title: Pdcd4 restrains the self-renewal and white-to-beige transdifferentiation of adipose-derived stem cells.
abstract: The stemness maintenance of adipose-derived stem cells (ADSCs) is important for adipose homeostasis and energy balance. Programmed cell death 4 (Pdcd4) has been demonstrated to be involved in the development of obesity, but its possible roles in ADSC function and adipogenic capacity remain unclear. In this study, we demonstrate that Pdcd4 is a key controller that limits the self-renewal and white-to-beige transdifferentiation of ADSCs. Pdcd4 deficiency in mice caused stemness enhancement of ADSCs as evidenced by increased expression of CD105, CD90, Nanog and Oct4 on ADSCs, together with enhanced in situ proliferation in adipose tissues. Pdcd4 deficiency promoted proliferation, colony formation of ADSCs and drove more ADSCs entering the S phase accompanied by AKT activation and cyclinD1 upregulation. Blockade of AKT signaling in Pdcd4-deficient ADSCs led to a marked decline in cyclinD1, S-phase entry and cell proliferation, revealing AKT as a target for repressing ADSC self-renewal by Pdcd4. Intriguingly, depletion of Pdcd4 promoted the transdifferentiation of ADSCs into beige adipocytes. A reduction in lipid contents and expression levels of white adipocyte markers including C/EBPα, PPAR-γ, adiponectin and αP2 was detected in Pdcd4-deficient ADSCs during white adipogenic differentiation, substituted by typical beige adipocyte characteristics including small, multilocular lipid droplets and UCP1 expression. More lactate produced by Pdcd4-deficient ADSCs might be an important contributor to the expression of UCP1 and white-to-beige transdifferentiation. In addition, an elevation of UCP1 expression was confirmed in white adipose tissues from Pdcd4-deficient mice upon high-fat diet, which displayed increased energy expenditure and resistance to obesity as compared with wild-type obese mice. These findings provide evidences that Pdcd4 produces unfavorable influences on ADSC stemness, which contribute to adipose dysfunction, obesity and metabolic syndromes, thereby proposing Pdcd4 as a potential intervening target for regulating ADSC function.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Shang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: C
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
mesh_terms: D050156:Adipogenesis; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D059305:Diet, High-Fat; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D051017:Apoptosis Regulatory Proteins; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D047495:PPAR gamma; C498443:Pdcd4 protein, mouse; C494174:Pou5f1 protein, mouse; D016601:RNA-Binding Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D019938:Cyclin D1