BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage.
Obesity is accompanied by an increase in both adipocyte number and size. The increase in adipocyte number is the result of recruitment to the adipocyte lineage of pluripotent stem cells present in the vascular stroma of adipose tissue. These pluripotent cells have the potential to undergo commitment and then differentiate into adipocytes, as well as myocytes, osteocytes, and chondrocytes. In this article, we show that both bone morphogenetic protein (BMP)2 and BMP4 can induce commitment of C3H10T1/2 pluripotent stem cells into adipocytes. After treatment of C3H10T1/2 stem cells with these BMPs during proliferation followed by exposure to differentiation inducers at growth arrest, nearly all cells enter the adipose development pathway, express specific adipocyte markers, and acquire the adipocyte phenotype. Overexpression of constitutively active BMP receptor (CA)-BMPr1A or CA-BMPr1B induces commitment in the absence of BMP2/4, whereas overexpression of a dominant-negative receptor dominant-negative-BMPr1A suppresses commitment induced by BMP. Also, knockdown of the expression of Smad4 (coregulator in the BMP/Smad signaling pathway) with RNAi disrupts commitment by the BMPs. However, knockdown of expression of p38 MAPK (an intermediary in the BMP/MAPK signaling pathway) with RNAi had little effect on BMP-induced commitment. Together, these findings indicate that the BMP/Smad signaling pathway has a dominant role in adipocyte lineage determination. Proteomic analysis identified lysyl oxidase (LOX), a bona fide downstream target gene of the BMP signaling pathway. Expression of LOX is induced by BMP2/4 during adipocyte lineage commitment, and knockdown of its expression disrupts the commitment process.
Huang
Haiyan
H
Department of Biochemistry and Molecular Biology, Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University Shanghai Medical College, Shanghai 200032, People's Republic of China.
Song
Tan-Jing
TJ
Li
Xi
X
Hu
Lingling
L
He
Qun
Q
Liu
Mei
M
Lane
M Daniel
MD
Tang
Qi-Qun
QQ
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology*; D008249:Protein-Lysine 6-Oxidase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D008249:Protein-Lysine 6-Oxidase; D048051:p38 Mitogen-Activated Protein Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II