Department of Global Health, University of Washington, Seattle, WA, USA.
Department of Pathology, University of Washington, Seattle, WA, USA.
J Hepatol. 2019 Sep;71(3):553-562. doi: 10.1016/j.jhep.2019.04.015. Epub 2019 May 9.
BACKGROUND & AIMS: Cells of hematopoietic origin, including macrophages, are generally radiation sensitive, but a subset of Kupffer cells (KCs) is relatively radioresistant. Here, we focused on the identity of the radioresistant KCs in unmanipulated mice and the mechanism of radioresistance.
We employed Emr1- and inducible CX3Cr1-based fate-mapping strategies combined with the RiboTag reporter to identify the total KCs and the embryo-derived KCs, respectively. The KC compartment was reconstituted with adult bone-marrow-derived KCs (bm-KCs) using clodronate depletion. Mice were lethally irradiated and transplanted with donor bone marrow, and the radioresistance of bone-marrow- or embryo-derived KCs was studied. Gene expression was analyzed using in situ mRNA isolation via RiboTag reporter mice, and the translatomes were compared among subsets.
Here, we identified the radioresistant KCs as the long-lived subset that is derived from CX3CR1-expressing progenitor cells in fetal life, while adult bm-KCs do not resist irradiation. While both subsets upregulated the Cdkn1a gene, encoding p21- protein, radioresistant embryo-derived KCs showed a greater increase in response to irradiation. In the absence of this molecule, the radioresistance of KCs was compromised. Replacement KCs, derived from adult hematopoietic stem cells, differed from radioresistant KCs in their expression of genes related to immunity and phagocytosis.
Here, we show that, in the murine liver, a subset of KCs of embryonic origin resists lethal irradiation through Cdkn1a upregulation and is maintained for a long period, while bm-KCs do not survive lethal irradiation.
Kupffer cells (KCs) are the tissue-resident macrophages of the liver. KCs can be originated from fetal precursors and from monocytes during the fetal stage and post-birth, respectively. Most immune cells in mice are sensitive to lethal-irradiation-induced death, while a subset of KCs resists radiation-induced death. These radioresistant KCs continue to live in the irradiated mice. We discovered that this relatively radioresistant KC subset are the fetal-derived KCs, and they achieve this through cell-cycle arrest. Understanding the radiobiology of KCs will provide valuable insights into the mechanisms that elicit radiation-induced liver disease.
造血细胞来源的细胞，包括巨噬细胞，通常对辐射敏感，但一部分库普弗细胞（KCs）具有相对的辐射抗性。在这里，我们专注于未受干预的小鼠中辐射抗性 KC 的特征及其辐射抗性的机制。
我们采用 Emr1 和诱导型 CX3Cr1 为基础的命运映射策略，结合 RiboTag 报告基因分别鉴定总 KC 和胚胎衍生的 KC。用氯膦酸盐耗竭重建 KC 区室，使用成年骨髓来源的 KC（bm-KC）。用致死剂量照射小鼠并移植供体骨髓，研究骨髓或胚胎来源的 KC 的辐射抗性。使用 RiboTag 报告基因小鼠通过原位 mRNA 分离分析基因表达，并比较各亚群的翻译组。
在这里，我们鉴定出辐射抗性 KC 为长寿命亚群，它来源于胎儿期表达 CX3CR1 的祖细胞，而成年 bm-KC 不能抵抗照射。虽然两个亚群均上调 Cdkn1a 基因，编码 p21-蛋白，但辐射抗性胚胎衍生的 KC 对照射的反应增加更大。在缺乏这种分子的情况下，KC 的辐射抗性受损。来自成年造血干细胞的替代 KC，在其与免疫和吞噬相关的基因表达方面与辐射抗性 KC 不同。
在这里，我们表明，在小鼠肝脏中，一部分胚胎起源的 KC 通过 Cdkn1a 的上调抵抗致死性照射，并长期维持，而 bm-KC 不能在致死性照射下存活。
库普弗细胞（KC）是肝脏的组织驻留巨噬细胞。KC 可以来源于胎儿前体，也可以来源于胎儿期和出生后的单核细胞。大多数免疫细胞在小鼠中对致死性辐射诱导的死亡敏感，而一部分 KC 抵抗辐射诱导的死亡。这些辐射抗性 KC 继续在照射的小鼠中存活。我们发现，这种相对辐射抗性的 KC 亚群是由胎儿衍生的 KC，它们通过细胞周期停滞来实现这一目的。了解 KC 的放射生物学将为辐射诱导的肝脏疾病的机制提供有价值的见解。
