Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling.
Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling.
复制标题
通过升高的 Jagged/Notch/Sox9 信号来挽救 Alagille 综合征中肝内胆管细胞的再生失败
DOI：
10.1073/pnas.2201097119
复制
发表时间：
2022-12-13
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管肝脏具有强大的愈合潜力，但再生衰竭是许多肝脏疾病的潜在条件，如Alagille综合征（ALGS），这是一种JAG1单倍体不足的疾病，其特征是新生儿肝胆管丧失，在大多数情况下无法再生。通过用斑马鱼滴定Jagged的等位基因剂量，我们能够一致地模拟这种ALGS胆管再生衰竭，并发现Jagged不足抑制了再生胆管细胞分支和分离成胆道网络所必需的Notch/Sox9活性的升高。此外，我们发现小分子Notch激动剂NoRA1可以增加Sox9的表达并挽救jag突变体的胆道再生，从而为这种疾病的治疗开辟了一条潜在的途径。尽管肝脏具有强大的愈合能力，但再生衰竭是许多肝脏疾病的基础，包括JAG1单倍体不足症，Alagille综合征（ALGS）。由于肝内管（IHD）缺乏导致的胆汁淤积在某些ALGS病例中得到解决，但在大多数情况下没有明确的机制或治疗干预措施。我们发现，调节jag1b和jag2b等位基因的剂量足以将这些不同的结果分层，这些结果可能会因Notch信号的遗传操纵而加剧或挽救，这表明jagb /Notch信号的扰动可能是导致ALGS肝脏严重程度的原因。尽管再生的IHD细胞会增殖，但它们仍然聚集在突变体中，由于远端IHD细胞中Notch信号的钝化升高，这些突变体无法恢复。Notch信号的增加是再生IHD细胞分支和分离到生长中的肝脏外周区域所必需的，而在ALGS中，胆道缺乏是常见的。镶嵌功能失得分析表明，Sox9b是细胞在IHD再生过程中自主调节这些细胞动力学所需的关键Notch转录效应因子。使用小分子Notch激动剂刺激ALGS患者成纤维细胞中Sox9的表达，增强肝脏sox9b的表达，缓解IHD缺乏和胆汁淤滞，提高斑马鱼突变体的存活率，从而为这种疾病提供了一种概念验证的治疗途径。
Despite the robust healing potential of the liver, regenerative failure is the underlying condition of numerous liver diseases as is the case with Alagille syndrome (ALGS), a JAG1 haploinsufficient disorder characterized by neonatal liver bile duct loss that fails to regenerate in most cases. By titrating the allele dosage of jag using zebrafish, we were able to consistently model this ALGS bile duct regenerative failure and found that insufficient Jagged dampens the elevated Notch/Sox9 activity necessary for regenerating cholangiocytes to branch and segregate into a biliary network. Moreover, we found that the small-molecule Notch agonist NoRA1 can increase Sox9 expression and rescue biliary regeneration in jag mutants, thereby paving a potential therapeutic avenue for this disorder. 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.
登录
查看更多内容
影响因子：
2.7
作者：
Huang, Wei;Beer, Rebecca L.;Delaspre, Fabien;Wang, Guangliang;Edelman, Hannah E.;Park, Hyewon;Azuma, Mizuki;Parsons, Michael J.
通讯作者：
Parsons, Michael J.
影响因子：
82.9
作者：
Huang, Ling;Holtzinger, Audrey;Muthuswamy, Senthil K.
通讯作者：
Muthuswamy, Senthil K.
影响因子：
30.8
作者：
Li, LH;Krantz, ID;Spinner, NB
通讯作者：
Spinner, NB
影响因子：
13.5
作者：
Adams, Joshua M.;Huppert, Kari A.;Jafar-Nejad, Hamed
通讯作者：
Jafar-Nejad, Hamed
影响因子：
13.5
作者：
Emerick, KM;Rand, EB;Piccoli, DA
通讯作者：
Piccoli, DA