The angiogenic related functions of bone marrow mesenchymal stem cells are promoted by CBDL rat serum via the Akt/Nrf2 pathway.
Hepatopulmonary syndrome (HPS) is a complication of severe liver disease. It is characterized by an arterial oxygenation defect. Recent studies have demonstrated that pulmonary angiogenesis contributes to the abnormal gas exchange found in HPS. Additionally, mesenchymal stem cells (MSCs) are considered the stable source of VEGF-producing cells and have the potential to differentiate into multiple cell types. However, it has not been determined whether bone marrow mesenchymal stem cells (BM-MSCs) are mobilized and involved in the pulmonary angiogenesis in HPS. In this study, a CFU-F assay showed that the number of peripheral blood MSCs was increased in common bile duct ligation (CBDL) rats; however, there was no significant difference found in the number of BM-MSCs. In vitro, CBDL rat serum induced the overexpression of CXCR4 and PCNA in BM-MSCs. Consistently, the directional migration as well as the proliferation ability of BM-MSCs were enhanced by CBDL rat serum, as determined by a transwell migration and MTT assays. Moreover, the secretion of VEGF by BM-MSCs increased after treatment with CBDL rat serum. We also found that the expression of phospho-Akt, phospho-ERK, and Nrf2 in BM-MSCs was significantly up-regulated by CBDL rat serum in a time dependent manner, and the blockage of the Akt/Nrf2 signalling pathway with an Akt Inhibitor or Nrf2 siRNA, instead of an ERK inhibitor, attenuated the migration, proliferation and paracrine capacity of BM-MSCs. In conclusion, these findings indicated that the number of MSCs increased in the peripheral blood of CBDL rats, and the Akt/Nrf2 pathway plays a vital role in promoting the angiogenic related functions of BM-MSCs, which could be a potent contributor to pulmonary angiogenesis in HPS.
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Cheng-Cheng
CC
Shen
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Bing
B
Chen
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Jian-Teng
JT
Gu
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Jiao-Lin
JL
Ning
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Lin
L
Chen
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
Jing
J
Zeng
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: yibin1974@163.com.
Bin
B
Yi
Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: lukaizhi2010@163.com.
Kai-Zhi
KZ
Lu
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003135:Common Bile Duct / Q000187:drug effects / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008026:Ligation; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D044967:Serum / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D018809:Proliferating Cell Nuclear Antigen; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
Angiogenesis; Common bile duct ligation; Hepatopulmonary syndrome; Mesenchymal stem cells