机构:[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041 People's Republic of China.四川大学华西医院[2]Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.[3]Morgridge Institute for Research, Madison, WI 53715.[4]Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI 53706.[5]Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.[6]Chengdu Organoidmed Medical Laboratory Ltd., Sichuan, 610041 People's Republic of China.[7]Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating jag1b and jag2b allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-of-function analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic sox9b expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.
基金:
W. M. Keck Foundation
(2017-01) and the National Institutes of Health (DP2DK098092, U01DK105541,
R01DK134099, and R01DK124583) to P.D.S.D., The Larry L. Hillblom Foundation
Fellowship (#2019-D-013-FEL) and the National Natural Science Foundation of
China (82270542) to C.Z., the Diabetes Research Connection (project #08) to
J.J.L., and the National Natural Science Foundation of China (81872068) to C.C.
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2022]版:
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版:
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者:
第一作者机构:[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041 People's Republic of China.[2]Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
通讯作者:
通讯机构:[2]Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.[7]Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
推荐引用方式(GB/T 7714):
Zhao Chengjian,Matalonga Jonathan,Lancman Joseph J,et al.Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling[J].Proceedings of the National Academy of Sciences of the United States of America.2022,119(50):e2201097119.doi:10.1073/pnas.2201097119.
APA:
Zhao Chengjian,Matalonga Jonathan,Lancman Joseph J,Liu Lu,Xiao Chaoxin...&Dong P Duc Si.(2022).Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling.Proceedings of the National Academy of Sciences of the United States of America,119,(50)
MLA:
Zhao Chengjian,et al."Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling".Proceedings of the National Academy of Sciences of the United States of America 119..50(2022):e2201097119