Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.
Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b.
复制标题
DOI：
10.1016/j.xcrm.2022.100754
复制
发表时间：
2022-10-18
影响因子：
14.3
通讯作者：
Monga, Satdarshan P.
中科院分区：
文献类型：
--
作者：
Hu, Shikai;Liu, Silvia;Bian, Yu;Poddar, Minakshi;Singh, Sucha;Cao, Catherine;McGaughey, Jackson;Bell, Aaron;Blazer, Levi L.;Adams, Jarret J.;Sidhu, Sachdev S.;Angers, Stephane;Monga, Satdarshan P.
尽管β-连环蛋白的作用是毋庸置疑的，但WNTS调节肝脏分区(LZ)和再生(LR)的确凿同一性仍不清楚。通过单细胞分析，我们鉴定了WNT2和WNT9b在第3区内皮细胞中的保守表达。WNT2和WNT9b的EC消除导致第3区的β-连环蛋白靶标丢失，而第1区的基因在第3区重新出现，解开了LZ过程的动态化。在肝脏Wnt信号缺陷的敲除表型模型中观察到LR受损。使用四价抗体激活Wnt信号，在敲除中挽救了LZ和LR，并在对照中诱导了第3区基因的表达和LR。在扑热息痛过量的急性肝功能衰竭(ALF)中，给予该激动剂也能促进LR，满足了尚未满足的临床需求。总之，我们报告了EC-Wnt2和Wnt9b在LZ和LR中的明确作用，并展示了Wnt激活剂作为ALF再生治疗的作用。Wnt2和Wnt9b在肝内皮细胞中的保守表达被证实Wnt2和Wnt9b在内皮细胞中的缺失影响3区基因的表达内皮细胞Wnt2和Wnt9b的缺失影响肝切除后的肝再生用Wnt2激动剂晚期治疗挽救了醋氨酚过量后的再生。Wnt2和Wnt9b在肝内皮细胞中有保守表达，其缺失导致3区基因表达减弱，1区基因在该区域出现，肝再生迟钝。WNT激动剂促进急性肝损伤模型再生。
The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-appearance of zone 1 genes in zone 3, unraveling dynamicity in the LZ process. Impaired LR observed in the knockouts phenocopied models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts and induced zone 3 gene expression and LR in controls. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF. Conserved expression of Wnt2 and Wnt9b in liver endothelial cells is identified Wnt2 and Wnt9b deletion from endothelial cells affects gene expression in zone 3 Endothelial Wnt2 and Wnt9b deletion affects liver regeneration after hepatectomy Late treatment with Wnt agonist rescues regeneration after acetaminophen overdose Hu et al. show conserved expression of Wnt2 and Wnt9b in liver endothelial cells whose deletion led to abrogation of expression of zone 3 genes, appearance of zone 1 genes in this area, and blunted liver regeneration. Wnt agonist stimulated regeneration in acute liver injury model.
登录
查看更多内容
影响因子：
11.8
作者：
Carroll, TJ;Park, JS;McMahon, AP
通讯作者：
McMahon, AP
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
14.9
作者：
Gans JD;Wolinsky M
通讯作者：
Wolinsky M
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
23.9
作者：
Ben-Moshe, Shani;Veg, Tamar;Itzkovitz, Shalev
通讯作者：
Itzkovitz, Shalev