Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney.
Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney.
复制标题
DOI：
10.1016/j.jhep.2017.12.016
复制
发表时间：
2018-04
影响因子：
25.7
通讯作者：
Ohashi K
中科院分区：
文献类型：
--
作者：
Utoh R;Komori J;Kuge H;Tatsumi K;Yamada M;Hirohashi S;Tsutsumi M;Amanuma T;Yoshioka A;Nakajima Y;Wake K;Okano T;Lagasse E;Ohashi K
自从普罗米修斯神话第一次被记述以来，肝脏惊人的再生能力就因其巨大的医学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，通过复杂的细胞间信号转导促进肝再生。然而，肝脏器官发生的机制，特别是成体肝细胞在异位部位的作用仍不清楚。在这项研究中，我们证明，肝细胞本身刺激肝脏器官发生形成器官大小的复杂3D肝脏，在小鼠的肾脏中展示自然的肝脏结构和功能。将分离的肝细胞移植到野百合碱(MCT)和肝部分切除(PHX)组小鼠的肾被膜下。为了确定新生肝脏中神经前体细胞的来源，将肝细胞移植到经MCT/PHX处理的绿色荧光蛋白(GFP)转基因小鼠或从GFP小鼠分离的骨髓(BM)细胞移植的野生型小鼠。移植于小鼠肾下间隙的肝细胞在自然肝脏的慢性肝损伤中持续生长。超过1.5年后，完整的器官大小的肝组织已经形成，其质量比受损的天然肝脏的质量更大。最值得注意的是，我们发现至少有三种与肝脏神经干细胞表型特征相似的神经干细胞是从包括骨髓在内的宿主组织中招募的。肾脏中的新生肝脏表现出肝脏特有的功能和结构，包括正弦血管系统、带状不均一性和胆管细胞的出现。此外，新生肝脏成功地挽救了致命性肝损伤的小鼠。我们的数据清楚地表明，成年肝细胞在通过NPC招募的异位部位的肝脏器官发生中起着组织者细胞的主导作用。
Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers due to its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through the complex intercellular signaling. However, the liver organogenetic mechanism, 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. 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 (GFP) transgenic mice or wild-type mice transplanted with bone marrow (BM) cells isolated from GFP mice. 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 yrs later, whole organ-sized liver tissues having a 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 BM. 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. Our data clearly showed that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.
登录
查看更多内容
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
13.5
作者：
DeLeve, Laurie D.
通讯作者：
DeLeve, Laurie D.
影响因子：
29.4
作者：
Harb R;Xie G;Lutzko C;Guo Y;Wang X;Hill CK;Kanel GC;DeLeve LD
通讯作者：
DeLeve LD
影响因子：
25.7
作者：
Fausto, N
通讯作者：
Fausto, N
影响因子：
2.5
作者：
Nonaka, Hidenori;Tanaka, Minoru;Miyajima, Atsushi
通讯作者：
Miyajima, Atsushi