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Cited by 30Liver physiology and pathologyChemokine receptors and signalingOrgan Transplantation Techniques and Outcomes

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CXC Chemokines Function as a Rheostat for Hepatocyte Proliferation and Liver Regeneration

Open access
Wilson, Gregory C., Kuboki, Satoshi, Freeman, Christopher M., Nojima, Hiroyuki, Schuster, Rebecca M., Edwards, Michael J., Lentsch, Alex B.·2015·PLOS ONE
DOI 10.1371/journal.pone.0120092PMC PMC4355613
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Abstract

BACKGROUND: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy. METHODS: Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration. RESULTS: We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration. CONCLUSIONS: Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.

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Fig 1 Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy. Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.
Fig 1 Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy. Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.CC BY · PubMed Central
Fig 2 Hepatocyte proliferation and liver regeneration in ischemic and non-ischemic liver lobes after I/R injury. (A) Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 3–5 per group. *P<0.05 compared to ischemic liver. (B) Liver mass of ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–5 per group. *P<0.05 compared to sham.
Fig 2 Hepatocyte proliferation and liver regeneration in ischemic and non-ischemic liver lobes after I/R injury. (A) Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 3–5 per group. *P<0.05 compared to ischemic liver. (B) Liver mass of ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–5 per group. *P<0.05 compared to sham.CC BY · PubMed Central
Fig 3 Effect of CXCR2 on hepatocyte proliferation and liver regeneration after I/R injury (A) and partial hepatectomy (B) was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. (A) Hepatocyte proliferation in post-ischemic liver (upper panel) after I/R injury showed a significant increase in CXCR2−/− mice. Data are mean ± SEM with n = 3–14 per group. *P<0.05 compared to wild-type mice. Hepatocyte proliferation and liver regeneration in non-ischemic liver (lower panel) after I/R injury was significantly reduced in CXCR2−/− mice. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to wild-type mice. (B) Hepatocyte proliferation and liver regeneration after partial hepatectomy showed a significant decrease in CXCR2−/− mice. Data are mean ± SEM with n = 3–4 per group. *P<0.05 compared to wild-type mice.
Fig 3 Effect of CXCR2 on hepatocyte proliferation and liver regeneration after I/R injury (A) and partial hepatectomy (B) was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. (A) Hepatocyte proliferation in post-ischemic liver (upper panel) after I/R injury showed a significant increase in CXCR2−/− mice. Data are mean ± SEM with n = 3–14 per group. *P<0.05 compared to wild-type mice. Hepatocyte proliferation and liver regeneration in non-ischemic liver (lower panel) after I/R injury was significantly reduced in CXCR2−/− mice. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to wild-type mice. (B) Hepatocyte proliferation and liver regeneration after partial hepatectomy showed a significant decrease in CXCR2−/− mice. Data are mean ± SEM with n = 3–4 per group. *P<0.05 compared to wild-type mice.CC BY · PubMed Central
Fig 4 Effects of exogenous MIP-2 and KC treatment on hepatocyte proliferation and liver regeneration after partial hepatectomy. Wild-type mice were injected intravenously with high doses or low doses of MIP-2 and KC, starting 24 hours after hepatectomy and continued daily. An identical volume of sterile phosphate-buffered saline (PBS) was used as a vehicle control. (A) Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 4–8 per group. *P<0.05 compared to vehicle group. Original magnification was 400X. (B) Liver regeneration was determined by increases in liver mass. Data are mean ± SEM with n = 4–8 per group. *P<0.05 compared to vehicle group.
Fig 4 Effects of exogenous MIP-2 and KC treatment on hepatocyte proliferation and liver regeneration after partial hepatectomy. Wild-type mice were injected intravenously with high doses or low doses of MIP-2 and KC, starting 24 hours after hepatectomy and continued daily. An identical volume of sterile phosphate-buffered saline (PBS) was used as a vehicle control. (A) Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 4–8 per group. *P<0.05 compared to vehicle group. Original magnification was 400X. (B) Liver regeneration was determined by increases in liver mass. Data are mean ± SEM with n = 4–8 per group. *P<0.05 compared to vehicle group.CC BY · PubMed Central
Fig 5 Effects of exogenous MIP-2 and KC treatment on hepatocyte proliferation in the normal liver. Wild-type mice were injected intravenously with low doses of MIP-2 and KC every 24 hours. An identical volume of sterile phosphate-buffered saline (PBS) was used as a vehicle control. Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 4–8 per group. Original magnification was 400X.
Fig 5 Effects of exogenous MIP-2 and KC treatment on hepatocyte proliferation in the normal liver. Wild-type mice were injected intravenously with low doses of MIP-2 and KC every 24 hours. An identical volume of sterile phosphate-buffered saline (PBS) was used as a vehicle control. Hepatocyte proliferation was determined by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and quantitative analysis of PCNA labeling. Data are mean ± SEM with n = 4–8 per group. Original magnification was 400X.CC BY · PubMed Central

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Metadata

Authors
Wilson, G. C., Kuboki, S., Freeman, C. M., Nojima, H., Schuster, R. M., Edwards, M. J., & Lentsch, A. B.
Affiliations
University of Cincinnati (US)
Corresponding author
Lentsch, Alex B.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-03-10
Volume
10
Issue
3
Pages
e0120092
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0120092
PMC
PMC4355613
OpenAlex
W2067485136
Cited by
29
References
15
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 3
FWCI
2.17
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG-025881, R01AG025881)
  • National Institute of General Medical Sciences (GM08478, T32GM008478)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 56029, R01DK056029, P30DK078392)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
CXC chemokines, CXCR2, liver regeneration, hepatocyte proliferation, ischemia-reperfusion injury, partial hepatectomy, CXCL2, keratinocyte-derived chemokine, hepatocyte death
MeSH terms
Animals, Liver, Liver Regeneration, Male, Mice, Inbred BALB C, Reperfusion Injury, Mice, Knockout, Hepatocytes, Receptors, Interleukin-8B, Cell Proliferation, Chemokine CXCL2

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