终末期肝病间充质干细胞归巢能力的影响因素及优化措施

刘宇馨; 张缭云

doi:10.12449/JCH250326

终末期肝病间充质干细胞归巢能力的影响因素及优化措施

DOI: 10.12449/JCH250326

刘宇馨,
张缭云^, ,

山西医科大学第一医院感染病科，太原 030001

基金项目:

山西省重点研发计划 (201903D421056)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘宇馨负责文献查找，资料分析，撰写论文；张缭云负责拟定写作思路，指导撰写文章，修改论文并最后定稿。

详细信息

通信作者:
张缭云， zlysgzy@163.com （ORCID： 0000-0002-7666-7368）

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出版历程
- 收稿日期: 2024-06-16
- 录用日期: 2024-08-22
- 出版日期: 2025-03-25

Influencing factors for the homing ability of mesenchymal stem cells in end-stage liver disease and optimization measures

Yuxin LIU,
Liaoyun ZHANG^{,
,}

Department of Infectious Diseases，The First Hospital of Shanxi Medical University，Taiyuan 030001，China

Research funding:

Key R & D Projects of Shanxi Province (201903D421056)

More Information

Corresponding author: ZHANG Liaoyun， zlysgzy@163.com （ORCID： 0000-0002-7666-7368）

摘要

摘要: 间充质干细胞（MSC）因其强大的自我再生、旁分泌及免疫调节特性成为终末期肝病潜在的细胞治疗手段，为晚期肝病治疗提供了新的方向。然而，受损肝脏中炎症、氧化应激和缺氧等复杂微环境的影响，以及静脉注射后大部分MSC滞留在肺毛细血管中且缺乏足够的归巢受体或黏附分子，导致MSC在归巢过程中出现大量凋亡或坏死，只有少数细胞能够成功归巢至肝脏，极大限制了MSC的临床应用。为优化MSC的增殖、迁移及归巢能力，目前已开发多种方法，如预处理、基因修饰及纳米封装技术等。本文将重点阐述影响MSC归巢能力的因素及优化终末期肝病中MSC归巢的措施，并深入分析MSC归巢的机制，以期提高细胞植入效率，促进肝脏修复和再生，为MSC在终末期肝病治疗中的应用开辟新路径。
- 终末期肝病 /
- 间质干细胞 /
- 归巢
Abstract: Mesenchymal stem cells （MSCs） have emerged as a promising cellular therapy for end-stage liver disease （ESLD） due to their robust self-regenerative， paracrine， and immunomodulatory characteristics， providing new directions for the treatment of advanced liver disease. However， the clinical application of MSCs is significantly limited by the fact that only a small number of MSCs can reach the liver due to massive apoptosis or necrosis during the homing process caused by the influence of the complex microenvironment （inflammation， oxidative stress， and hypoxia） of the injured liver and the fact that a substantial proportion of MSCs become trapped in the pulmonary capillaries following intravenous administration with a lack of sufficient homing receptors or adhesion molecules. Various strategies have been developed to optimize the proliferation， migration， and homing abilities of MSCs， including preconditioning， gene modification， and nanoencapsulation technology. This article elaborates on the influencing factors for the homing ability of MSCs， the strategies to optimize their homing in ESLD， and the mechanism of the homing of MSCs， in order to improve cell transplantation efficiency， promote liver repair and regeneration， and pave the way for the application of MSCs in the treatment of ESLD.
- End Stage Liver Disease /
- Mesenchymal Stem Cells /
- Homing

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表 1 基因修饰增强MSC在肝病中的归巢

Table 1. Gene modification enhances MSC homing in liver disease

MSC类型	基因	载体	肝病模型	具体机制
BM-MSC^［3］	CXCR-4	腺病毒	肝移植后	激活CXCR-4/SDF-1α，抑制caspase-3表达和肝酶释放
	CXCR-4	慢病毒	急性肝损伤	通过HGF/c-Met和PI3K/Akt通路的同步激活来增强MSC归巢
	c-Met	慢病毒	ALF	通过激活HGF/c-Met通路来增强MSC对肝脏的归巢
	EPO	慢病毒	ALF	抑制IL-6和TGF-β1表达并上调MMP-9表达
	HGF	腺病毒	肝硬化	改善MSC归巢，促进肝脏修复
	FGF4	慢病毒	肝硬化	改善MSC的增殖和迁移
UC-MSC^［3］	CCR-2	慢病毒	ALF	增强CCR-2/CCL-2轴来增强MSC归巢
	CXCL-9	慢病毒	肝纤维化	增强MSC黏附、爬行和扩散能力
	VEGF165	腺病毒	ALF	改善MSC归巢
AD-MSC^［3］	BCAT1	腺病毒	肝硬化	增强MSC对肝脏的归巢和定位
	FGF21	质粒	肝纤维化	抑制p-JNK、NF-κB、p-Smad2/3信号通路，减少纤维化因子释放，减轻肝纤维化
注：EPO，促红细胞生成素；MMP-9，基质金属蛋白酶9；FGF，成纤维细胞生长因子；VEGF，血管内皮生长因子；BCAT，支链氨基酸转氨酶；p-JNK，磷酸化c-Jun氨基末端激酶；p-Smad，磷酸化Smad蛋白。

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表 2 不同预处理策略对MSC肝脏归巢的作用机制及影响

Table 2. Mechanisms and effects of different preconditioning strategies on MSC homing to the liver

预处理	具体机制	影响
缺氧^［19］	通过HGF/c-Met趋化，激活ERK1/2、P38、PI3K/Akt通路	增强MSC迁移和对ALF的修复
褪黑素^［20］	抗氧化，抑制促炎细胞因子表达，减弱凋亡因子Bax表达	改善肝功能，减少肝细胞凋亡坏死，抑制肝纤维化
维生素E^［21］	抗氧化，抑制促炎细胞因子表达，降低纤维化标志物如Ⅰ型胶原表达	改善肝功能，减轻肝损伤，抑制肝纤维化
IL-6^［27］	抗氧化，抗凋亡基因Bcl-xl上调，Bax、caspase-3、TNF-α上调	增强MSC归巢，改善肝功能，减轻肝细胞凋亡
牛蒡多糖^［28］	抗氧化，抑制Wnt/β-catenin通路阻止肝星状细胞活化和胶原形成	增强MSC肝脏归巢，减轻肝纤维化
IL-1β^［22］	增强MSC表面CXCR-4表达及向SDF-1的迁移	增强MSC对肝脏的归巢，提高对ALF的疗效
雷帕霉素^［23］	诱导自噬增强MSC表面CXCR-4表达及对CXCL-12的迁移	增强MSC对肝脏的归巢，改善肝损伤
UTMB^［24］	增强MSC表面CXCR-4表达	增强MSC对纤维化肝脏的归巢，改善肝纤维化
TC14012^［25］	增强MSC表面CXCR-7表达	增强MSC对肝脏的归巢，改善肝纤维化
聚乙二醇修饰^［29］	抑制静脉给药MSC的肺包埋，抑制肝脏内白细胞浸润	增强MSC对肝脏的归巢，提高对ALF的疗效

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表 3 不同纳米材料对MSC归巢的作用机制及影响

Table 3. Mechanisms and effects of different nanomaterials on MSC homing

纳米材料	作用机制	影响
金纳米粒子^［35］	激活PI3K/Akt/eNOS， α5β3/FAK/RhoGTPase通路	提高MSC迁移能力
四面体框架核酸^［39］	增加MAPK通路中Erk1/2，P38磷酸化	增强归巢，促进MSC肝源性分化
铁基磁性纳米颗粒^［36-37］	增强MSC的CXCR-4表达，MRI监测MSC	提高MSC归巢效率，改善肝脏炎症
二氧化硅纳米颗粒^［37-38］	增加MSC的CXCR-4表达及对SDF-1α的迁移	提高MSC对肝脏的归巢
石墨烯氧化物^［40］	抑制肝酶释放，降低促炎细胞因子水平，增加VEGF和MMP-9表达	提高肝衰竭存活率

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