小分子诱导成熟肝细胞转化为CD24+肝前体样细胞的机制和应用研究
结题报告
批准号:
31872823
项目类别:
面上项目
资助金额:
60.0 万元
负责人:
鄢和新
依托单位:
学科分类:
C0703.细胞增殖及细胞周期
结题年份:
2022
批准年份:
2018
项目状态:
已结题
项目参与者:
焦英甫、顾希垚、赵玉洁、刘晓华、唐丹、王占魁、刘艳、黄伟健
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中文摘要
慢性肝功能失代偿发生于众多肝脏疾病的终末阶段,以肝移植作为首选治疗手段,因供体不足无法满足需求。近来通过移植组织前体细胞治疗不同器官纤维化伴发功能失代偿取得良好的效果,但如何在慢性肝损伤治疗中提高肝前体细胞再生功能及移植效率,及其分子调控机制亟需进一步研究。我们前期发现体外通过小分子重编程,可诱导成熟肝细胞转化为肝前体样细胞,移植后可定植于受损肝脏并重建功能;近期我们进一步研究发现肝前体样细胞均表达CD24并伴随Notch信号通路活化。本项目拟通过应用小分子组合将小鼠成熟肝细胞重编程为肝前体细胞,明确CD24分子维持肝前体细胞自我更新及生物学特性的作用;探索Notch通路活化对肝前体细胞CD24表达和功能的影响;进而通过不同小分子组合介导Notch通路活化或抑制,靶向调控CD24阳性肝前体样细胞转化,在不同肝损伤疾病模型中,干预乃至逆转肝功能失代偿的发展进程,为肝病治疗提供新的靶点和思路。
英文摘要
Chronic liver dysfunction occurs in numerous terminal stage of liver disease, however liver transplantation, the preferred treatment for liver dysfuction, is far from satisfactory due to organ deficiency. Although recently some researches have successfully tried the transplantation of stem cells or progenitor cells to rescue organ dysfunction with fibrosis , whether mature hepatocyte-derived liver progenitor cells (LPCs) have therapeutic effects in chronic hepatic insufficiency remains unknown. We have previously found that small molecules can be used to induce conversion of mature hepatocytes into progenitor cells in vitro, with proliferation, redifferentiation and repopulation capabilities. Furthermore, these cells highly express CD24 and Notch signal pathway is also up-regulated. Here, we focus on the application of small molecules-induced hepatocyte-to-LPC conversion. Firstly our purpose is to figure out the role of CD24 in regulating biological characteristics of LPCs. Then based on the models of Liver dysfunction, this study will reveal how activation of Notch pathway influences the expression of CD24. Finally, the combinations of small molecules, alteration of Notch signaling pathway, which targets to regulate the conversion of CD24 + LPCs, may intervene or even reverse the development process of liver dysfunction. Our studies may provide a novel method for the treatment of chronic liver dysfunction.
慢性肝功能失代偿发生于众多肝脏疾病的终末阶段,以肝移植作为首选治疗手段,因供体不足无法满足需求。近来通过移植组织前体细胞治疗不同器官纤维化伴发功能失代偿取得良好的效果,但如何在慢性肝损伤治疗中提高肝前体细胞再生功能及移植效率,及其分子调控机制亟需进一步研究。我们发现体外通过小分子重编程,可诱导成熟肝细胞转化为肝前体样细胞,移植后可定植于受损肝脏并重建功能;进一步我们研究发现肝前体样细胞均表达CD24,可通过体内应用小分子组合将CCl4诱导慢性肝纤维化小鼠内成熟肝细胞重编程为CD24肝前体细胞,同时可促进肝内活化的星状细胞凋亡,可在慢性肝损伤疾病模型中起到干预乃至逆转肝功能失代偿的发展进程,为肝病治疗提供新的靶点和思路。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Establishment of Functional Liver Spheroids From Human Hepatocyte-Derived Liver Progenitor-Like Cells for Cell Therapy.
从人肝细胞来源的肝祖样细胞建立功能性肝球体用于细胞治疗。
DOI:10.3389/fbioe.2021.738081
发表时间:2021
期刊:Frontiers in bioengineering and biotechnology
影响因子:5.7
作者:Liu WM;Zhou X;Chen CY;Lv DD;Huang WJ;Peng Y;Wu HP;Chen Y;Tang D;Guo LN;Wang XL;Zhang HD;Liu XH;Yang LQ;Yu WF;Yan HX
通讯作者:Yan HX
Assessment of long-term functional maintenance of primary human hepatocytes to predict drug-induced hepatoxicity in vitro
评估原代人肝细胞的长期功能维持以预测体外药物引起的肝毒性
DOI:10.1007/s00204-021-03050-y
发表时间:2021-04-14
期刊:ARCHIVES OF TOXICOLOGY
影响因子:6.1
作者:Chen, Yi;Tang, Dan;Yan, Hexin
通讯作者:Yan, Hexin
DOI:10.1016/j.biopha.2019.109010
发表时间:2019-06
期刊:Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子:--
作者:Zhen-yu Wang;Wei-Jian Li;Qigen Li;Hong-Shu Jing;Tianjie Yuan;Gongbo Fu;Dan Tang;Hongdan Zhang;Hexin Yan;B. Zhai
通讯作者:Zhen-yu Wang;Wei-Jian Li;Qigen Li;Hong-Shu Jing;Tianjie Yuan;Gongbo Fu;Dan Tang;Hongdan Zhang;Hexin Yan;B. Zhai
Expansion and differentiation of human hepatocyte-derived liver progenitor-like cells and their use for the study of hepatotropic pathogens.
人肝细胞来源的肝祖样细胞的扩增和分化及其在嗜肝病原体研究中的应用
DOI:10.1038/s41422-018-0103-x
发表时间:2019-01
期刊:Cell research
影响因子:44.1
作者:Fu GB;Huang WJ;Zeng M;Zhou X;Wu HP;Liu CC;Wu H;Weng J;Zhang HD;Cai YC;Ashton C;Ding M;Tang D;Zhang BH;Gao Y;Yu WF;Zhai B;He ZY;Wang HY;Yan HX
通讯作者:Yan HX
DOI:10.7150/thno.54457
发表时间:2021
期刊:Theranostics
影响因子:12.4
作者:Huang WJ;Zhou X;Fu GB;Ding M;Wu HP;Zeng M;Zhang HD;Xu LY;Gao Y;Wang HY;Yan HX
通讯作者:Yan HX
肝细胞来源的肝前体样细胞(HepLPCs)通过诱导肝星状细胞Necroptosis抑制肝纤维化的作用和机制研究
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    52万元
  • 批准年份:
    2022
  • 负责人:
    鄢和新
  • 依托单位:
国内基金
海外基金