Single-cell transcriptomics reveals conserved cell identities and fibrogenic phenotypes in zebrafish and human liver.
Single-cell transcriptomics reveals conserved cell identities and fibrogenic phenotypes in zebrafish and human liver.
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DOI：
10.1002/hep4.1930
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发表时间：
2022-07
影响因子：
5.1
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中科院分区：
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肝纤维化的潜在机制是多方面的，并且仍然难以捉摸，没有批准的抗纤维化治疗。成年斑马鱼一直是研究肝纤维化的未充分利用的工具。我们的目的是表征成年斑马鱼肝脏的单细胞转录组，以确定其作为研究肝纤维化模型的实用性。我们使用成年斑马鱼肝脏的单细胞RNA测序（scRNA-seq）来研究单细胞水平的分子和细胞动力学。我们对人类肝脏的scRNA-seq进行了比较分析，重点是肝星状细胞（HSC），肝纤维化中的驱动细胞。scRNA-seq揭示了构成斑马鱼肝脏的肝细胞类型的转录独特群体。与人类肝脏scRNA-seq数据的联合聚类证明了斑马鱼中转录谱和人类标记基因的高度保守性。人类和斑马鱼的HSC显示出转录谱的保守性，我们发现collectin亚家族成员11（colec 11）作为斑马鱼HSC的一种新的保守标记。为了证明scRNA-seq使用斑马鱼研究肝纤维化的能力，我们在具有甘露糖磷酸异构酶（MPI）突变和特征性早期肝纤维化的儿科肝病的斑马鱼模型上进行了scRNA-seq。我们发现纤维化信号通路和上游调控因子在MPI缺失的斑马鱼和人类HSC中保守。斑马鱼转录组的CellPhoneDB分析确定神经纤毛蛋白1是肝纤维化的潜在驱动因素。结论：这项研究建立了第一个成年斑马鱼肝脏的scRNA-seq图谱，突出了与人类肝脏的高度相似性，并加强了其作为研究肝纤维化模型的价值。我们在正常和纤维化状态下生成了成年斑马鱼肝脏转录组的第一个单细胞表征。我们的工作为肝脏研究提供了急需的资源，并断言成年斑马鱼在研究肝纤维化方面的有用性。
The mechanisms underlying liver fibrosis are multifaceted and remain elusive with no approved antifibrotic treatments available. The adult zebrafish has been an underutilized tool to study liver fibrosis. We aimed to characterize the single‐cell transcriptome of the adult zebrafish liver to determine its utility as a model for studying liver fibrosis. We used single‐cell RNA sequencing (scRNA‐seq) of adult zebrafish liver to study the molecular and cellular dynamics at a single‐cell level. We performed a comparative analysis to scRNA‐seq of human liver with a focus on hepatic stellate cells (HSCs), the driver cells in liver fibrosis. scRNA‐seq reveals transcriptionally unique populations of hepatic cell types that comprise the zebrafish liver. Joint clustering with human liver scRNA‐seq data demonstrates high conservation of transcriptional profiles and human marker genes in zebrafish. Human and zebrafish HSCs show conservation of transcriptional profiles, and we uncover collectin subfamily member 11 (colec11) as a novel, conserved marker for zebrafish HSCs. To demonstrate the power of scRNA‐seq to study liver fibrosis using zebrafish, we performed scRNA‐seq on our zebrafish model of a pediatric liver disease with mutation in mannose phosphate isomerase (MPI) and characteristic early liver fibrosis. We found fibrosis signaling pathways and upstream regulators conserved across MPI‐depleted zebrafish and human HSCs. CellPhoneDB analysis of zebrafish transcriptome identified neuropilin 1 as a potential driver of liver fibrosis. Conclusion: This study establishes the first scRNA‐seq atlas of the adult zebrafish liver, highlights the high degree of similarity to human liver, and strengthens its value as a model to study liver fibrosis. We generated the first single‐cell characterization of the adult zebrafish liver transcriptome, in both normal and fibrotic states. Our work provides a much‐needed resource for liver research and asserts the usefulness of the adult zebrafish to study liver fibrosis.