title: The effects of mesenchymal stem cells on c-kit up-regulation and cell-cycle re-entry of neonatal cardiomyocytes are mediated by activation of insulin-like growth factor 1 receptor.
abstract: C-kit-positive neonatal cardiomyocytes (NCMs) contribute to myocardial regeneration. However, the myocardium itself cannot give rise to a robust regenerative response owing to the limited numbers of c-kit-positive resident stem cells present in the heart. It has been shown that mesenchymal stem cells (MSCs) can enhance cardiac repair via the release of paracrine factors such as insulin-like growth factor (IGF-1). We investigated whether the increased expression of c-kit in NCMs mediates the beneficial effects of MSCs on cardiac repair. MSCs and NCMs were prepared from Lewis rats and co-cultured in a Transwell system, which allowed the diffusion of secreted factors but prevented cell contact between the two cell types. The proliferation of NCMs was determined by BrdU assay. The expression of c-kit was assessed by real-time PCR and flow cytometry. The apoptosis rate of NCMs in response to hypoxia was determined by flow cytometry. We found that the expression of c-kit in NCMs was increased by paracrine factors released by MSCs. The effect of paracrine factors on c-kit expression was attenuated by IGF-1 receptor-neutralizing antibody. Furthermore, we found that increased c-kit expression requires IGF-1 receptor activation via the phosphatidylinositol 3 kinase/Akt-mediated pathway. These findings provide a new paradigm for the biological effects of IGF-1 and have significant implications for understanding the beneficial effects of MSCs on myocardial regeneration.
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, People's Republic of China. yuxycn@hotmail.com
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Shan
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Lin
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Song
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt