Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure.
Mesenchymal stem cells (MSCs) have been studied for the treatment of acute liver failure (ALF) for several years. MSCs may exert their effect via complex paracrine mechanisms. Heme oxygenase (HO) 1, a rate-limiting enzyme in heme metabolism, exerts a wide range of anti-inflammatory, anti-apoptotic and immunoregulatory effects in a variety of diseases. However, the relationship between MSCs and HO-1 in the treatment of ALF is still unclear. We investigated the preventive and therapeutic potential of intravenously administered BMSCs.



Bone marrow-derived mesenchymal stem cells (BMSCs) obtained from Sprague-Dawley rats were isolated and cultured. We employed BMSCs, hemin (a HO-1 inducer) and zinc protoporphyrin (ZnPP, the HO-1 activity inhibitor) in D-galactosamine (D-Gal)/lipopolysaccharides (LPS)-induced ALF rats. Rats were sacrificed at days 1, 3, 5, and 7 post-transfusion, respectively. Blood samples and liver tissues were collected. Hepatic injury, HO-1 activity, chemokines, inflammatory cytokines, the number and oxidative activity of neutrophils, ki67, and TUNEL-positive cells were evaluated.



HO-1 induction or BMSCs transplantation attenuated D-galactosamine/lipopolysaccharide-induced increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBIL), ammonia, and inflammatory cytokines. Treatment with hemin or BMSCs also inhibited neutrophil infiltration, oxidative activity, and hepatocyte apoptosis. The protective effect of BMSCs was partially neutralized by ZnPP, suggesting the key role of HO-1 in the process.



These findings may correlate with inhibition of nuclear factor-κ B activation. BMSCs ameliorated ALF by increasing the HO-1 expression, which reduced PMN infiltration and function, and played an important anti-inflammatory and anti-apoptotic role. Proposed mechanism by which BMSCs reduce inflammation, neutrophil activation, and hepatocyte apoptosis and promote hepatocyte proliferation via HO-1. BMSCs increase HO-1 expression in liver via Nrf2. HO-1 protects against LPS/D-Gal-induced ALF by inhibiting neutrophil infiltration and inflammatory burst, and hepatocyte apoptosis and necrosis. HO-1 also promotes hepatocyte proliferation.
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Zhi-Heng
ZH
Zhang
Department of Anesthesiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Wei
W
Zhu
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Hao-Zhen
HZ
Ren
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Xin
X
Zhao
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.|Department of Hepatobiliary Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China.
Shuai
S
Wang
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Hu-Cheng
HC
Ma
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. njsxl2000@163.com.
Xiao-Lei
XL
Shi
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002469:Cell Separation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000473:pathology / Q000628:therapy*; D008115:Liver Regeneration; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020556:Neutrophil Infiltration; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016897:Respiratory Burst
D000893:Anti-Inflammatory Agents; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D008315:Malondialdehyde; D009195:Peroxidase; D051547:Heme Oxygenase-1
Acute liver injury; Heme oxygenase-1; Inflammation; Mesenchymal stem cells; NF-κB; Neutrophils; PMNs