title: Crif1 Promotes Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells After Irradiation by Modulating the PKA/CREB Signaling Pathway.
abstract: Dysfunction of the hematopoietic microenvironment is the main obstacle encountered during hematopoiesis reconstruction in patients with acute hematopoietic radiation syndrome. Bone marrow mesenchymal stem cells (BM-MSCs) play a crucial supporting role in hematopoiesis by maintaining the balance between adipogenic and osteogenic differentiation. In this study, we found that irradiation decreased the colony-forming efficiency of BM-MSCs and impaired the balance between adipogenic and osteogenic differentiation. Following irradiation, BM-MCSs became strongly predisposed to adipogenesis, as evidenced by increased oil red O staining and elevated mRNA and protein levels of the adipogenic markers and transcription factors PPARγ and AP2. Overexpression of the essential adipogenesis regulator Crif1 in BM-MSCs promoted adipogenesis after irradiation exposure by upregulating adipogenesis-related genes, including C/EBPβ, PPARγ, and AP2. We found that Crif1 promoted the phosphorylation of cAMP response element binding protein (CREB) through direct interaction with protein kinase A (PKA)-α. Phosphorylation of CREB was inhibited in Crif1-knockdown BM-MSCs even in the presence of a PKA agonist (db-cAMP) and could be suppressed in Crif1-overexpressing BM-MSCs by a PKAα inhibitor (H-89). These results suggest that Crif1 is an indispensable regulator of PKAα cat that modulates the PKA/CREB signaling pathway to promote adipogenic differentiation of BM-MSCs after irradiation.
authors.affiliation: Department of Hematology and, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ran
authors.affiliation: Department of Hematology and, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine, California, USA.
authors.forename: Jiang F
authors.initials: JF
authors.lastname: Zhong
authors.affiliation: Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Li
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000528:radiation effects; D009687:Nuclear Proteins / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C115163:CREB1 protein, human; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C476586:GADD45GIP1 protein, human; D009687:Nuclear Proteins; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Adipogenesis; Bone marrow mesenchymal stem cells; Protein kinase A; Radiation