Open AccessCrif1 Promotes Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells After Irradiation by Modulating the PKA/CREB Signaling Pathway
Author(s) -
Zhang Xi,
Xiang Lixin,
Ran Qian,
Liu Yao,
Xiang Yang,
Xiao Yanni,
Chen Li,
Li Fengjie,
Zhong Jiang F.,
Li Zhongjun
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2019
Subject(s) - adipogenesis , creb , haematopoiesis , mesenchymal stem cell , cyclic amp response element binding protein , biology , phosphorylation , gene knockdown , microbiology and biotechnology , protein kinase a , bone marrow , stem cell , signal transduction , transcription factor , immunology , biochemistry , gene
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. S tem C ells 2015;33:1915–1926