PDF(Pubmed)
Abstract：
The combination of lineage tracing and immunohistochemistry has helped to identify subpopulations and fate of hepatic stellate cells (HSC) in murine liver. HSC are sinusoidal pericytes that act as myofibroblast precursors after liver injury. Single cell RNA sequencing approaches have recently helped to differentiate central and portal HSC. A specific Cre line to lineage trace portal HSC has not yet been described. We used three Cre lines (Lrat-Cre, PDGFRβ-CreERT2 and SMMHC-CreERT2) known to label mesenchymal cells including HSC in combination with a tdTomato-expressing reporter. All three Cre lines labeled populations of HSC as well as smooth muscle cells (SMC). Using the SMMHC-CreERT2, we identified a subtype of HSC in the periportal area of the hepatic lobule (termed zone 1-HSC). We lineage traced tdTomato-expressing zone 1-HSC over 1 year, described fibrotic behavior in two fibrosis models and investigated their possible role during fibrosis. This HSC subtype resides in zone 1 under healthy conditions; however, zonation is disrupted in preclinical models of liver fibrosis (CCl4 and MASH). Zone 1-HSC do not transform into αSMA-expressing myofibroblasts. Rather, they participate in sinusoidal capillarization. We describe a novel subtype of HSC restricted to zone 1 under physiological conditions and its possible function after liver injury. In contrast to the accepted notion, this HSC subtype does not transform into αSMA-positive myofibroblasts; rather, zone 1-HSC adopt properties of capillary pericytes, thereby participating in sinusoidal capillarization.
摘要：
谱系追踪和免疫组织化学的结合有助于鉴定小鼠肝脏中肝星状细胞（HSC）的亚群和命运。HSC是肝损伤后充当肌成纤维细胞前体的窦周细胞。单细胞RNA测序方法最近有助于区分中枢和门静脉HSC。尚未描述特定的Cre系到谱系示踪门户HSC。我们使用了三条Cre线(Lrat-Cre，PDGFRβ-CreERT2和SMMHC-CreERT2）已知与tdTomato表达报告分子组合标记包括HSC的间充质细胞。所有三个Cre系标记HSC以及平滑肌细胞(SMC)的群体。使用SMMHC-CreERT2，我们在肝小叶的门静脉周围区域（称为1-HSC区）中鉴定了HSC的亚型。我们谱系追踪tdTomato表达区1-HSC超过1年，描述了两种纤维化模型中的纤维化行为，并研究了它们在纤维化过程中的可能作用。这种HSC亚型在健康条件下位于1区;然而，在肝纤维化的临床前模型（CCl4和MASH）中，分区被破坏。区1-HSC不转化为表达αSMA的肌成纤维细胞。相反，他们参与正弦毛细管化。我们描述了一种在生理条件下仅限于1区的新型HSC亚型及其在肝损伤后的可能功能。与公认的概念相反，这种HSC亚型不会转化为αSMA阳性肌成纤维细胞；相反，区1-HSC采用毛细管周细胞的特性，从而参与正弦毛细管化。
