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PBX homeobox 1 enhances hair follicle mesenchymal stem cell proliferation and reprogramming through activation of the AKT/glycogen synthase kinase signaling pathway and suppression of apoptosis.
Stem Cell Res Ther. 2019 08 23; 10(1):268.SC

Abstract

BACKGROUND

PBX homeobox 1 (PBX1) is involved in the maintenance of the pluripotency of human embryonic and hematopoietic stem cells; however, the effects of PBX1 in the self-renewal and reprogramming of hair follicle mesenchymal stem cells (HF-MSCs) are unclear. The AKT/glycogen synthase kinase (GSK) 3β pathway regulates cell metabolism, proliferation, apoptosis, and reprogramming, and p16 and p21, which act downstream of this pathway, regulate cell proliferation, cell cycle, and apoptosis induced by reprogramming. Here, we aimed to elucidate the roles of PBX1 in regulating the proliferation and reprogramming of HF-MSCs.

METHODS

A lentiviral vector designed to carry the PBX1 sequence or PBX1 short hairpin RNA sequence was used to overexpress or knock down PBX1. The roles of PBX1 in proliferation and apoptosis were investigated by flow cytometry. Real-time polymerase chain reaction was performed to evaluate pluripotent gene expression. Dual-luciferase reporter assays were performed to examine the transcriptional activity of the NANOG promoter. Western blotting was performed to identify the molecules downstream of PBX1 involved in proliferation and reprogramming. Caspase3 activity was detected to assess HF-MSC reprogramming. The phosphatidylinositol 3-kinase/AKT inhibitor LY294002 was used to inhibit the phosphorylation and activity of AKT.

RESULTS

Overexpression of PBX1 in HF-MSCs increased the phosphorylation of AKT and nuclear translocation of β-catenin, resulting in the progression of the cell cycle from G0/G1 to S phase. Moreover, transfection with a combination of five transcription factors (SOMKP) in HF-MSCs enhanced the formation of alkaline phosphatase-stained colonies compared with that in HF-MSCs transfected with a combination of four transcription factors (SOMK). PBX1 upregulated Nanog transcription by activating the promoter and promoted the expression of endogenous SOX2 and OCT4. Furthermore, PBX1 expression activated the AKT/glycogen synthase kinase (GSK) 3β pathway and reduced apoptosis during the early stages of reprogramming. Inhibition of phospho-AKT or knockdown of PBX1 promoted mitochondrion-mediated apoptosis and reduced reprogramming efficiency.

CONCLUSIONS

PBX1 enhanced HF-MSC proliferation, and HF-MSCs induced pluripotent stem cells (iPSC) generation by activating the AKT/GSK3β signaling pathway. During the reprogramming of HF-MSCs into HF-iPSCs, PBX1 activated the NANOG promoter, upregulated NANOG, and inhibited mitochondrion-mediated apoptosis via the AKT/GSK3β pathway during the early stages of reprogramming.

Authors+Show Affiliations

The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China.Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, 130021, China.Department of Pediatrics, The First Hospital of Jilin University, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China.Stem Cell and Tissue Engineering Research Laboratory, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, China.Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, 999077, China.The Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, China. jy_liu@jlu.edu.cn. Department of Toxicology, School of Public Health, Jilin University, 1163 Xinmin Avenue, Changchun, 130021, China. jy_liu@jlu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31443676

Citation

Jiang, Yixu, et al. "PBX Homeobox 1 Enhances Hair Follicle Mesenchymal Stem Cell Proliferation and Reprogramming Through Activation of the AKT/glycogen Synthase Kinase Signaling Pathway and Suppression of Apoptosis." Stem Cell Research & Therapy, vol. 10, no. 1, 2019, p. 268.
Jiang Y, Liu F, Zou F, et al. PBX homeobox 1 enhances hair follicle mesenchymal stem cell proliferation and reprogramming through activation of the AKT/glycogen synthase kinase signaling pathway and suppression of apoptosis. Stem Cell Res Ther. 2019;10(1):268.
Jiang, Y., Liu, F., Zou, F., Zhang, Y., Wang, B., Zhang, Y., Lian, A., Han, X., Liu, Z., Liu, X., Jin, M., Wang, D., Li, G., & Liu, J. (2019). PBX homeobox 1 enhances hair follicle mesenchymal stem cell proliferation and reprogramming through activation of the AKT/glycogen synthase kinase signaling pathway and suppression of apoptosis. Stem Cell Research & Therapy, 10(1), 268. https://doi.org/10.1186/s13287-019-1382-y
Jiang Y, et al. PBX Homeobox 1 Enhances Hair Follicle Mesenchymal Stem Cell Proliferation and Reprogramming Through Activation of the AKT/glycogen Synthase Kinase Signaling Pathway and Suppression of Apoptosis. Stem Cell Res Ther. 2019 08 23;10(1):268. PubMed PMID: 31443676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PBX homeobox 1 enhances hair follicle mesenchymal stem cell proliferation and reprogramming through activation of the AKT/glycogen synthase kinase signaling pathway and suppression of apoptosis. AU - Jiang,Yixu, AU - Liu,Feilin, AU - Zou,Fei, AU - Zhang,Yingyao, AU - Wang,Bo, AU - Zhang,Yuying, AU - Lian,Aobo, AU - Han,Xing, AU - Liu,Zinan, AU - Liu,Xiaomei, AU - Jin,Minghua, AU - Wang,Dianliang, AU - Li,Gang, AU - Liu,Jinyu, Y1 - 2019/08/23/ PY - 2019/04/23/received PY - 2019/08/12/accepted PY - 2019/08/08/revised PY - 2019/8/25/entrez PY - 2019/8/25/pubmed PY - 2020/7/14/medline KW - AKT KW - Apoptosis KW - Glycogen synthase kinase 3β KW - Hair follicle mesenchymal stem cells KW - NANOG KW - PBX homeobox 1 SP - 268 EP - 268 JF - Stem cell research & therapy JO - Stem Cell Res Ther VL - 10 IS - 1 N2 - BACKGROUND: PBX homeobox 1 (PBX1) is involved in the maintenance of the pluripotency of human embryonic and hematopoietic stem cells; however, the effects of PBX1 in the self-renewal and reprogramming of hair follicle mesenchymal stem cells (HF-MSCs) are unclear. The AKT/glycogen synthase kinase (GSK) 3β pathway regulates cell metabolism, proliferation, apoptosis, and reprogramming, and p16 and p21, which act downstream of this pathway, regulate cell proliferation, cell cycle, and apoptosis induced by reprogramming. Here, we aimed to elucidate the roles of PBX1 in regulating the proliferation and reprogramming of HF-MSCs. METHODS: A lentiviral vector designed to carry the PBX1 sequence or PBX1 short hairpin RNA sequence was used to overexpress or knock down PBX1. The roles of PBX1 in proliferation and apoptosis were investigated by flow cytometry. Real-time polymerase chain reaction was performed to evaluate pluripotent gene expression. Dual-luciferase reporter assays were performed to examine the transcriptional activity of the NANOG promoter. Western blotting was performed to identify the molecules downstream of PBX1 involved in proliferation and reprogramming. Caspase3 activity was detected to assess HF-MSC reprogramming. The phosphatidylinositol 3-kinase/AKT inhibitor LY294002 was used to inhibit the phosphorylation and activity of AKT. RESULTS: Overexpression of PBX1 in HF-MSCs increased the phosphorylation of AKT and nuclear translocation of β-catenin, resulting in the progression of the cell cycle from G0/G1 to S phase. Moreover, transfection with a combination of five transcription factors (SOMKP) in HF-MSCs enhanced the formation of alkaline phosphatase-stained colonies compared with that in HF-MSCs transfected with a combination of four transcription factors (SOMK). PBX1 upregulated Nanog transcription by activating the promoter and promoted the expression of endogenous SOX2 and OCT4. Furthermore, PBX1 expression activated the AKT/glycogen synthase kinase (GSK) 3β pathway and reduced apoptosis during the early stages of reprogramming. Inhibition of phospho-AKT or knockdown of PBX1 promoted mitochondrion-mediated apoptosis and reduced reprogramming efficiency. CONCLUSIONS: PBX1 enhanced HF-MSC proliferation, and HF-MSCs induced pluripotent stem cells (iPSC) generation by activating the AKT/GSK3β signaling pathway. During the reprogramming of HF-MSCs into HF-iPSCs, PBX1 activated the NANOG promoter, upregulated NANOG, and inhibited mitochondrion-mediated apoptosis via the AKT/GSK3β pathway during the early stages of reprogramming. SN - 1757-6512 UR - https://www.unboundmedicine.com/medline/citation/31443676/PBX_homeobox_1_enhances_hair_follicle_mesenchymal_stem_cell_proliferation_and_reprogramming_through_activation_of_the_AKT/glycogen_synthase_kinase_signaling_pathway_and_suppression_of_apoptosis_ L2 - https://stemcellres.biomedcentral.com/articles/10.1186/s13287-019-1382-y DB - PRIME DP - Unbound Medicine ER -