Bone marrow stromal cells control the growth of hepatic stellate cells in vitro. Dig Dis Sci. 2008;53:2969-2974. [PubMed] [DOI] |
| 42. | Matsumoto K, Tajima H, Okazaki H, Nakamura T. Negative regulation of hepatocyte growth factor gene expression in human lung fibroblasts and leukemic cells by transforming growth factor-beta 1 and glucocorticoids. J Biol Chem. 1992;267:24917-24920. [PubMed] |
| 43. | Matsuda-Hashii Y, Takai K, Ohta H, Fujisaki H, Tokimasa S, Osugi Y, Ozono K, Matsumoto K, Nakamura T, Hara J. Hepatocyte growth factor plays roles in the induction and autocrine maintenance of bone marrow stromal cell IL-11, SDF-1 alpha, and stem cell factor. Exp Hematol. 2004;32:955-961. [PubMed] [DOI] |
| 44. | Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002;59:514-523. [PubMed] |
| 45. | Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, Yarmush ML. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007;363:247-252. [PubMed] [DOI] |
| 46. | Oe H, Kaido T, Mori A, Onodera H, Imamura M. Hepatocyte growth factor as well as vascular endothelial growth factor gene induction effectively promotes liver regeneration after hepatectomy in Solt-Farber rats. Hepatogastroenterology. 2005;52:1393-1397. [PubMed] |
| 47. | Shi MN, Huang YH, Zheng WD, Zhang LJ, Chen ZX, Wang XZ. Relationship between transforming growth factor beta1 and anti-fibrotic effect of interleukin-10. World J Gastroenterol. 2006;12:2357-2362. [PubMed] |
| 48. | Matsuda Y, Matsumoto K, Ichida T, Nakamura T. Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. J Biochem. 1995;118:643-649. [PubMed] |
| 49. | Zheng WD, Zhang LJ, Shi MN, Chen ZX, Chen YX, Huang YH, Wang XZ. Expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 in hepatic stellate cells during rat hepatic fibrosis and its intervention by IL-10. World J Gastroenterol. 2005;11:1753-1758. [PubMed] |
| 50. | Oertel M, Shafritz DA. Stem cells, cell transplantation and liver repopulation. Biochim Biophys Acta. 2008;1782:61-74. [PubMed] |
| 51. | Oh SH, Witek RP, Bae SH, Zheng D, Jung Y, Piscaglia AC, Petersen BE. Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology. 2007;132:1077-1087. [PubMed] [DOI] |