探索多配体 scavenger 受体 Stabilin-1 和 Stabilin-2 缺陷型肝窦内皮细胞的转录组网络。

Exploring the transcriptomic network of multi-ligand scavenger receptor Stabilin-1- and Stabilin-2-deficient liver sinusoidal endothelial cells.

机构信息

Department of Dermatology, Venereology and Allergy, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim 68167, Germany.

Center for Medical Research, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.

出版信息

Gene. 2021 Feb 5;768:145284. doi: 10.1016/j.gene.2020.145284. Epub 2020 Oct 31.

DOI:10.1016/j.gene.2020.145284

PMID:33130055

Abstract

The Class H scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are two of the most highly expressed genes in liver sinusoidal endothelial cells (LSECs). While Stab1-deficient (Stab1KO) and Stab2-deficient (Stab2KO) mice are phenotypically unremarkable, Stab1/2-double-deficient (StabDKO) mice exhibit perisinusoidal liver fibrosis, glomerulofibrotic nephropathy and a reduced life expectancy. These conditions are caused by insufficiently scavenged circulating noxious blood factors. The effects of either Stab-single- or double-deficiency on LSEC differentiation and function, however, have not yet been thoroughly investigated. Therefore, we performed comprehensive transcriptomic analyses of primary LSECs from Stab1KO, Stab2KO and StabDKO mice. Microarray analysis revealed dysregulation of pathways and genes involved in established LSEC functions while sinusoidal endothelial marker gene expression was grossly unchanged. 82 genes were significantly altered in Stab1KO, 96 genes in Stab2KO and 238 genes in StabDKO compared with controls; 42 genes were found to be commonly dysregulated in all three groups and all of these genes were downregulated. These commonly downregulated genes (CDGs) were categorized as "potential scavengers," "cell adhesion molecules," "TGF-β/BMP-signaling" or "collagen and extracellular matrix (ECM) components". Among CDGs, Colec10, Lumican and Decorin, were the most strongly down-regulated genes and the corresponding proteins impact on the interaction of LSECs with chemokines, ECM components and carbohydrate structures. Similarly, "chemokine signaling," "cytokine-cytokine receptor interaction" and "ECM-receptor interaction," were the GSEA categories which represented most of the downregulated genes in Stab1KO and Stab2KO LSECs. In summary, our data show that loss of a single Stabilin scavenger receptor - and to a greater extent of both receptors - profoundly alters the transcriptomic repertoire of LSECs. These alterations may affect LSEC-specific functions, especially interactions of LSECs with the ECM and during inflammation as well as clearance of the peripheral blood.

摘要

H 类清道夫受体 Stabilin-1（Stab1）和 Stabilin-2（Stab2）是肝脏窦内皮细胞（LSEC）中表达最丰富的基因之一。虽然 Stab1 缺陷（Stab1KO）和 Stab2 缺陷（Stab2KO）小鼠表型无明显异常，但 Stab1/2 双缺陷（StabDKO）小鼠表现出肝窦周围纤维化、肾小球纤维性肾病和预期寿命缩短。这些情况是由循环中有害血液因子清除不足引起的。然而，Stab 单缺陷或双缺陷对 LSEC 分化和功能的影响尚未得到充分研究。因此，我们对 Stab1KO、Stab2KO 和 StabDKO 小鼠的原代 LSEC 进行了全面的转录组分析。微阵列分析显示，参与已建立的 LSEC 功能的途径和基因发生失调，而窦内皮标记基因表达则大体不变。与对照组相比，Stab1KO 中有 82 个基因显著改变，Stab2KO 中有 96 个基因改变，StabDKO 中有 238 个基因改变；在所有三组中，有 42 个基因被发现共同失调，所有这些基因都下调。这些共同下调的基因（CDGs）被归类为“潜在的清道夫”、“细胞粘附分子”、“TGF-β/BMP 信号”或“胶原和细胞外基质（ECM）成分”。在 CDGs 中，Colec10、Lumican 和 Decorin 是下调最明显的基因，相应的蛋白质影响 LSEC 与趋化因子、ECM 成分和碳水化合物结构的相互作用。同样，“趋化因子信号”、“细胞因子-细胞因子受体相互作用”和“ECM-受体相互作用”是 GSEA 类别，代表了 Stab1KO 和 Stab2KO LSEC 中大多数下调基因。总之，我们的数据表明，单个 Stabilin 清道夫受体的缺失——而且更重要的是两个受体的缺失——会极大地改变 LSEC 的转录组谱。这些改变可能会影响 LSEC 的特定功能，特别是 LSEC 与 ECM 的相互作用以及在炎症和外周血清除过程中的作用。