Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages

Abstract

Highlights d Single-cell analyses provide a comprehensive atlas of liver cell lineage emergence d A distinct, migratory, hepatomesenchymal hybrid cell type is identified d Liver endothelial and mesenchymal progenitors emerge during early hepatogenesis d Candidate cell-cell interactions are identified within the primitive liver sinusoid

The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover

“…This pattern of mRNA distribution suggests that Tmem2 is expressed in liver sinusoidal endothelial cells. This is consistent with a single-cell RNAseq data set (40)…”

Angiodiversity and organotypic functions of sinusoidal endothelial cells

“…2c). Subsequently, the divergence of sinusoidal and vascular EC from the common EC progenitor occurs around E9.5 [34]. A mouse single-cell molecular map during gastrulation and mesoderm diversification validated the origin of the hematoendothelial lineages with the expression of Flk1/ Kdr and Tal1 as molecular switch determining lineage fate to either EC or hematopoietic cells during mesoderm diversification [43,44].…”

“…2a). Yet, the transcriptional signatures of sinusoidal EC can be captured as early as E8.75 [34]. Following colonization of the liver by yolk sac-derived stem cells, expansion of hematopoietic stem and progenitor cells (HSPC) starts in the fetal liver around this time of development [35].…”

“…Vice versa, hepatoblasts induce LSEC specification in a paracrine manner via both, direct interaction and VEGF signaling [32,33,37]. Similarly, autocrine/paracrine-acting Notch and transforming growth factor β (TGF-β) pathway signaling play pivotal roles during LSEC development [34].…”

Applications of liver organoids

“…A c c e p t e d 末期肝病甚至肝癌 [55] 。目前并没有针对 MAFLD 的药物，由于缺乏相应治疗以及全 球肥胖流行率的快速升高， 未来几十年非酒精性脂肪肝病患病率可能会进一步加 剧，将给全球带来严重的医疗负担 [54] 。 有研究利用体外 2D 肝脏肿瘤细胞系来模拟 MAFLD，但 由于肿瘤特性以及永生 化造成的代谢特征变化，限制了其在该病中的模拟 [56] 。另外一种解决方案则是利 用动物模型尽可能模拟人类非酒精性脂肪肝炎疾病 [57] [63] 。此外， 肝脏类器官体也可以模拟遗传性肝脏代谢疾病，包括囊性纤维病 [29] ，α-1-抗胰 蛋白酶(A1AT)缺乏症 [34] ，I 型瓜氨酸血症 [64] ，溶酶体酸性脂肪酶缺乏症 [61] ，线 粒体 DNA 缺失综合症 [65] 和 Alagille 综合征 [43] [71] ，最终会有助于体外构建更加复杂有序的类器官体。比如，最近已经 有关于肝胆胰复杂类器官 [20] 和垂体下行神经通路的复杂类器官体 [72] 的工作出现。 在获得复杂的类器官体之后，如何实现类器官的可控形成，从而获得功能和 结构均一、有序的类器官体，甚至将其工程化生产是该领域面临的又一挑战。这 需要人们更加深入的了解胚胎时期肝脏器官发育原理和肝组织损伤过程的再生 理论，并基于这些基本理论知识，设计出具有多层组织复杂性和高阶功能的肝脏 类器官。利用特定细胞形成生发中心产生诱导因子梯度 [73] ，或者通过基因编辑手 段人为设计细胞与细胞的接触方式 [74] ，或者利用微流控系统，在灌注培养的系统 中添加定向的诱导因子梯度等方式精确控制营养物质和细胞的定位， 可能会促进 形成特定的有序结构 [75] 。 Alagille 综合征 多能干细胞分化来源的肝胆类器官 [43]…”