title: Hypoxia-inducible factor-2 alpha promotes the proliferation of human placenta-derived mesenchymal stem cells through the MAPK/ERK signaling pathway.
abstract: Human placenta-derived mesenchymal stem cells (hPMSCs) reside in a physiologically low-oxygen microenvironment. Hypoxia influences a variety of stem cell cellular activities, frequently involving hypoxia-inducible factor-2 alpha (HIF-2α). This research showed that hPMSCs cultured in hypoxic conditions (5% O2) exhibited a more naïve morphology and had a higher proliferative capability and higher HIF-2α expression than hPMSCs cultured in normoxic conditions (21% O2). Similar to the hypoxic cultures, hPMSCs over-expressing HIF-2α showed higher proliferative potential and higher expression of CCND1 (CyclinD1), MYC (c-Myc), POU5F1 (Oct4) and the components of the MAPK/ERK pathway. In contrast, these genes were down-regulated in the HIF-2α-silenced hPMSCs. After adding the MAPK/ERK inhibitor PD0325901, cell growth and the expression of CCND1 and MYC were inhibited. Furthermore, the chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA) showed that HIF-2α bound to the MAPK3 (ERK1) promoter, indicative of its direct regulation of MAPK/ERK components at the transcriptional level during hPMSC expansion. Taken together, our results suggest that HIF-2α facilitated the preservation of hPMSC stemness and promoted their proliferation by regulating CCND1 and MYC through the MAPK/ERK signaling pathway.
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Chengxing
authors.initials: C
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yu
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Pan
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Yang
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Guangshu
authors.initials: G
authors.lastname: Hao
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
authors.forename: Hongcui
authors.initials: H
authors.lastname: Cao
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D010920:Placenta / Q000166:cytology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001549:Benzamides; D004159:Diphenylamine; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C506614:mirdametinib