背景:Kupffer细胞(KC)起源于出生前的卵黄囊祖细胞。在整个成年期,它们独立于循环单核细胞(MO)的输入处于稳定状态,并在耗尽后2周内得到补充,但在成人中再繁殖KC的起源尚不清楚.当前的范式表明,重新填充KC起源于预先存在的KC或单核细胞,但是仍然缺乏命运映射的证据。
方法:我们首先使用组织驻留的巨噬细胞特异性和单核细胞特异性命运图谱小鼠模型追踪了预先存在的KCs和单核细胞的命运,分别。其次,我们进行了遗传谱系追踪,以确定参与小鼠KC耗竭反应的祖细胞类型.最后,我们追踪造血干细胞(HSC)的命运在HSC特异性命运映射小鼠模型,在反复四氯化碳治疗引起的慢性肝脏炎症的背景下。
结果:通过使用命运映射鼠标模型,我们没有发现任何证据表明再繁殖的KC起源于先前存在的KC或MOs,并且发现在对KC耗尽的反应中,造血干细胞在骨髓中增殖,动员到血液中,过继转移到肝脏并分化为KCs。然后,在慢性肝脏炎症的背景下,我们证实,再繁殖的KCs直接起源于HSC。
结论:综合来看,这些发现提供了体内命运图谱证据,表明重新繁殖的KCs直接源自HSC,这提出了一个全新的理解的细胞起源的再增殖KCs和阐明不同作用的KCs在肝脏稳态和疾病。
Kupffer cells (KCs) originate from yolk-sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at a steady state and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adults remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence.
We first traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models, respectively. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC-depletion in mice. Finally, we traced the fate of hematopoietic stem cells (HSCs) in an HSC-specific fate-mapping mouse model, in the context of chronic liver inflammation induced by repeated carbon tetrachloride treatment.
By using fate-mapping mouse models, we found no evidence that repopulating KCs originate from preexisting KCs or MOs and found that in response to KC-depletion, HSCs proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Then, in the chronic liver inflammation context, we confirmed that repopulating KCs originated directly from HSCs.
Taken together, these findings provided in vivo fate-mapping evidence that repopulating KCs originate directly from HSCs, which presents a completely novel understanding of the cellular origin of repopulating KCs and shedding light on the divergent roles of KCs in liver homeostasis and diseases.