The role of growth factors in maintenance of stemness in bone marrow-derived mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are an active topic of research in regenerative medicine due to their ability to secrete a variety of growth factors and cytokines that promote healing of damaged tissues and organs. In addition, these secreted growth factors and cytokines have been shown to exert an autocrine effect by regulating MSC proliferation and differentiation. We found that expression of EGF, FGF-4 and HGF were down-regulated during serial passage of bone marrow-derived mesenchymal stem cells (BMSCs). Proliferation and differentiation potentials of BMSCs treated with these growth factors for 2 months were evaluated and compared to BMSCs treated with FGF-2, which increased proliferation of BMSCs. FGF-2 and -4 increased proliferation potentials at high levels, about 76- and 26-fold, respectively, for 2 months, while EGF and HGF increased proliferation of BMSCs by less than 2.8-fold. Interestingly, differentiation potential, especially adipogenesis, was maintained only by HGF treatment. Treatment with FGF-2 rapidly induced activation of AKT and later induced ERK activation. The basal level of phosphorylated ERK increased during serial passage of BMSCs treated with FGF-2. The expression of LC3-II, an autophagy marker, was gradually increased and the population of senescent cells was increased dramatically at passage 7 in non-treated controls. But FGF-2 and FGF-4 suppressed LC3-II expression and down-regulated senescent cells during long-term (i.e. 2month) cultures. Taken together, depletion of growth factors during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF) through suppression of AKT and ERK signaling.
Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Young Woo
YW
Eom
Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Ji-Eun
JE
Oh
Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Jong In
JI
Lee
Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea; Department of Internal Medicine, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Soon Koo
SK
Baik
Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei Univ., Wonju, Republic of Korea.
Ki-Jong
KJ
Rhee
Pharmicell Co., Ltd., Sungnam, Republic of Korea.
Ha Cheol
HC
Shin
Pharmicell Co., Ltd., Sungnam, Republic of Korea.
Yong Man
YM
Kim
Department of Basic Science, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Chan Mug
CM
Ahn
Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea.
Jee Hyun
JH
Kong
Pharmicell Co., Ltd., Sungnam, Republic of Korea. Electronic address: khsmd@pharmicell.com.
Hyun Soo
HS
Kim
Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju, Republic of Korea. Electronic address: kyshim@yonsei.ac.kr.
Kwang Yong
KY
Shim
D000328:Adult; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051519:Fibroblast Growth Factor 4 / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055815:Young Adult
C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; C066855:HGF protein, human; D036341:Intercellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
Autophagy; Bone marrow-derived mesenchymal stem cell; Growth factor; Senescence; Stemness