Intrahepatic cholangiocyte regeneration from an Fgf‐dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome

Notch信号通路 阿拉吉尔综合征 生物 斑马鱼 祖细胞 细胞生物学 再生(生物学) 胆管上皮细胞 干细胞 基因敲除 胆汁淤积 内分泌学 信号转导 遗传学 细胞培养 基因
作者
Chengjian Zhao,Joseph J. Lancman,Yi Yang,Keith P. Gates,Dan Cao,Lindsey Barske,Jonathan Matalonga,Xiangyu Pan,Jiaye He,Alyssa Graves,Jan Huisken,Chong Chen,P. Duc Si Dong
出处
期刊:Hepatology [Wiley]
卷期号:75 (3): 567-583 被引量:13
标识
DOI:10.1002/hep.32173
摘要

Abstract Background and Aims Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene JAGGED1 , leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown. Approach and Results Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch‐dependent mechanism. Combining multiple lineage tracing strategies with whole‐liver three‐dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte‐to‐IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue‐specific mosaic analysis with an inducible dominant‐negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids. Conclusions Our data show that IHD cells regenerate upon resumption of Jagged/Notch signaling, from multipotent progenitors originating from an Fgf‐dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
等待的背包关注了科研通微信公众号
刚刚
陶宇完成签到,获得积分20
刚刚
科目三应助徐之易采纳,获得10
刚刚
如意一笑完成签到,获得积分10
1秒前
jinzejin完成签到,获得积分10
1秒前
2秒前
youyou2679发布了新的文献求助10
2秒前
2秒前
clearwind完成签到,获得积分10
3秒前
欣喜夏岚完成签到,获得积分10
3秒前
4秒前
aqa发布了新的文献求助10
4秒前
乔项琦完成签到,获得积分10
5秒前
英俊的铭应助mr.pork采纳,获得10
5秒前
大模型应助渣155136采纳,获得10
5秒前
Ywffffff发布了新的文献求助10
5秒前
mengyijie2发布了新的文献求助10
5秒前
5秒前
多次拒绝SCI约稿的莉莉完成签到,获得积分10
5秒前
十一发布了新的文献求助10
6秒前
努力的小明明完成签到,获得积分10
6秒前
Gavin应助呆萌代桃采纳,获得20
6秒前
Grayson完成签到,获得积分10
7秒前
7秒前
陶宇发布了新的文献求助10
7秒前
复杂汉堡完成签到,获得积分20
8秒前
bro完成签到,获得积分10
8秒前
9秒前
9秒前
wangtingyu发布了新的文献求助10
10秒前
123456完成签到,获得积分10
10秒前
Jasper应助石文采纳,获得10
12秒前
科研通AI5应助趣乐多采纳,获得30
12秒前
完美世界应助杨小羊采纳,获得10
13秒前
elebug完成签到,获得积分10
13秒前
喜悦幻雪完成签到,获得积分10
13秒前
14秒前
14秒前
呆萌不正完成签到 ,获得积分10
14秒前
14秒前
高分求助中
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Mechanistic Modeling of Gas-Liquid Two-Phase Flow in Pipes 2500
Kelsen’s Legacy: Legal Normativity, International Law and Democracy 1000
Handbook on Inequality and Social Capital 800
Conference Record, IAS Annual Meeting 1977 610
Interest Rate Modeling. Volume 3: Products and Risk Management 600
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3546979
求助须知:如何正确求助?哪些是违规求助? 3123961
关于积分的说明 9357531
捐赠科研通 2822555
什么是DOI,文献DOI怎么找? 1551574
邀请新用户注册赠送积分活动 723561
科研通“疑难数据库(出版商)”最低求助积分说明 713801