药学学报

Disease	BMSCs transplantation method	BMSCs transplantation route	Phase	ClinicalTrials.gov identifier
Early and middle stage of liver cirrhosis on the basis of HBV infection	Autologous BMSCs transplantation	Portal vein	Phase Ⅱ	NCT00993941
HBV-related liver cirrhosis	Autologous BMSCs transplantation	Hepatic artery	Phase Ⅰ/Ⅱ	NCT01724697
Liver cirrhosis resulting from chronic HBV	Allogenic BMSCs transplantation	Portal vein or hepatic artery	Phase Ⅱ	NCT01223664
Liver cirrhosis with refractory ascites	Autologous BMSCs transplantation	Liver artery	Phase Ⅲ	NCT01854125

Disease	BMSCs transplantation method	BMSCs transplantation route	Phase	ClinicalTrials.gov identifier
Early and middle stage of liver cirrhosis on the basis of HBV infection	Autologous BMSCs transplantation	Portal vein	Phase Ⅱ	NCT00993941
HBV-related liver cirrhosis	Autologous BMSCs transplantation	Hepatic artery	Phase Ⅰ/Ⅱ	NCT01724697
Liver cirrhosis resulting from chronic HBV	Allogenic BMSCs transplantation	Portal vein or hepatic artery	Phase Ⅱ	NCT01223664
Liver cirrhosis with refractory ascites	Autologous BMSCs transplantation	Liver artery	Phase Ⅲ	NCT01854125

Traditional Chinese formular	Change in related indicator	Possibly related mechanism or pathway
Yiguan Decoction^[94]	Alb, AFP, HNF4α mRNA, CK-18↑; Wnt3α, β-catenin↓	Down-regulate Wnt/β-catenin signaling pathway
Zuoguiwan^[95]	Wnt1, EGF, FGF2, FGF16, MAPKK1, E2F, CSF3, Myd88, sFRP1, sFRP5, CSF2R, CNTFR, caspase12↑; MAPK9, Rac1, GSK3, Wnt10a, IL12a, Akt2, Activin AR, PKCγ↓	Affect Wnt, MAPK, TGF-β, Jak-STAT and Toll-like receptor signaling pathways
Biejiajian Pills^[96]	ALB↑; ALT, AST, TBIL, SDF-1↓	Act on SDF-1/CRCX4
Ruanganjian^[97]	ALB↑; ALT, AST↓	Improve the content of albumin in plasma

Traditional Chinese formular	Change in related indicator	Possibly related mechanism or pathway
Yiguan Decoction^[94]	Alb, AFP, HNF4α mRNA, CK-18↑; Wnt3α, β-catenin↓	Down-regulate Wnt/β-catenin signaling pathway
Zuoguiwan^[95]	Wnt1, EGF, FGF2, FGF16, MAPKK1, E2F, CSF3, Myd88, sFRP1, sFRP5, CSF2R, CNTFR, caspase12↑; MAPK9, Rac1, GSK3, Wnt10a, IL12a, Akt2, Activin AR, PKCγ↓	Affect Wnt, MAPK, TGF-β, Jak-STAT and Toll-like receptor signaling pathways
Biejiajian Pills^[96]	ALB↑; ALT, AST, TBIL, SDF-1↓	Act on SDF-1/CRCX4
Ruanganjian^[97]	ALB↑; ALT, AST↓	Improve the content of albumin in plasma

骨髓间充质干细胞改善肝纤维化机制的研究进展

PDF下载

丁翼 , 罗晓敏 , 杨斌 , 张博宇 , 顾健 ^* , 袁志翔 ^*

药学学报 | 综述 2022,57(4): 863-874

收起

药学学报 | 综述 2022, 57(4): 863-874

骨髓间充质干细胞改善肝纤维化机制的研究进展

全屏

丁翼, 罗晓敏, 杨斌, 张博宇, 顾健^*, 袁志翔^*

作者信息

西南民族大学药学院, 四川成都 610041

通讯作者:

*顾健, Tel: 86-28-85656463, E-mail: gujiancd@163.com;

袁志翔, Tel: 86-28-85656463, E-mail: Zhixiang-yuan@hotmail.com

Research progress on the mechanism of bone marrow mesenchymal stem cells in improving liver fibrosis

Yi DING, Xiao-min LUO, Bin YANG, Bo-yu ZHANG, Jian GU^*, Zhi-xiang YUAN^*

Affiliations

College of Pharmacy, Southwest Minzu University, Chengdu 610041, China

出版时间: 2022-04-12 doi: 10.16438/j.0513-4870.2021-1220

文章导航

摘要

收起

肝纤维化以肝脏组织瘢痕为特征, 是慢性肝脏疾病发展为肝癌的中间病理过程, 发生机制涉及多种信号通路, 其逆转性是目前的研究热点。骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs) 是一种具有多向分化潜能的成体干细胞, 在体内和体外均具备分化为肝样细胞, 发挥正常肝细胞功能的能力。现代药理实验研究表明, 单独使用BMSCs或联合活性因子、中药或中药单体、基因修饰等方式可以促进其增殖、分化、迁移, 提高治疗效果, 发挥改善肝纤维化的作用。通过归纳总结现有文献, 从肝纤维化发病机制、肝纤维化改善机制、BMSCs生物学特性及其改善机制等方面对BMSCs改善肝纤维化疗效机制进行综述, 为后期发展BMSCs细胞疗法提供参考。

关键词

肝纤维化 / 改善机制 / 骨髓间充质干细胞 / 联合治疗 / 作用机制研究 / 应用前景

Abstract

收起

Liver fibrosis is characterized by scarring of liver tissue, which is an intermediate pathological process of chronic liver disease developing into liver cancer. Its mechanism involves multiple signal pathways, and its reversibility is a current research hotspot. Bone marrow mesenchymal stem cells (BMSCs) are adult stem cells with multi-differentiation potential. They have ability to differentiate into liver-like cells in vivo and in vitro to perform normal liver cell functions. Modern pharmacological experimental studies have shown that the use of BMSCs alone or in combination with active factors, Chinese medicine or Chinese medicine monomers, genetic modification and other methods can promote their proliferation, differentiation, and migration, improve the therapeutic effect, and play a role in improving liver fibrosis. By summarizing the existing literature, the therapeutic mechanism of BMSCs in improving liver fibrosis is reviewed from the aspects of the pathogenesis of liver fibrosis, the improvement mechanism of liver fibrosis, the biological characteristics of BMSCs and its improvement mechanism, so as to provide reference for the later development of BMSCs cell therapy.

Key words

liver fibrosis / improvement mechanism / bone marrow mesenchymal stem cell / combination therapy / mechanism study / application prospect

引用本文

丁翼, 罗晓敏, 杨斌, 张博宇, 顾健, 袁志翔. 骨髓间充质干细胞改善肝纤维化机制的研究进展. 药学学报, 2022 , 57 (4) : 863 -874 . DOI: 10.16438/j.0513-4870.2021-1220

Yi DING, Xiao-min LUO, Bin YANG, Bo-yu ZHANG, Jian GU, Zhi-xiang YUAN. Research progress on the mechanism of bone marrow mesenchymal stem cells in improving liver fibrosis[J]. Acta Pharmaceutica Sinica, 2022 , 57 (4) : 863 -874 . DOI: 10.16438/j.0513-4870.2021-1220

正文

收起

外界因素如酒精^[1]、四氯化碳^[2] (carbon tetrachloride, CCl₄)、高脂饮食^[3]等多种致病因素会导致肝脏慢性炎症, 进而发展成肝脏损伤的另外一种形式, 即肝纤维化(hepatic fibrosis, HF)。肝纤维化是一种可逆的病理生理过程^[4], 是慢性肝病发展为肝硬化肝癌的必要途径, 其基本特征是细胞外基质(extracellular matrix, ECM) 过度、异常沉积^{[5, 6]}。肝纤维化最终会发展为肝硬化等晚期肝病。鉴于现有医疗手段, 肝移植是治疗晚期肝病的唯一可行治疗手段, 但因价格昂贵、供体资源稀缺、移植存在排斥反应等, 很难成为高效的治疗手段^[7], 因此, 寻找另外一种有效且高效的方法用于治疗晚期肝病十分有意义。

间充质干细胞(mesenchymal stem cells, MSCs) 是干细胞家族中重要一员, MSCs作为一种治疗疾病手段具有增殖、自我更新和免疫原性低, 可进行异体移植^[8]。在骨髓中被发现分离的MSCs, 被称为骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)。BMSCs是一类具有自我更新和多向分化潜能的成体干细胞, 可分化为脂肪细胞、软骨细胞和成骨细胞^[9]。因其特有的优势, 如增殖分化、免疫调节功能、分泌多种因子等^[10], 在基础实验和临床研究中, BMSCs治疗不同外界因素导致的肝纤维化是研究热点, 其治疗机制也一直被深入研究。本文就BMSCs改善肝纤维化机制的研究进行综述。

1 肝纤维化成因

收起

肝纤维化的成因复杂, 涉及多方面的因子和细胞因素。在外界不利因素的影响下, 肝实质细胞发生损伤和凋亡, 同时炎性细胞向损伤区聚集, 释放趋化因子, 引起肝星状细胞(hepatic stellate cells, HSC) 激活, 激活的HSC通过增生和分泌细胞外基质参与肝纤维化的形成和肝内结构的重建, 通过分泌促进纤维细胞、成纤维细胞和骨髓衍生的髓纤维细胞来产生胶原蛋白, 奠定肝纤维化病理学的基础^[11] (图 1)。以下从因子、氧化应激等方面介绍肝纤维化成因机制及改善肝纤维化机制。

1.1 转化生长因子-β1 (transforming growth factor-β1, TGF-β1)

在肝纤维化的形成过程中, TGF-β1是HSC的关键活化剂, 也是致肝纤维化的重要细胞因子之一。在正常HSC中, TGF-β1几乎不表达。当肝损伤时, Kupffer细胞、肝窦内皮细胞和肝细胞分泌TGF-β1^{[12, 13]}, TGF-β1上调与ECM合成相关的细胞受体, 增强了ECM组分表达^[14], 促进产生肝纤维化。TGF-β1介导的信号通路抑制HSC的凋亡, 诱导其合成产生过量的基质蛋白, 影响基质降解蛋白酶的产生并上调蛋白酶抑制剂, 促进ECM的产生并抑制其降解^[15]。Smad蛋白(Smad proteins, Smad) 家族是TGF-β1下游的关键信号转导分子, TGF-β1/Smad信号通路在肝纤维化发展过程中发挥重要作用^[16]。TGF-β1通过与TGF-β受体II (TGF-β receptor II, TβRII) 结合来引发细胞内信号传导, 激活TGF-β受体型I (TGF-β receptor I, TβRI) 激酶, 导致Smad2和Smad3的磷酸化^[15]。此外, TGF-β1激活丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)、核因子κB (nuclear factor-κB, NF-κB) 和磷脂酰肌醇-3-激酶(phosphoinositide 3-kinase, PI3K) 通路使HSC活化造成肝纤维化。因此, 阻断TGF-β1的表达是抑制肝纤维化的重要途径。

1.2 血小板衍生生长因子(platelet-derived growth factor, PDGF)

PDGF与HSC的增殖、分化、迁移有关^[17], 促进胶原蛋白的产生和沉积, 并将HSC转化为肌纤维细胞。正常生理情况下, PDGF在血小板α-粒子中表达, 当肝脏受损时, PDGF在受损内皮细胞、HSC中高度表达。血小板衍生生长因子受体(platelet-derived growth factor receptor, PDGFR) 是PDGF蛋白质家族的受体, 属于酪胺酸激酶受体的一种, 主要位于血管内皮细胞、成纤维细胞和Kupffer细胞^[18]。PDGF激活HSC并活化细胞膜上的PDGFR, 使PDGFR增加, 增强细胞趋化性, 参与ECM的生成^[19]。PDGFR与配体结合后使受体各亚单位二聚化, 酪氨酸激酶区活化, 受体自身磷酸化, 引起不同信号转导通路级联反应的发生。PDGFR通路的激活涉及关键下游信号通路, 如肾素血管紧张素系统(renin-angiotensin-system, RAS) 途径和PI3K途径。通过抑制PDGF的表达能够在一定程度上减缓肝纤维化的发展进程。

1.3 缺氧诱导因子-1α (hypoxia inducible factor 1α, HIF-1α)

HIF-1α是缺氧诱导因子-1 (hypoxia inducible factor 1, HIF-1) 的组成部分, 在正常氧浓度下其含量极低^[20], 在缺氧状态下, HIF-1α降解受阻, 在细胞内堆积, 堆积的HIF-1α易位到细胞核内, 与核内的含β亚基的HIF-1结合, 形成二聚体, 进而与缺氧反应元件(hypoxia-responsive elements, HRE) 相结合, 促进产生多种蛋白质, 调节机体以适应缺氧环境^[21]。已有实验证明, HIF-1α与肝损伤密切相关^[22-27]。细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK) 是一类丝/苏氨酸蛋白激酶, ERK/HIF-1α信号通路被认为在进行性纤维化的发生中起重要作用。有研究表明HIF-1α可能至少部分通过ERK通路促进肝纤维化, 这可能与抑制ERK通路来抑制HIF-1α活性或HIF-1α易位有关^[28]。雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 参与细胞生长和增殖^[29], HIF-1α活性升高会使mTOR的表达量增加, 表明HIF-1α/mTOR信号通路在肝纤维化发生和发展中起重要作用^[30]。因此, 通过阻断ERK/HIF-1α、HIF-1α/mTOR信号通路及抑制HIF-1α的表达来减轻肝纤维化具有可行性。

1.4 氧化应激

氧化应激(oxidative stress, OS) 是指体内氧化与抗氧化作用失衡的一种状态, 偏向于氧化状态, 导致中性粒细胞炎性浸润, 蛋白酶分泌增加, 大量氧化中间产物生成。在慢性肝损伤的过程中, 脂质过氧化是诱发肝纤维化的重要因素之一, 脂质过氧化会使丙二醛(malondialdehyde, MDA) 含量升高, 刺激Kupffer细胞产生相关因子, 诱导肝细胞凋亡坏死, 胶原生成, 促进肝纤维化发展^[31-34]。活性氧(reactive oxygen species, ROS) 是体内一类氧的单电子还原产物, 其来源途径之一是线粒体。肝脏中富含大量线粒体, 当肝脏受损时, 酶活性降低, 产生的ROS大量堆积, 难以清除。ROS攻击细胞膜脂上的多不饱和脂肪酸, 诱导肝细胞产生MDA, 直接破坏组织细胞中的脂质分子、蛋白质及DNA, 进而发生脂质过氧化, 引起肝细胞的凋亡和其他生理病理反应, 这些与TGF-β、MAPK、PI3K、核因子E2相关因子2/血红素加氧酶-1 (nuclear factor E2 related factor 2/heme oxygenase-1, Nrf2/HO-1) 信号通路有关^[35-43]。

2 肝纤维化改善机制

收起

2.1 抑制HSC活化

HSC的活化受到肝实质细胞和非实质细胞相互作用、细胞质基质组成成分和整合素介导相互作用的影响, 活化HSC具有增殖、收缩、炎症和趋化作用^{[44, 45]}。TGF-β1是促使HSC活化、增殖的关键细胞因子, 被认为是最有效的纤维化因子之一。TGF-β1促进并维持胶原蛋白基因在自分泌环中的表达, 上调组织金属蛋白酶抑制剂(tissue inhibitor of matrix metalloproteinases, TIMPs) 表达^[46], TGF-β/Smad信号通路在肝纤维化发展过程中起着重要作用^[16]。miRNA是真核生物体中约有22个核苷酸的内源非编码小RNA, 参与细胞的存活、增殖、自噬和凋亡等过程^{[47, 48]}。阻断β受体后miRNA-200a过表达, α-平滑肌肌动蛋白(alpha-smooth muscle actin, α-SMA) 的表达水平下调, HSC上皮-间质转化(epithelial-mesenchymal transition, EMT) 过程受到抑制^[49]。通过抑制HSC活化相关基因表达和通路传导, 达到抑制HSC活化的目的, 能够改善肝纤维化。

2.2 抑制炎症反应

发生炎症时, 多种介质会损伤肝窦和血管内皮稳态, 引起肝脏微血栓形成, 促使肝细胞变性坏死, 受损肝细胞会分泌更多的炎性细胞因子, 诱发HSC活化, 促进肝纤维化发展^[50]。脂多糖(lipopolysaccharide, LPS) 攻击肝脏, 激活Kupffer细胞和HSC, 释放一系列炎性因子, 使肝组织中白介素-1 (interleukin-1, IL-1)、IL-6、肿瘤坏死因子α (tumor necrosis factor α, TNF-α) 明显升高, Ⅰ型胶原表达合成升高, 炎症因子启动炎症的级联反应, 导致肝组织炎症反应和肝纤维化发展^[51]。炎症因子分泌增加, 能够促进肝纤维化的发生, 反之, 肝纤维化发展受到抑制^{[52, 53]}。因此, 通过抑制炎症反应能够减缓肝纤维化的进展, 达到抵抗肝纤维化的作用。

2.3 促进HSC凋亡

凋亡是细胞程序性死亡的一种形式, 活化的HSC可以通过凋亡来减少^[54]。肝纤维化的逆转伴随着炎症微环境的消退和活化的HSC数量的减少。活化的HSC会激活NF-κB通路, 使抗凋亡蛋白如B淋巴细胞瘤-2基因(B-cell lymphoma-2, Bcl-2) 的表达增强, 诱导其分泌来抵抗HSC凋亡^[55]。阻断NF-κB通路可能促进HSC凋亡, 减缓或减轻肝纤维化程度。自然杀伤细胞(natural killer cell, NK) 能够直接杀死活化的HSC并产生干扰素-γ (interferon gamma, IFN-γ) 促进该行为, 在抑制肝纤维化方面发挥作用^[56]。因此, 通过促进HSC的凋亡能够直接减少活化的HSC数量, 抑制肝纤维化的发展。

2.4 调节胶原蛋白代谢

肝纤维化的特征是ECM的异常沉积, 胶原蛋白是ECM的主要成分之一^[5]。ECM的稳态是依靠基质金属蛋白酶(matrix metalloproteinases, MMPs) 和TIMPs的调控。TIMP-1可以抑制胶原酶的生物活性, 导致胶原沉积。抑制肝脏组织中TIMP-1和Ⅰ型胶原的表达, 重建MMP-2/TIMP-2和MMP-9/TIMP-1的平衡, 可以减轻肝纤维化程度, 这提示促进胶原降解和抑制胶原表达能够改善肝纤维化^{[57, 58]}。调节胶原蛋白的代谢, 可能成为抗肝纤维化的一个策略。

3 BMSCs生物学特性及改善肝纤维化机制

收起

3.1 MSCs生物学特性

MSCs是一类具有自我更新和多向分化潜能的成体干细胞。MSCs可以从骨髓、脂肪、牙髓、外周血等组织中获取。国际细胞治疗学会提出了以下定义MSCs的最低标准: ①贴壁生长; ②存在特定的细胞表面抗原标记物CD73、CD90、CD105, 同时不存在CD14、CD34、CD45和人类白细胞DR抗原(human leukocyte antigen DR, HLA-DR) 等其他标记物; ③在体外有分化为脂肪细胞、软骨细胞和成骨细胞的能力。BMSCs是从骨髓中提取分离的, 其具有增殖分化能力强、免疫原性低、免疫调节和易获取等特点^[59]。已有研究证明, BMSCs分化的肝细胞能够代替受损肝细胞并发挥作用, 分化过程中, BMSCs会分泌多种细胞因子, 发挥旁分泌作用。此外, 移植的BMSCs会降低氧化应激水平, 抑制HSC活化和促进HSC凋亡^[60-62]。BMSCs凭借其特点优势和功能优势, 可能成为治疗肝纤维化的最有前途的候选细胞之一。

3.2 BMSCs改善肝纤维化机制

3.2.1 BMSCs归巢机制

干细胞与周围相邻的细胞、ECM以及多种细胞因子等构成微环境, 称为“干细胞巢” (niche), niche为干细胞提供养分, 决定干细胞分化方向, 指导干细胞行动。MSCs归巢可定义为: MSCs在目标组织的脉管系统里被捕获, 随后跨越血管内皮细胞迁移至目标组织的过程^[63]。微环境的改变是使BMSCs发生归巢行为的重要因素之一。当机体组织受损, 组织会释放各种趋化因子、黏附因子以及生长因子等各种信号因子, 吸引内源性或外源性的BMSCs向受损的组织部位迁移且定向分布, 优势分布。趋化因子是一类小分子分泌蛋白, 能够趋化反应细胞发生迁移, 而趋化因子受体能够介导趋化因子的行动。一般而言, 趋化受体能够感受到外部环境中趋化因子浓度改变的信号, 并引导细胞向趋化因子浓度高的地方迁移^[64]。基质衍生因子1α (stromal cell-derived factor 1α, SDF-1α) 是一种由骨髓内皮细胞和基质细胞表达的特异性趋化因子家族的化学引诱蛋白, 特异性趋化因子受体4 (CXC chemokine receptor 4, CXCR4) 是BMSCs的一种受体且能与SDF-1α结合。大量研究表明, SDF-1α/CXCR4轴在干细胞归巢、趋化、黏附因子表达、移植、增殖和存活等方面发挥重要作用^{[65, 66]}。当机体损伤, SDF-1α在损伤部位产生, 其浓度会高于骨髓处, 同时CXCR4表达增强, 促进骨髓处的MSCs迁移至损伤处^[67]。但是, 归巢的具体机制尚不明确, 现认为某些特定的信号分子与细胞膜上的相应受体结合, 共同驱动其归巢行为。

3.2.2 BMSCs旁分泌机制及细胞-细胞接触

BMSCs的生物学特性使其具有异体移植的可能性, 归巢行为使其可能具有定向增殖分化的能力, 这提示BMSCs能够迁移至受损组织并分化为局部成分, BMSCs移植可能成为一种新型的治疗方式。

BMSCs可以通过多种途径改善肝纤维化。一方面, BMSCs可以通过减少炎症反应、胶原沉积以及重塑受损肝细胞来修复肝纤维化^[68]。另一方面, BMSCs会分泌多种可溶性因子如TNF-3α、IL-10、肝细胞生长因子(hepatocyte growth factor, HGF), 抑制胶原合成, 诱导HSC凋亡^[69] (图 2)。一般来说, MMPs和TIMP分别对肝纤维化起着抑制与促进作用。尾静脉注射BMSCs于肝纤维化小鼠体内, 使肝脏胶原蛋白和组织脂质过氧化降低, 上调MMP-9和MMP-13的表达, 下调TIMP-1的表达^[70]。荧光标记BMSCs可以明显观察到受损肝组织中显现荧光, 血清中转氨酶活性降低^[71]。BMSCs可以通过影响MMPs的表达来减少胶原沉积, 减轻肝纤维化。BMSCs激活Nrf2/HO-1, 抑制了MDA、NF-κB p65和炎性细胞因子的产生, 增强了抗氧化剂的表达, 抑制氧化应激, 减少炎症反应进而阻碍肝纤维化的发展^[72]。MSCs通过旁分泌机制和细胞-细胞接触机制调节HSC活化和凋亡, 可溶性因子对肝细胞具有抗凋亡和促进分裂作用。共培养下的BMSCs能够直接抑制HSC活化能力, 减少ECM沉积^[73], 全身灌注MSCs培养基能够抑制体内肝细胞死亡, 增强肝再生能力^[74], 调节HSC活性的机制与TNF-α、IL-10、HGF的分泌有关, 其中TNF-α和IL-10在抑制胶原产生和HSC增殖方面可能具有协同作用^[75]。另有研究发现, MSC分泌的神经生长因子(nerve growth factor, NGF) 能够促进HSC凋亡, NF-κB Bcl-xl参与了此过程^[76]。细胞-细胞接触能够直接影响HSC, 共培养体系下, BMSCs部分通过Notch通路激活介导的细胞-细胞接触模式, 显著抑制HSC增殖, 并下调α-SMA表达^[77]。BMSCs分泌HGF并介导Toll样受体4 (Toll-like receptor 4, TLR4)/骨髓分化因子88 (myeloid differentiation factor 88, MyD88)/NF-κB信号通路来影响细胞-细胞接触, 从而抑制HSC的增殖和活化^[78]。总的来说, BMSCs能够改善肝纤维化主要归因于其归巢机制、具备多向分化潜能以及分泌多种影响周围组织的活性因子。

虽然目前BMSCs在临床上改善肝纤维化的研究还未大范围普及, 但是已有部分学者进行了肝硬化相关临床研究。兹通过https://clinicaltrials.gov/网站收集BMSCs治疗肝硬化的相关临床研究(表 1)。这类临床研究收治不同年龄段的患者进行长期治疗, 在治疗结束后检测生理病理指标变化, 评估BMSCs的安全性和有效性。中山大学学者针对乙型肝炎病毒(hepatitis B virus, HBV) 相关的早中期肝硬化(NCT00993941) 和慢性HBV肝硬化(NCT01223664) 分别进行BMSCs自体移植和同种异体移植, 观察临床症状改变, 评估Child-Pugh得分以及考察肝功能。对于BMSCs移植的安全性和有效性研究, 空军军医大学学者对HBV相关肝硬化患者通过肝动脉自体移植BMSCs, 治疗一年后评价患者存活率(NCT01724697)。南京解放军总医院学者收治难治性腹水肝硬化患者, 并对其进行肝动脉自体移植BMSCs, 治疗周期结束后检测肝功能、腹水变化和Child-Pugh评分(NCT01854125)。

4 BMSCs联合用药改善肝纤维化

收起

作为一种新型的治疗方式, 已有文献^[79-81]报道BMSCs联合活性因子、中药或中药单体、基因修饰等方式能够改善肝脏指标, 改善肝纤维化。

4.1 BMSCs联合活性因子改善肝纤维化

有多种细胞生长因子对BMSCs向肝细胞分化有一定的影响。其中HGF、成纤维细胞生长因子(fibroblast growth factor, FGF) 已在体外实验被证明能够诱导BMSCs向肝细胞的分化, 分化得到的肝细胞能够表达肝脏特异性标志物白蛋白(albumin, Alb)、角蛋白18 (keratin-18, CK-18), 行使肝细胞糖原储存、尿素产生等功能^[82-84]。HGF能够促进细胞迁移、增殖, 调控干细胞不同生物反应, 同时在肝脏的发育与再生过程中起着重要作用。将BMSCs短期暴露于HGF中可以诱导Met受体(一种具有细胞内酪氨酸激酶结构域的跨膜蛋白) 和下游效应子ERK1/2、p38MAPK和PI3K/Akt的激活, 而K252A酪氨酸激酶抑制剂可抑制HGF的诱导反应^[85]。FGF可由内皮细胞分泌, 促进新血管形成, 修复受损的内皮细胞。在一项探究细胞因子对BMSCs分化的研究中, FGF能够诱导BMSCs向肝细胞分化, 并从内胚层模式的初始阶段起作用^[86]。体外加入细胞因子来模拟因子分泌影响BMSCs向肝样细胞分化, 提示联合细胞因子有利于BMSCs向肝细胞分化, 有助于治疗肝纤维化。但各种因子的加入顺序可能会影响分化效果, 需要进一步探究。

4.2 BMSCs联合中药改善肝纤维化

目前中药广泛用于肝脏疾病的临床治疗, 具有毒副作用小、不良反应少以及改善患者症状等特点, 中医药的经络、活血、行气等在治疗肝脏疾病方面具有潜在的靶向作用^[87]。BMSCs结合中医药或许能够为治疗肝纤维化提供新思路。BMSCs的增殖效率对改善肝纤维化有着重要作用, 而有些中药及其提取物能够促进其增殖。黄芪中的黄芪甲苷^[88]和黄芪多糖^[89]均能对BMSCs的增殖起促进作用, 可能机制与其促进BMSCs对干细胞因子(stem cell factor, SCF)、血管内皮生长因子(vascular endothelial growth factor, VEGF)、SDF-1 mRNA表达有关。中药提取物也可以提高BMSCs的抗凋亡能力, 提高其存活率。淫羊藿苷能够显著上调HGF水平, 并通过上调HGF/c-Met通路, 在BMSCs抗凋亡活性中起到关键作用^[90]。通过促进BMSCs的增殖可以进一步提高向肝细胞分化的成功率。在虫草多糖体外诱导BMSCs分化研究中, 虫草多糖组甲胎蛋白(alpha fetoprotein, AFP)、Alb、CK-18表达增加, 糖原染色呈阳性, 表明虫草多糖成功诱导BMSCs向肝样细胞分化^[91]。20 µmol·L^-1姜黄素能够单独诱导BMSCs向肝细胞分化, 与FGF-4联合使用不仅可以降低姜黄素诱导浓度, 降低毒性, 还能提高诱导分化效率^[92]。大黄提取物能促进BMSCs的增殖分化为正常肝细胞, 其中的微量物质可能促进肝细胞分泌活性物质及生长因子, 促进肝细胞的再生和修复^[93]。此外, BMSCs联合中药复方也能促进其增殖分化为肝样细胞, 达到改善肝纤维化的目的。表 2^[94-97]总结了部分中药复方联合BMSCs改善肝纤维化的药理作用及机制研究。

4.3 基因修饰BMSCs改善肝脏指标

BMSCs同时也是理想的基因治疗细胞载体, 易被腺病毒、慢病毒、腺相关病毒以及逆转录病毒转染, 修饰后的BMSCs不仅能提高其归巢增殖分化的能力, 还能表达目的基因, 在组织再生、器官损伤修复和免疫调节等方面改善BMSCs功能^[98], 使二者具有协同作用。SDF-1α/CXCR4轴参与MSCs的募集过程, 在MSCs归巢、趋化因子表达等方面有着重要作用, 趋化因子的表达有助于MSCs的归巢^{[65, 66, 99]}。CXCR4修饰的人源骨髓MSCs (CXCR4-MSCs) 能够显著升高SDF-1α浓度并保持在相对稳定的水平, 在肝脏中能够检测到强烈的标记MSCs的荧光信号而在脾脏中不能检测到荧光信号, 这表明CXCR4-MSCs大量准确地迁移至受损肝脏, CXCR4促进MSCs的归巢效应, 改善肝功能^[100]。TGF-β1是致肝纤维化的关键因素, 而Smad7是TGF-β1/Smad信号通路的负调节因子。采用慢病毒转染的方式成功构建能够稳定表达Smad7和增强型绿色荧光蛋白(enhanced green fluorescent protein, EGFP) 的BMSCs (Smad7-EGFP-BMSCs), 在与HSC共培养体系中, Smad7-EGFP-BMSCs促进HSC的早期凋亡, Smad7和MMP-1的mRNA水平和蛋白水平明显增加, TGF-β1、Smad2、Smad3和TIMP-1的mRNA水平和蛋白水平降低, 此外, α-SMA、Ⅰ型胶原(type Ⅰ collagen, Col Ⅰ) 和Ⅲ型胶原(type Ⅲ collagen, Col Ⅲ) 表达降低。Smad7-EGFP-BMSCs影响肝纤维化相关蛋白表达, 可能通过调节TGF-β1/Smad信号通路抑制HSCs的纤维化^[101]。HGF是一种成纤维细胞、内皮细胞等间质细胞分泌的多功能细胞因子, 具有促进血管生成、修复受损组织以及抗纤维化的作用^[102-104]。在大鼠肝纤维化模型中, HGF-BMSCs即基因修饰表达HGF的BMSCs, 通过调节HSC活性、促进大鼠内源性HGF表达, 并抑制TGF-β1表达来减少活体肝移植胶原沉积, 这提示HGF-BMSCs治疗可能成为一种预防活体肝移植致肝纤维化的新策略^[105]。此外, 移植的HGF-MSCs促进MMP-9、MMP-13、MMP-14的表达, 抑制TIMP-1的表达, 表明HGF-MSCs可能是治疗肝纤维化的一种新的有效工具^[106]。FGF能够调节细胞增殖、分化和迁移, 其中FGF-4是有丝分裂活性最高的FGF之一^{[107, 108]}。过表达FGF-4的BMSCs移植到肝硬化大鼠中, FGF-4能够在早期促进BMSCs定位于肝脏, 促进Jagged-1阳性干细胞增殖以及细胞核抗原(proliferating cell nuclear antigen, PCNA) 和上皮黏附分子(epithelial cell adhesion molecule, EpCAM) 的表达, 表明FGF-4转导的BMSCs可能通过移植的微环境促进肝脏再生^[109]。

5 新型载药系统: MSCs及其外泌体

收起

肝纤维化不加以控制很有可能发展为肝癌, MSCs可以作为一种载药系统治疗肝癌和其他癌症^[110]。癌症化疗的主要目的是将药物递送至肿瘤微环境, 在杀死癌细胞的同时毒性最低。BMSCs能够融入肿瘤组织中, 过表达TNF相关凋亡诱导配体(TNF-related apoptosis-inducing ligand, TRAIL) 的MSCs能够将产生的TRAIL递送至肿瘤组织中, 显著降低肿瘤生长^[111]。有研究发现, 在含紫杉醇的培养基中, BMSCs与紫杉醇相互整合且以时间依赖的方式缓慢释放, 使得BMSCs获得有效的抗肿瘤活性, 这种活性呈剂量依赖性, 能够减缓肿瘤的发生生长^[112]。但是, 载药MSCs在递送的过程中会对非靶向组织产生毒性, 导致其受损^[113], 因此, 药物浓度、载药量、细胞数量等有待进一步研究。由于MSCs载药能力有限, 研究人员将研究热点转移至MSC衍生的外泌体(MSC-exosomes, MSC-Exos)。MSC-Exos具有与MSCs相似的生物学功能, 但具有体积更小、可以穿透生物膜、免疫原性低等特点^[114]。在治疗方面, MSC-Exos能够抑制细胞凋亡、促进细胞再生、血管生成和组织修复、调节免疫和炎症反应^[115]。与MSCs相比, MSC-Exos具有其他独特的优势: ①外泌体易于收集, 多种MSCs都能分泌外泌体且分泌量大; ②外泌体体积小, 可以长期稳定储存; ③外泌体不会增殖, 在临床上不会致瘤, 安全性高于MSCs。葡萄糖调节蛋白/BiP (glucose regulated protein/BiP, GRP78) 在抗癌药物索拉非尼耐药的癌细胞中过表达, 在一项研究中, siGRP78修饰的MSC-Exos与索拉非尼结合, 靶向癌细胞中的GRP78并在体内体外抑制癌细胞的生长、侵袭和转移, 逆转癌细胞对索拉非尼的耐药性^[116]。目前, MSCs作为载体实现对肿瘤靶向治疗具有可行性, 但由于MSCs的局限性, 外泌体作为药物或基因载体更具有发展前景。总的来说, MSCs及其外泌体作为一种载药系统在临床治疗肿瘤方面具有很大的应用前景, 但需要大量的研究来阐述其治疗机制, 发挥治疗潜力。

6 讨论与展望

收起

肝纤维化作为由慢性肝病发展为肝癌的中间过程, 其可逆的特性成为抗肝纤维化、治疗肝脏疾病的研究热点。但目前临床并没有十分有效的手段来治疗肝纤维化。BMSCs自身具备分化为肝细胞潜能、免疫调节特性、分泌多种细胞因子以及抗氧化能力, 可能成为改善、治疗肝纤维化最有前途的细胞之一。除单独使用BMSCs治疗外, 也可以与各种活性因子、中药或中药单体以及基因修饰相结合使治疗更加有效。尽管已有不少体外和动物体内实验证实BMSCs能够分化为肝细胞, 并在一定程度上改善肝纤维化, 达到治疗的目的, 但是临床上对于BMSCs治疗肝纤维化的研究报道甚少。BMSCs疗法在应用于临床治疗肝纤维化之前, 需要解决以下问题来提高改善效果: ①改进移植方式。目前在动物实验中, 多采用门静脉注射、肝动脉注射、外周静脉注射、腹腔注射以及局部注射的方式移植BMSCs, 临床上移植方式包括门静脉注射、肝动脉注射和外周静脉注射。不同的移植方式对BMSCs的存活率和归巢率有着很大影响, 需要确定最佳的植入方式; ②提高归巢效率。移植的时间和数量影响MSCs的归巢效率, 早期细胞的归巢效率要好于经过培养的细胞, 原代MSC的归巢率可以达到55%~65%, 但培养24 h后归巢率仅有10%^[117]。由于原代MSCs数量少, 需要经过体外培养扩增, 以增加细胞数量, 但会使其归巢能力降低, 故需要寻找合适的辅助方法在获取大量干细胞的同时提高其归巢效率; ③明确其治疗肝纤维化机制。肝纤维化是多种内外因素共同作用下的疾病, 多种信号通路与肝纤维化相关; BMSCs能够分泌多种活性因子以完成增殖、分化、迁移等生理过程。明确分泌的活性因子与致肝纤维化信号通路之间的关联, 有助于提高治疗效果; ④降低致瘤性。由于MSCs能够产生广谱的细胞因子、趋化因子和生长因子, 因此被认为是可能促进肿瘤生长的关键细胞^{[118, 119]}。肿瘤衍生囊泡将蛋白质和核酸递送至MSCs, 并与MSCs表面受体相互作用, MSCs摄取蛋白质和核酸, 使自身分泌肿瘤生长所必需的因子。MSCs外泌体携带和传递mRNA、miRNA和蛋白质, 一方面直接作用于肿瘤细胞, 促进其生长, 另一方面改变肿瘤微环境中的非肿瘤细胞表型和功能特征, 增强其促肿瘤能力^[120]。在治疗方面可考虑通过分子或基因调节沉默肿瘤微环境中由MSCs介导的促肿瘤效应来降低致瘤性。此外, 目前BMSCs改善肝纤维化、肝硬化的临床试验研究面临受试患者少、受试区域小的问题、临床试验个体差异大、缺乏可比性以及可重复性差等重难点, 未来的临床研究需要加入大量的对照实验、双盲实验以及扩大受试范围, 不断探究BMSCs临床改善肝纤维化、肝硬化的潜力。综上, BMSCs改善肝纤维化作为一种新型细胞疗法, 展现出巨大的治疗潜力, 如能顺利解决上述问题, 其应用于临床必将发挥出前所未有的治疗能力, 让数以百万的肝病患者受益。

作者贡献: 丁翼、罗晓敏、杨斌、张博宇、顾健和袁志翔共同进行文献收集与阅读; 丁翼负责撰写; 顾健和袁志翔负责思路设计和文稿校审。

利益冲突: 所有作者均认可文章无相关利益冲突。

基金

收起

国家自然科学基金资助项目(82174083)
西南民族大学中央高校基本科研业务费专项资金优秀学生培养工程项目(2021NYYXS100)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

Furuya S, Chappell GA, Iwata Y, et al. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways[J]. Toxicol Appl Pharmacol, 2016, 310: 129-139.

https://doi.org/10.1016/j.taap.2016.09.011

[2]

Wang R, Song F, Li S, et al. Salvianolic acid A attenuates CCl₄-induced liver fibrosis by regulating the PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways[J]. Drug Des Devel Ther, 2019, 13: 1889-1900.

https://doi.org/10.2147/DDDT.S194787

[3]

Lin HY, Wang FS, Yang YL, et al. microRNA-29a suppresses CD36 to ameliorate high fat diet-induced steatohepatitis and liver fibrosis in mice[J]. Cells, 2019, 8: 1298.

https://doi.org/10.3390/cells8101298

[4]

Liu X, Wu Y, Yang Y, et al. Role of NLRC5 in progression and reversal of hepatic fibrosis[J]. Toxicol Appl Pharmacol, 2016, 294: 43-53.

https://doi.org/10.1016/j.taap.2016.01.012

[5]

Shan L, Liu Z, Ci L, et al. Research progress on the anti-hepatic fibrosis action and mechanism of natural products[J]. Int Immunopharmacol, 2019, 75: 105765.

https://doi.org/10.1016/j.intimp.2019.105765

[6]

Yang Y, Yang F, Wu X, et al. EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1[J]. Can J Physiol Pharmacol, 2016, 94: 498-507.

https://doi.org/10.1139/cjpp-2015-0437

[7]

Wang J, Cen P, Chen J, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure[J]. Stem Cell Res Ther, 2017, 8: 137.

https://doi.org/10.1186/s13287-017-0576-4

[8]

Gu J, Huang L, Zhang C, et al. Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial[J]. Stem Cell Res Ther, 2020, 11: 43.

https://doi.org/10.1186/s13287-019-1545-x

[9]

Ciuffreda MC, Malpasso G, Musarò P, et al. Protocols for in vitro differentiation of human mesenchymal stem cells into osteogenic, chondrogenic and adipogenic lineages[J]. Methods Mol Biol, 2016, 1416: 149-158.

[10]

Chu DT, Phuong TNT, Tien NLB, et al. An update on the progress of isolation, culture, storage, and clinical application of human bone marrow mesenchymal stem/stromal cells[J]. Int J Mol Sci, 2020, 21: 708.

https://doi.org/10.3390/ijms21030708

[11]

Zhang CY, Yuan WG, He P, et al. Liver fibrosis and hepatic stellate cells: etiology, pathological hallmarks and therapeutic targets[J]. World J Gastroenterol, 2016, 22: 10512-10522.

https://doi.org/10.3748/wjg.v22.i48.10512

[12]

Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis[J]. Annu Rev Pathol, 2011, 6: 425-456.

https://doi.org/10.1146/annurev-pathol-011110-130246

[13]

Li X, Wang Y, Wang H, et al. Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis[J]. Inflamm Res, 2015, 64: 1-7.

[14]

Mu M, Zuo S, Wu RM, et al. Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway[J]. Drug Des Devel Ther, 2018, 12: 4107-4115.

https://doi.org/10.2147/DDDT.S186726

[15]

Xu F, Liu C, Zhou D, et al. TGF-β/Smad pathway and its regulation in hepatic fibrosis[J]. J Histochem Cytochem, 2016, 64: 157-167.

https://doi.org/10.1369/0022155415627681

[16]

Yoshida K, Murata M, Yamaguchi T, et al. TGF-β/Smad signaling during hepatic fibro-carcinogenesis (review)[J]. Int J Oncol, 2014, 45: 1363-1371.

https://doi.org/10.3892/ijo.2014.2552

[17]

Kocabayoglu P, Lade A, Lee YA, et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis[J]. J Hepatol, 2015, 63: 141-147.

https://doi.org/10.1016/j.jhep.2015.01.036

[18]

Ying HZ, Chen Q, Zhang WY, et al. PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (review)[J]. Mol Med Rep, 2017, 16: 7879-7889.

https://doi.org/10.3892/mmr.2017.7641

[19]

Damanik FFR, Verkoelen N, van Blitterswijk C, et al. Control delivery of multiple growth factors to actively steer differentiation and extracellular matrix protein production[J]. Adv Biol, 2021, 5: e2000205.

https://doi.org/10.1002/adbi.202000205

[20]

Nath B, Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases[J]. Hepatology, 2012, 55: 622-633.

https://doi.org/10.1002/hep.25497

[21]

Zhan L, Huang C, Meng XM, et al. Hypoxia-inducible factor-1α in hepatic fibrosis: a promising therapeutic target[J]. Biochimie, 2015, 108: 1-7.

https://doi.org/10.1016/j.biochi.2014.10.013

[22]

Zhang F, Lu S, He J, et al. Ligand activation of PPARγ by ligustrazine suppresses pericyte functions of hepatic stellate cells via SMRT-mediated transrepression of HIF-1α[J]. Theranostics, 2018, 8: 610-626.

https://doi.org/10.7150/thno.22237

[23]

Han J, He Y, Zhao H, et al. Hypoxia inducible factor-1 promotes liver fibrosis in nonalcoholic fatty liver disease by activating PTEN/p65 signaling pathway[J]. J Cell Biochem, 2019, 120: 14735-14744.

https://doi.org/10.1002/jcb.28734

[24]

Lee TY, Leu YL, Wen CK. Modulation of HIF-1α and STAT3 signaling contributes to anti-angiogenic effect of YC-1 in mice with liver fibrosis[J]. Oncotarget, 2017, 8: 86206-86216.

https://doi.org/10.18632/oncotarget.21039

[25]

Moczydlowska J, Miltyk W, Hermanowicz A, et al. HIF-1α as a key factor in bile duct ligation-induced liver fibrosis in rats[J]. J Invest Surg, 2017, 30: 41-46.

https://doi.org/10.1080/08941939.2016.1183734

[26]

Cao F, Zhang Y, Li W, et al. Mogroside IVE attenuates experimental liver fibrosis in mice and inhibits HSC activation through downregulating TLR4-mediated pathways[J]. Int Immunopharmacol, 2018, 55: 183-192.

https://doi.org/10.1016/j.intimp.2017.12.023

[27]

Sparkenbaugh EM, Saini Y, Greenwood KK, et al. The role of hypoxia-inducible factor-1α in acetaminophen hepatotoxicity[J]. J Pharmacol Exp Ther, 2011, 338: 492-502.

https://doi.org/10.1124/jpet.111.180521

[28]

Zhao Y, Ma X, Wang J, et al. Curcumin protects against CCl₄-induced liver fibrosis in rats by inhibiting HIF-1α through an ERK-dependent pathway[J]. Molecules, 2014, 19: 18767-18780.

https://doi.org/10.3390/molecules191118767

[29]

Laplante M, Sabatini DM. mTOR signaling in growth control and disease[J]. Cell, 2012, 149: 274-293.

https://doi.org/10.1016/j.cell.2012.03.017

[30]

Zhao Y, Ma X, Wang J, et al. Paeoniflorin alleviates liver fibrosis by inhibiting HIF-1α through mTOR-dependent pathway[J]. Fitoterapia, 2014, 99: 318-327.

https://doi.org/10.1016/j.fitote.2014.10.009

[31]

Liu MX, Liu Y, Yang M, et al. Effects of pyrazinamide on lipid peroxidation in L02 cells[J]. Chin J Pharmacov (中国药物警戒), 2021 https://kns.cnki.net/kcms/detail/11.5219.R.20210601.0826.004.html

[32]

Feng JL, Shen HR, Li X, et al. Effect of Fangji Huangqi Decoction on liver mitochondrial per-oxidative injury in hepatic fibrosis mice induced by lipopolysaccharide and nitrosodimethylamine[J]. Tradit Chin Drug Res Clin Pharmacol (中药新药与临床药理), 2010, 21: 506-508. https://www.cnki.com.cn/Article/CJFDTOTAL-ZCYO202122007.htm

[33]

Luangmonkong T, Suriguga S, Mutsaers HAM, et al. Targeting oxidative stress for the treatment of liver fibrosis[J]. Rev Physiol Biochem Pharmacol, 2018, 175: 71-102.

[34]

Yang S, Zhou X, Xu FZ, et al. The role of Kupffer cell in acetaminophen-induced liver injury[J]. Chem Life (生命的化学), 2019, 39: 104-111. https://www.cnki.com.cn/Article/CJFDTOTAL-SMHX202102006.htm

[35]

Ezhilarasan D. Oxidative stress is bane in chronic liver diseases: clinical and experimental perspective[J]. Arab J Gastroenterol, 2018, 19: 56-64.

https://doi.org/10.1016/j.ajg.2018.03.002

[36]

Xu Y, Gao W, Zhang Y, et al. ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells[J]. Int J Oncol, 2018, 53: 1055-1068.

[37]

Dhar D, Baglieri J, Kisseleva T, et al. Mechanisms of liver fibrosis and its role in liver cancer[J]. Exp Biol Med (Maywood), 2020, 245: 96-108.

https://doi.org/10.1177/1535370219898141

[38]

Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling[J]. Cell Signal, 2012, 24: 981-990.

https://doi.org/10.1016/j.cellsig.2012.01.008

[39]

Wolin MS. Reactive oxygen species and the control of vascular function[J]. Am J Physiol Heart Circ Physiol, 2009, 296: H539-H549.

https://doi.org/10.1152/ajpheart.01167.2008

[40]

Singel KL, Segal BH. NOX2-dependent regulation of inflammation[J]. Clin Sci (Lond), 2016, 130: 479-490.

https://doi.org/10.1042/CS20150660

[41]

Qi S, Feng Z, Li Q, et al. Inhibition of ROS-mediated activation Src-MAPK/AKT signaling by orientin alleviates H₂O₂-induced apoptosis in PC12 cells[J]. Drug Des Devel Ther, 2018, 12: 3973-3984.

https://doi.org/10.2147/DDDT.S178217

[42]

Xiao Y, Wang J, Chen Y, et al. Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling[J]. Cell Signal, 2014, 26: 925-932.

https://doi.org/10.1016/j.cellsig.2014.01.003

[43]

Fang S, Cai Y, Li P, et al. Exendin-4 alleviates oxidative stress and liver fibrosis by activating Nrf2/HO-1 in streptozotocin-induced diabetic mice[J]. J South Med Univ (南方医科大学学报), 2019, 39: 464-470. https://www.cnki.com.cn/Article/CJFDTOTAL-HNYD201901013.htm

[44]

Mallat A, Lotersztajn S. Reversion of hepatic stellate cell to a quiescent phenotype: from myth to reality?[J]. J Hepatol, 2013, 59: 383-386.

https://doi.org/10.1016/j.jhep.2013.03.031

[45]

Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis[J]. Compr Physiol, 2013, 3: 1473-1492.

[46]

Huang Y, Deng X, Liang J. Modulation of hepatic stellate cells and reversibility of hepatic fibrosis[J]. Exp Cell Res, 2017, 352: 420-426.

https://doi.org/10.1016/j.yexcr.2017.02.038

[47]

Matsuyama H, Suzuki HI. Systems and synthetic microRNA biology: from biogenesis to disease pathogenesis[J]. Int J Mol Sci, 2019, 21: 132.

https://doi.org/10.3390/ijms21010132

[48]

Han S, Zhang T, Kusumanchi P, et al. Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications[J]. J Investig Med, 2020, 68: 1208-1216.

https://doi.org/10.1136/jim-2020-001420

[49]

El-Wakeel SA, Rahmo RM, El-Abhar HS. Anti-fibrotic impact of carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-β1/EMT track[J]. Sci Rep, 2018, 8: 14327.

https://doi.org/10.1038/s41598-018-32309-1

[50]

Gong PY, Yin KH, Li XD, et al. Clinical and pharmacological research progress of Tibetan medicine in prevention and treatment for hepatic fibrosis[J]. Acta Pharm Sin (药学学报), 2021, 56: 2995-3003. http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract18418.shtml

[51]

Sun L. The Role and Mechanism of Lipopolysaccharide on Rat Hepatic Stellate Cells-mediated Hepatic Fibrosis (LPS在大鼠肝星状细胞介导肝纤维化的作用及机制研究) [D]. Changchun: Jilin University, 2016.

[52]

Tian ZZ. Effect of LPS-TLR4 Pathway in Hepatic Fibrogenesis of Rats Fed Ethanol Liquid Diet (LPS-TLR4通路在慢性酒精摄入大鼠肝纤维化发生的作用) [D]. Changchun: Jilin University, 2014.

[53]

Li P, Yang ZT, Peng BC, et al. Effect of Phyllanthus emblica L. on immunity hepatic fibrosis in rats (Ⅰ)[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2010, 16: 171-173. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202001013.htm

[54]

Mallat A, Lotersztajn S. Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis[J]. Am J Physiol Cell Physiol, 2013, 305: C789-C799.

https://doi.org/10.1152/ajpcell.00230.2013

[55]

Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story[J]. Gut, 2015, 64: 830-841.

https://doi.org/10.1136/gutjnl-2014-306842

[56]

Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis[J]. Biochim Biophys Acta, 2013, 1832: 1061-1069.

https://doi.org/10.1016/j.bbadis.2012.09.008

[57]

Xue J, Peng YR, Huang YP, et al. Effect of Langqing Ata on meta-bolism of collagen in rat hepatic fibrosis model[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2012, 18: 260-265. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX201823022.htm

[58]

Ren JJ, Huang TJ, Zhang QQ, et al. Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice[J]. Hepatobiliary Pancreat Dis Int, 2019, 18: 38-47.

https://doi.org/10.1016/j.hbpd.2018.08.008

[59]

Fernández Vallone VB, Romaniuk MA, et al. Mesenchymal stem cells and their use in therapy: what has been achieved?[J]. Differen-tiation, 2013, 85: 1-10.

https://doi.org/10.1016/j.diff.2012.08.004

[60]

Charbord P. Bone marrow mesenchymal stem cells: historical overview and concepts[J]. Hum Gene Ther, 2010, 21: 1045-1056.

https://doi.org/10.1089/hum.2010.115

[61]

Nasir GA, Mohsin S, Khan M, et al. Mesenchymal stem cells and interleukin-6 attenuate liver fibrosis in mice[J]. J Transl Med, 2013, 11: 78.

https://doi.org/10.1186/1479-5876-11-78

[62]

Kuo TK, Hung SP, Chuang CH, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells[J]. Gastroenterology, 2008, 134: 2111-21, 2121. e1-3.

https://doi.org/10.1053/j.gastro.2008.03.015

[63]

Aithal AP, Bairy LK, Seetharam RN. Safety and therapeutic potential of human bone marrow-derived mesenchymal stromal cells in regenerative medicine[J]. Stem Cell Investig, 2021, 8: 10.

https://doi.org/10.21037/sci-2020-036

[64]

Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details[J]. Cell Stem Cell, 2009, 4: 206-216.

https://doi.org/10.1016/j.stem.2009.02.001

[65]

Hughes CE, Nibbs RJB. A guide to chemokines and their receptors[J]. FEBS J, 2018, 285: 2944-2971.

https://doi.org/10.1111/febs.14466

[66]

Wojakowski W, Tendera M, Michałowska A, et al. Mobilization of CD34/CXCR4⁺, CD34/CD117⁺, c-met⁺ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction[J]. Circulation, 2004, 110: 3213-3220.

https://doi.org/10.1161/01.CIR.0000147609.39780.02

[67]

Bowie MB, McKnight KD, Kent DG, et al. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect[J]. J Clin Invest, 2006, 116: 2808-2816.

https://doi.org/10.1172/JCI28310

[68]

Wang GD, Liu YX, Wang X, et al. The SDF-1/CXCR4 axis promotes recovery after spinal cord injury by mediating bone marrow-derived from mesenchymal stem cells[J]. Oncotarget, 2017, 8: 11629-11640.

https://doi.org/10.18632/oncotarget.14619

[69]

Fang B, Shi M, Liao L, et al. Systemic infusion of FLK1⁺ mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice[J]. Transplantation, 2004, 78: 83-88.

[70]

Wang J, Bian C, Liao L, et al. Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms[J]. Hepatol Res, 2009, 39: 1219-1228.

https://doi.org/10.1111/j.1872-034X.2009.00564.x

[71]

Yagi K, Kojima M, Oyagi S, et al. Application of mesenchymal stem cells to liver regenerative medicine[J]. Yakugaku Zasshi, 2008, 128: 3-9.

https://doi.org/10.1248/yakushi.128.3

[72]

Rabani V, Shahsavani M, Gharavi M, et al. Mesenchymal stem cell infusion therapy in a carbon tetrachloride-induced liver fibrosis model affects matrix metalloproteinase expression[J]. Cell Biol Int, 2010, 34: 601-605.

https://doi.org/10.1042/CBI20090386

[73]

Sitanggang EJ, Antarianto RD, Jusman SWA, et al. Bone marrow stem cells anti-liver fibrosis potency: inhibition of hepatic stellate cells activity and extracellular matrix deposition[J]. Int J Stem Cells, 2017, 10: 69-75.

https://doi.org/10.15283/ijsc16048

[74]

van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo[J]. Hepatology, 2008, 47: 1634-1643.

https://doi.org/10.1002/hep.22236

[75]

Berardis S, Dwisthi Sattwika P, Najimi M, et al. Use of mesenchymal stem cells to treat liver fibrosis: current situation and future prospects[J]. World J Gastroenterol, 2015, 21: 742-758.

https://doi.org/10.3748/wjg.v21.i3.742

[76]

Lin N, Hu K, Chen S, et al. Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells[J]. Life Sci, 2009, 85: 291-295.

https://doi.org/10.1016/j.lfs.2009.06.007

[77]

Chen S, Xu L, Lin N, et al. Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells[J]. Life Sci, 2011, 89: 975-981.

https://doi.org/10.1016/j.lfs.2011.10.012

[78]

Wang PP, Xie DY, Liang XJ, et al. HGF and direct mesenchymal stem cells contact synergize to inhibit hepatic stellate cells activation through TLR4/NF-κB pathway[J]. PLoS One, 2012, 7: e43408.

https://doi.org/10.1371/journal.pone.0043408

[79]

Hu C, Zhao L, Duan J, et al. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis[J]. J Cell Mol Med, 2019, 23: 1657-1670.

https://doi.org/10.1111/jcmm.14115

[80]

Dong S, Su SB. Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis[J]. J Integr Med, 2014, 12: 147-155.

https://doi.org/10.1016/S2095-4964(14)60022-4

[81]

Hu C, Zhao L, Li L. Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases[J]. J Mol Med (Berl), 2021, 99: 179-192.

https://doi.org/10.1007/s00109-020-02031-5

[82]

Khadrawy SM, Mohamed HM, Mahmoud AM. Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats[J]. Environ Sci Pollut Res Int, 2021, 28: 2019-2030.

https://doi.org/10.1007/s11356-020-10637-y

[83]

Snykers S, De Kock J, Vanhaecke T, et al. Differentiation of neonatal rat epithelial cells from biliary origin into immature hepatic cells by sequential exposure to hepatogenic cytokines and growth factors reflecting liver development[J]. Toxicol In Vitro, 2007, 21: 1325-1331.

https://doi.org/10.1016/j.tiv.2007.03.013

[84]

Snykers S, Vanhaecke T, Papeleu P, et al. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells[J]. Toxicol Sci, 2006, 94: 330-341;discussion 235-239. https://www.cnki.com.cn/Article/CJFDTOTAL-SJKF201904008.htm

[85]

Chivu M, Dima SO, Stancu CI, et al. In vitro hepatic differentiation of human bone marrow mesenchymal stem cells under differential exposure to liver-specific factors[J]. Transl Res, 2009, 154: 122-132.

https://doi.org/10.1016/j.trsl.2009.05.007

[86]

Forte G, Minieri M, Cossa P, et al. Hepatocyte growth factor effects on mesenchymal stem cells: proliferation, migration, and differentiation[J]. Stem Cells, 2006, 24: 23-33.

https://doi.org/10.1634/stemcells.2004-0176

[87]

Wang Y, Zhang H, Wang H. Progress of interference of traditional Chinese medicine on cirrhosis treated with bone marrow mesenchymal stem cells[J]. Evid Based Complement Alternat Med, 2021, 2021: 5569274.

[88]

Peng XJ, Bai H, Wang CB, et al. Effect of astragaloside IV on the proliferation and cell factor expression in hBMSC[J]. Prog Mod Biomed (现代生物医学进展), 2014, 14: 1452-1455. https://www.cnki.com.cn/Article/CJFDTOTAL-SWCX202104005.htm

[89]

Huang J, Zhang J, Xu ZW. Effect of astragalus polysaccharide on the proliferation of bone marrow mesenchymal stem cells and the expression of stem cell factor in vitro[J]. Fudan Univ J Med Sci (复旦学报(医学版)), 2011, 38: 343-348. https://www.cnki.com.cn/Article/CJFDTOTAL-GWZX201604018.htm

[90]

Wang L, Li S, Wang HY, et al. In a rat model of acute liver failure, icaritin improved the therapeutic effect of mesenchymal stem cells by activation of the hepatocyte growth factor/c-Met pathway[J]. Evid Based Complement Alternat Med, 2019, 2019: 4253846.

[91]

Liu JK, Song YF, Liu YZ, et al. Cordyceps polysaccharide induces differentiation of adult rat mesenchymal stem cells into a hepatocyte lineage in vitro[J]. Chin J Tissue Eng Res (中国组织工程研究), 2012, 16: 9221-9225. https://www.cnki.com.cn/Article/CJFDTOTAL-XDKF202101023.htm

[92]

Chen Y, Zou WJ, Wang SF, et al. Curcumin induces the differentiation of bone marrow mesenchymal stem cells into hepatocytes[J]. Chin Tradit Pat Med (中成药), 2014, 30: 1124-1128. https://www.cnki.com.cn/Article/CJFDTOTAL-ZCYA201812005.htm

[93]

Dan YE, Wang F. Analysis on the therapeutic effect of rhubarb extract in the model of rats with acute liver failure[J]. China Modern Doctor (中国现代医生), 2017, 55: 32-34, 169. https://www.cnki.com.cn/Article/CJFDTOTAL-GGYY201512007.htm

[94]

Ping J, Chen HY, Zhou Y. Effect of Yiguan Decoction on differentiation of bone marrow mesenchymal stem cells into hepatocytelike cells: an experimental research[J]. Chine J Integr Tradit West Med (中国中西医结合杂志), 2014, 34: 348-354. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZXJ201507015.htm

[95]

Li HM, Gui WJ, Li JJ, et al. Effects of Zuoguiwan on the liver regeneration related gene signaling pathway in female mice with male mice bone marrow transplant[J]. J Clin Rehabilit Tissue Eng Res (中国组织工程研究与临床康复), 2008, 12: 6069-6073. https://www.cnki.com.cn/Article/CJFDTOTAL-XDKF202106024.htm

[96]

Huang JJ, Huang HN, Wang ZC, et al. Effect of Biejiajian Pills interfering with SDF-1/CXCR4 signaling pathway on bone marrow mesenchymal stem cell transplantation in treatment of liver fibrosis[J]. Lishizhen Med Mater Med Res (时珍国医国药), 2018, 29: 1565-1567. https://www.cnki.com.cn/Article/CJFDTOTAL-SZGY202012015.htm

[97]

An WD. Differentiation of Induced MSCs In Vivo and In Vitro with Rats Hepatic Fibrogenesis Environment and the Effect of RGJ (骨髓间充质干细胞定向分化肝细胞并肝内移植及软肝煎应用对肝纤维化形成大鼠肝功能影响的研究) [D]. Dalian: Dalian Medical University, 2005.

[98]

Varkouhi AK, Monteiro APT, Tsoporis JN, et al. Genetically modified mesenchymal stromal/stem cells: application in critical illness[J]. Stem Cell Rev Rep, 2020, 16: 812-827.

https://doi.org/10.1007/s12015-020-10000-1

[99]

Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis[J]. Biomed Res Int, 2013, 2013: 561098.

[100]

Ma HC, Shi XL, Ren HZ, et al. Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration[J]. World J Gastroenterol, 2014, 20: 14884-14894.

https://doi.org/10.3748/wjg.v20.i40.14884

[101]

Wu SP, Yang Z, Li FR, et al. Smad7-overexpressing rat BMSCs inhibit the fibrosis of hepatic stellate cells by regulating the TGF-β1/Smad signaling pathway[J]. Exp Ther Med, 2017, 14: 2568-2576.

https://doi.org/10.3892/etm.2017.4836

[102]

Iekushi K, Taniyama Y, Kusunoki H, et al. Hepatocyte growth factor attenuates transforming growth factor-β-angiotensin II crosstalk through inhibition of the PTEN/Akt pathway[J]. Hypertension, 2011, 58: 190-196.

https://doi.org/10.1161/HYPERTENSIONAHA.111.173013

[103]

Nakamura T, Sakai K, Nakamura T, et al. Hepatocyte growth factor twenty years on: much more than a growth factor[J]. J Gastroenterol Hepatol, 2011, 26Suppl 1): 188-202. https://www.cnki.com.cn/Article/CJFDTOTAL-GGYY201505006.htm

[104]

Iekushi K, Taniyama Y, Azuma J, et al. Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts[J]. J Hypertens, 2010, 28: 2454-2461.

https://doi.org/10.1097/HJH.0b013e32833e4149

[105]

Yu Y, Lu L, Qian X, et al. Antifibrotic effect of hepatocyte growth factor-expressing mesenchymal stem cells in small-for-size liver transplant rats[J]. Stem Cells Dev, 2010, 19: 903-914.

https://doi.org/10.1089/scd.2009.0254

[106]

Kim MD, Kim SS, Cha HY, et al. Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis[J]. Exp Mol Med, 2014, 46: e110.

https://doi.org/10.1038/emm.2014.49

[107]

Kosaka N, Sakamoto H, Terada M, et al. Pleiotropic function of FGF-4: its role in development and stem cells[J]. Dev Dyn, 2009, 238: 265-276.

https://doi.org/10.1002/dvdy.21699

[108]

Choi SC, Kim SJ, Choi JH, et al. Fibroblast growth factor-2 and-4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways[J]. Stem Cells Dev, 2008, 17: 725-736.

https://doi.org/10.1089/scd.2007.0230

[109]

Wang J, Xu L, Chen Q, et al. Bone mesenchymal stem cells overexpressing FGF4 contribute to liver regeneration in an animal model of liver cirrhosis[J]. Int J Clin Exp Med, 2015, 8: 12774-12782.

[110]

Chang X, Ma Z, Zhu G, et al. New perspective into mesenchymal stem cells: molecular mechanisms regulating osteosarcoma[J]. J Bone Oncol, 2021, 29: 100372.

https://doi.org/10.1016/j.jbo.2021.100372

[111]

Loebinger MR, Eddaoudi A, Davies D, et al. Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer[J]. Cancer Res, 2009, 69: 4134-4142.

https://doi.org/10.1158/0008-5472.CAN-08-4698

[112]

Pessina A, Bonomi A, Coccè V, et al. Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy[J]. PLoS One, 2011, 6: e28321.

https://doi.org/10.1371/journal.pone.0028321

[113]

Krueger TEG, Thorek DLJ, Denmeade SR, et al. Mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise[J]. Stem Cells Transl Med, 2018, 7: 651-663.

https://doi.org/10.1002/sctm.18-0024

[114]

Nawaz M, Fatima F, Vallabhaneni KC, et al. Extracellular vesicles: evolving factors in stem cell biology[J]. Stem Cells Int, 2016, 2016: 1073140.

[115]

Baek G, Choi H, Kim Y, et al. Mesenchymal stem cell-derived extracellular vesicles as therapeutics and as a drug delivery platform[J]. Stem Cells Transl Med, 2019, 8: 880-886.

https://doi.org/10.1002/sctm.18-0226

[116]

Li H, Yang C, Shi Y, et al. Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma[J]. J Nanobiotechnology, 2018, 16: 103.

https://doi.org/10.1186/s12951-018-0429-z

[117]

Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture[J]. Leukemia, 2003, 17: 160-170.

https://doi.org/10.1038/sj.leu.2402763

[118]

Dostert G, Mesure B, Menu P, et al. How do mesenchymal stem cells influence or are influenced by microenvironment through extracellular vesicles communication?[J]. Front Cell Dev Biol, 2017, 5: 6.

[119]

Lopatina T, Gai C, Deregibus MC, et al. Cross talk between cancer and mesenchymal stem cells through extracellular vesicles carrying nucleic acids[J]. Front Oncol, 2016, 6: 125.

[120]

Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment[J]. Semin Immunol, 2018, 35: 69-79.

https://doi.org/10.1016/j.smim.2017.12.003

2022年第57卷第4期

PDF下载

158

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2021-1220

接收时间：2021-08-23
首发时间：2025-12-22
出版时间：2022-04-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2021-08-23
修回日期：2021-09-28

基金

国家自然科学基金资助项目(82174083)

西南民族大学中央高校基本科研业务费专项资金优秀学生培养工程项目(2021NYYXS100)

作者信息

西南民族大学药学院, 四川成都 610041

通讯作者:

*顾健, Tel: 86-28-85656463, E-mail: gujiancd@163.com;

袁志翔, Tel: 86-28-85656463, E-mail: Zhixiang-yuan@hotmail.com

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2021-1220

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Disease	BMSCs transplantation method	BMSCs transplantation route	Phase	ClinicalTrials.gov identifier
Early and middle stage of liver cirrhosis on the basis of HBV infection	Autologous BMSCs transplantation	Portal vein	Phase Ⅱ	NCT00993941
HBV-related liver cirrhosis	Autologous BMSCs transplantation	Hepatic artery	Phase Ⅰ/Ⅱ	NCT01724697
Liver cirrhosis resulting from chronic HBV	Allogenic BMSCs transplantation	Portal vein or hepatic artery	Phase Ⅱ	NCT01223664
Liver cirrhosis with refractory ascites	Autologous BMSCs transplantation	Liver artery	Phase Ⅲ	NCT01854125

Disease

BMSCs transplantation method

BMSCs transplantation route

Phase

ClinicalTrials.gov identifier

Early and middle stage of liver cirrhosis on the basis of HBV infection

Autologous BMSCs transplantation

Portal vein

Phase Ⅱ

NCT00993941

HBV-related liver cirrhosis

Autologous BMSCs transplantation

Hepatic artery

Phase Ⅰ/Ⅱ

NCT01724697

Liver cirrhosis resulting from chronic HBV

Allogenic BMSCs transplantation

Portal vein or hepatic artery

Phase Ⅱ

NCT01223664

Liver cirrhosis with refractory ascites

Autologous BMSCs transplantation

Liver artery

Phase Ⅲ

NCT01854125

Traditional Chinese formular	Change in related indicator	Possibly related mechanism or pathway
Yiguan Decoction^[94]	Alb, AFP, HNF4α mRNA, CK-18↑; Wnt3α, β-catenin↓	Down-regulate Wnt/β-catenin signaling pathway
Zuoguiwan^[95]	Wnt1, EGF, FGF2, FGF16, MAPKK1, E2F, CSF3, Myd88, sFRP1, sFRP5, CSF2R, CNTFR, caspase12↑; MAPK9, Rac1, GSK3, Wnt10a, IL12a, Akt2, Activin AR, PKCγ↓	Affect Wnt, MAPK, TGF-β, Jak-STAT and Toll-like receptor signaling pathways
Biejiajian Pills^[96]	ALB↑; ALT, AST, TBIL, SDF-1↓	Act on SDF-1/CRCX4
Ruanganjian^[97]	ALB↑; ALT, AST↓	Improve the content of albumin in plasma

Traditional Chinese formular

Change in related indicator

Possibly related mechanism or pathway

Yiguan Decoction^[94]

Alb, AFP, HNF4α mRNA, CK-18↑; Wnt3α, β-catenin↓

Down-regulate Wnt/β-catenin signaling pathway

Zuoguiwan^[95]

Wnt1, EGF, FGF2, FGF16, MAPKK1, E2F, CSF3, Myd88, sFRP1, sFRP5, CSF2R, CNTFR, caspase12↑; MAPK9, Rac1, GSK3, Wnt10a, IL12a, Akt2, Activin AR, PKCγ↓

Affect Wnt, MAPK, TGF-β, Jak-STAT and Toll-like receptor signaling pathways

Biejiajian Pills^[96]

ALB↑; ALT, AST, TBIL, SDF-1↓

Act on SDF-1/CRCX4

Ruanganjian^[97]

ALB↑; ALT, AST↓

Improve the content of albumin in plasma