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Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney
Journal of Hepatology ( IF 25.7 ) Pub Date : 2018-04-01 , DOI: 10.1016/j.jhep.2017.12.016
Rie Utoh , Junji Komori , Hiroyuki Kuge , Kohei Tatsumi , Masumi Yamada , Shinji Hirohashi , Masahiro Tsutsumi , Toshihiro Amanuma , Akira Yoshioka , Yoshiyuki Nakajima , Kenjiro Wake , Teruo Okano , Eric Lagasse , Kazuo Ohashi

BACKGROUND & AIMS Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers because of its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through complex intercellular signaling. However, the mechanism of liver organogenesis, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. METHODS Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein transgenic mice or wild-type mice transplanted with bone marrow cells isolated from green fluorescent protein-mice. RESULTS Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 years later, whole organ-sized liver tissues with greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including bone marrow. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury. CONCLUSION Our data clearly show that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment. LAY SUMMARY The role of adult hepatocytes at ectopic locations has not been clarified. In this study, we demonstrated that engrafted hepatocytes in the kidney proliferated, recruited non-parenchymal cells from host tissues including bone marrow, and finally created an organ-sized, complex liver system that exhibited liver-specific architectures and functions. Our results revealed previously undescribed functions of hepatocytes to direct liver organogenesis through non-parenchymal cell recruitment and organize multiple cell types into a complex 3D liver at ectopic sites. Transcript profiling: Microarray data are deposited in GEO (GEO accession: GSE99141).

中文翻译:

成年肝细胞通过肾脏中的非实质细胞募集指导肝脏器官发生

背景与目的自从普罗米修斯神话首次出现以来,肝脏惊人的再生能力因其巨大的医疗潜力而吸引了研究人员。多种类型的肝细胞,包括肝细胞和肝非实质细胞 (NPC),通过复杂的细胞间信号传导促进肝脏再生。然而,肝脏器官发生的机制,尤其是成年肝细胞在异位部位的作用,仍然未知。在这项研究中,我们证明单独的肝细胞刺激肝脏器官发生形成器官大小的复杂 3D 肝脏,在小鼠肾脏中表现出天然肝脏结构和功能。方法将分离的肝细胞移植到野百合碱 (MCT) 和部分肝切除术 (PHx) 处理的小鼠的肾囊下。为了确定新肝脏中 NPC 的起源,将肝细胞移植到 MCT/PHx 处理的绿色荧光蛋白转基因小鼠或移植了从绿色荧光蛋白小鼠分离的骨髓细胞的野生型小鼠中。结果 移植到小鼠肾下间隙的肝细胞响应于天然肝脏的慢性肝损伤而持续生长。1.5 多年后,形成了比受损的天然肝脏更大质量的完整器官大小的肝脏组织。最值得注意的是,我们发现从包括骨髓在内的宿主组织中招募了至少三种与肝脏 NPC 具有相似表型特征的 NPC。肾脏中的新肝脏表现出肝脏特有的功能和结构,包括正弦血管系统、带状异质性、和胆管细胞的出现。此外,新肝脏成功地拯救了患有致命肝损伤的小鼠。结论我们的数据清楚地表明,成人肝细胞作为组织细胞在异位部位通过 NPC 募集的肝脏器官发生中起主导作用。常规总结 成人肝细胞在异位部位的作用尚未阐明。在这项研究中,我们证明肾脏中移植的肝细胞增殖,从包括骨髓在内的宿主组织中募集非实质细胞,并最终创建了一个器官大小的复杂肝脏系统,该系统具有肝脏特异性的结构和功能。我们的结果揭示了肝细胞以前未描述的功能,通过非实质细胞募集来指导肝脏器官发生,并将多种细胞类型组织成异位部位的复杂 3D 肝脏。
更新日期:2018-04-01
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