Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation.
Adipose tissue expansion, resulting from adipocyte hyperplasia and/or hypertrophy, is a hallmark of obesity. Adipocytes are derived from mesenchymal stem cells (MSCs) through adipogenesis, a process involving three key steps: proliferation, commitment and differentiation. Although studies have elaborated on the mechanisms regulating adipocyte commitment and differentiation, the factors that control MSC proliferation remain largely unknown. Previously, we demonstrated that bone morphogenetic protein 3 (Bmp3), the expression of which was upregulated in our rat model of hyperplasic visceral adiposity, potently stimulated MSC proliferation. In the present study, we investigate the molecular target of Bmp3. We conducted DNA microarray analysis on MSCs treated with and without Bmp3 and identified WNT1-inducible signaling pathway protein 1 (Wisp1) as a differentially expressed gene, whose expression was upregulated 3.7-fold by Bmp3. Wisp1 is a proliferative agent in various non-adipose cell types and is implicated in adipogenesis. Therefore, we tested the hypothesis that Wisp1 mediates Bmp3 stimulation of MSC proliferation. We showed that Bmp3 increased the expression of Wisp1 as early as 3 h following Bmp3 treatment in MSCs. Importantly, the upregulated Wisp1 expression preceded Bmp3-induced MSC proliferation, as determined by [(3)H]-thymidine incorporation. Furthermore, treatment of MSCs with recombinant Wisp1 led to a concentration-dependent increase in [(3)H]-thymidine incorporation with a maximal increase of 300%. In addition, siRNA-mediated knockdown of Wisp1 expression attenuated Bmp3-induced MSC proliferation. Taken together, our present findings reveal Wisp1 as a novel target of Bmp3 and suggest that the Bmp3/Wisp1 signaling pathway play a key role in MSC proliferation, and consequently adipogenesis.
Departments of Obstetrics and Gynaecologyand Physiology and Pharmacology, Children's Health Research Institute and Lawson Health Research Institute, Western University, Room A5-132, 800 Commissioners Road East, London, Ontario, Canada, N6C 2V5.
Maria
M
Cernea
Departments of Obstetrics and Gynaecologyand Physiology and Pharmacology, Children's Health Research Institute and Lawson Health Research Institute, Western University, Room A5-132, 800 Commissioners Road East, London, Ontario, Canada, N6C 2V5.
Wei
W
Tang
Departments of Obstetrics and Gynaecologyand Physiology and Pharmacology, Children's Health Research Institute and Lawson Health Research Institute, Western University, Room A5-132, 800 Commissioners Road East, London, Ontario, Canada, N6C 2V5.
Haiyan
H
Guan
Departments of Obstetrics and Gynaecologyand Physiology and Pharmacology, Children's Health Research Institute and Lawson Health Research Institute, Western University, Room A5-132, 800 Commissioners Road East, London, Ontario, Canada, N6C 2V5 kyang@uwo.ca.
Kaiping
K
Yang
D050156:Adipogenesis; D000818:Animals; D055398:Bone Morphogenetic Protein 3 / Q000502:physiology*; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D059467:Transcriptome
C525758:Bmp3 protein, mouse; D055398:Bone Morphogenetic Protein 3; D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D011518:Proto-Oncogene Proteins
Bmp3; Wisp1; adipogenesis; mesenchymal stem cells; proliferation