Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.
Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches.
复制标题
DOI：
10.1136/gutjnl-2014-308176
复制
发表时间：
2016-04
期刊：
影响因子：
24.5
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Michelotti GA;Tucker A;Swiderska-Syn M;Machado MV;Choi SS;Kruger L;Soderblom E;Thompson JW;Mayer-Salman M;Himburg HA;Moylan CA;Guy CD;Garman KS;Premont RT;Chute JP;Diehl AM
胆管反应（DR）包括沿Hering管沿着的反应性导管样细胞（RDC）的动员和Disse间隙中肝星状细胞（HSC）的成肌纤维细胞（MF）分化。干细胞龛中的血管周围细胞产生多效生长因子（PTN）以抑制PTN受体，蛋白酪氨酸磷酸酶受体zeta-1（PTPRZ 1），从而增强磷蛋白依赖性信号传导。我们假设DR是由PTN/PTPRZ 1信号调节的。在胆管结扎（BDL）之前和之后检查PTN-GFP、PTN敲除（KO）、PTPRZ 1-KO和野生型（WT）小鼠的PTN、PTPRZ 1和DR。还用PTN处理来自WT、PTN-KO和PTPRZ 1-KO小鼠的RDC和HSC以确定对下游信号传导磷蛋白、基因表达、生长和迁移的影响。还询问了DR患者的肝活检。虽然静止HSC和RDC系表达PTN和PTPRZ 1 mRNA，但在健康肝脏中均未发现PTN和PTPRZ 1蛋白。BDL诱导MF-HSC中的PTN，并增加MF-HSC和RDC中的PTPRZ 1。在WT小鼠中，BDL触发了DR，其特征在于胶原、RDC和MF-HSC的门静脉周围积聚。该DR的所有方面在PTN-KO小鼠中增加，在PTPRZ 1-KO小鼠中抑制。体外研究显示，控制细胞-细胞粘附和迁移的磷酸蛋白依赖于PTN的积累，从而抑制细胞迁移。PTPRZ 1阳性细胞在胆管板缺损和成人胆汁淤积性疾病患者的DR中很突出。PTN及其受体PTPRZ 1通过控制成体肝祖细胞龛中驻留细胞的迁移来调节对肝损伤的DR。
The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling. PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated. Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases. PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches.