Highlights
- •Kupffer cell-specific Cre-driven RiboTag reporter allows translatome analysis.
- •Fetal-derived Kupffer cells are relatively radioresistant.
- •Adult monocyte-derived Kupffer cells are sensitive to lethal irradiation.
- •p21Cip/WAF1 regulates the radioresistance of the fetal subset.
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.
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 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.
Results
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-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.
Conclusions
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.
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 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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: May 08, 2019
Accepted:
April 15,
2019
Received in revised form:
April 10,
2019
Received:
January 3,
2019
Identification
Copyright
Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
