Switch from Canonical to Noncanonical Wnt Signaling Mediates High Glucose‐Induced Adipogenesis

• Published in: Stem cells (Dayton, Ohio) Vol. 32; no. 6; pp. 1649 - 1660
• Main Authors: Keats, Emily C., Dominguez, James M., Grant, Maria B., Khan, Zia A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2014
• Subjects: AC133 Antigen; Adipogenesis; Adipogenesis - drug effects; Aged; Angiopoietin-2 - metabolism; Animals; Antigens, CD - metabolism; beta Catenin - metabolism; Bone marrow; Bone Marrow - pathology; Cell Differentiation - drug effects; Cell‐autogenous regulation; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Glucose; Glucose - pharmacology; Glycoproteins - metabolism; Humans; Kinases; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Middle Aged; Models, Biological; Noncanonical signaling; Peptides - metabolism; Protein kinase C; Protein Kinase C - metabolism; Rats, Sprague-Dawley; Small Molecule Libraries - pharmacology; Stem cells; Transplants & implants; Wnt Proteins - metabolism; Wnt signaling; Wnt Signaling Pathway - drug effects; Cell-autogenous regulation; Noncanonical signaling; Protein kinase C; Wnt signaling; Diabetes; Adipogenesis
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.1659

Human bone marrow mesenchymal progenitor cells (MPCs) are multipotent cells that play an essential role in endogenous repair and the maintenance of the stem cell niche. We have recently shown that high levels of glucose, conditions mimicking diabetes, cause impairment of MPCs, resulting in enhanced adipogenesis and suppression of osteogenesis. This implies that diabetes may lead to reduced endogenous repair mechanisms through altering the differentiation potential of MPCs and, consequently, disrupting the stem cell niche. Phenotypic alterations in the bone marrow of long‐term diabetic patients closely resemble this observation. Here, we show that high levels of glucose selectively enhance autogenous Wnt11 expression in MPCs to stimulate adipogenesis through the Wnt/protein kinase C noncanonical pathway. This novel mechanism may account for increased bone marrow adipogenesis, severe bone loss, and reduced vascular stem cells leading to chronic secondary complications of diabetes. Stem Cells 2014;32:1649–1660