Fetal origin confers radio-resistance on liver macrophages via p21 cip1/WAF1 .

BACKGROUND AND 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.

METHODS: 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, transplanted with donor bone marrow and the radioresistance of bone marrow- or embryo-derived KC were studied. Gene expression was analyzed using in situ mRNA isolation via RiboTag reporter mice, and the translatomes were compared among subsets.

RESULTS: Here we identify 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-cip1/WAF1 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.

CONCLUSION: Here we show that in the murine liver a subset of KCs of embryonic origin resists lethal irradiation through Cdkn1a upregulation, and are maintained for a long period, while bm-KCs do not survive lethal irradiation.

LAY SUMMARY: 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 is the fetal-derived KCs and they achieve this through cell cycle arrest. Understanding the radiobiology of KCs will provide valuable insights into mechanisms that elicit Radiation Induced Liver Disease.