Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
Hepatology. 2021 Jun;73(6):2510-2526. doi: 10.1002/hep.31565. Epub 2021 May 28.
Mitogen-activated protein kinase kinase (MKK) 7 and MKK4 are upstream activators of c-Jun NH -terminal kinases (JNKs) and have been shown to be required for the early development of the liver. Although it has been suggested that MKK7 might be involved in the regulation of hepatocyte proliferation, the functional role of MKK7 in the liver has remained unclear.
Here, we examined phenotypic alterations in liver-specific or hepatocyte/hematopoietic cell-specific MKK7 knockout (KO) mice, which were generated by crossing MKK7 with albumin-cyclization recombination (Alb-Cre) or myxovirus resistance protein 1-Cre mice, respectively. The livers of Alb-Cre MKK7 mice developed without discernible tissue disorganization. MKK7 KO mice responded normally to liver injuries incurred by partial hepatectomy or injection of CCl . However, tissue repair following CCl -induced injury was delayed in MKK7 KO mice compared with that of control mice. Furthermore, after repeated injections of CCl for 8 weeks, the liver in MKK7 KO mice showed intense fibrosis with increased protractive hepatocyte proliferation, suggesting that MKK7 deficiency might affect regenerative responses of hepatocytes in the altered tissue microenvironment. MKK7 KO hepatocytes demonstrated normal proliferative activity when cultured in monolayers. However, MKK7 KO significantly suppressed branching morphogenesis of hepatocyte aggregates within a collagen gel matrix. Microarray analyses revealed that suppression of branching morphogenesis in MKK7 KO hepatocytes was associated with a reduction in mRNA expression of transgelin, glioma pathogenesis related 2, and plasminogen activator urokinase-type (Plau); and forced expression of these genes in MKK7 KO hepatocytes partially recovered the attenuated morphogenesis. Furthermore, hepatocyte-specific overexpression of Plau rescued the impaired tissue repair of MKK7 KO mice following CCl -induced injury.
MKK7 is dispensable for the regenerative proliferation of hepatocytes but plays important roles in repair processes following parenchymal destruction, possibly through modulation of hepatocyte-extracellular matrix interactions.
丝裂原活化蛋白激酶激酶（MKK）7 和 MKK4 是 c-Jun N 端激酶（JNK）的上游激活物，已被证明对肝脏的早期发育是必需的。虽然有人提出 MKK7 可能参与了肝细胞增殖的调节，但 MKK7 在肝脏中的功能作用仍不清楚。
在这里，我们研究了通过分别与白蛋白环化重组（Alb-Cre）或副流感病毒抗性蛋白 1-Cre 小鼠杂交而产生的肝特异性或肝/造血细胞特异性 MKK7 敲除（KO）小鼠的表型改变。Alb-Cre MKK7 小鼠的肝脏发育没有明显的组织紊乱。MKK7 KO 小鼠对部分肝切除或 CCl 注射引起的肝损伤正常反应。然而，与对照小鼠相比，MKK7 KO 小鼠的 CCl 诱导损伤后的组织修复延迟。此外，在重复注射 CCl 8 周后，MKK7 KO 小鼠的肝脏显示出强烈的纤维化，伴有增殖性肝细胞增殖增加，这表明 MKK7 缺失可能影响在改变的组织微环境中的肝细胞的再生反应。当在单层培养时，MKK7 KO 肝细胞显示出正常的增殖活性。然而，MKK7 KO 显著抑制胶原凝胶基质中肝细胞聚集体的分支形态发生。微阵列分析显示，MKK7 KO 肝细胞分支形态发生的抑制与转凝胶蛋白、神经胶质瘤发病相关蛋白 2 和尿激酶型纤溶酶原激活物（Plau）的 mRNA 表达减少有关；在 MKK7 KO 肝细胞中强制表达这些基因部分恢复了减弱的形态发生。此外，肝特异性过表达 Plau 挽救了 MKK7 KO 小鼠在 CCl 诱导损伤后的受损组织修复。
MKK7 对于肝细胞的再生性增殖不是必需的，但在实质破坏后的修复过程中发挥重要作用，可能通过调节肝细胞-细胞外基质相互作用来实现。
