title: Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content.
abstract: Pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, has been linked to distinct diseases involving adipose or bone tissue, the metabolic syndrome, and osteogenesis imperfecta (OI) type VI. Since mesenchymal stem cell (MSC) differentiation into adipocytes vs. osteoblasts can be regulated by specific factors, PEDF-directed dependency of murine and human MSCs was assessed. PEDF inhibited adipogenesis and promoted osteoblast differentiation of murine MSCs, osteoblast precursors, and human MSCs. Blockade of adipogenesis by PEDF suppressed peroxisome proliferator-activated receptor-γ (PPARγ), adiponectin, and other adipocyte markers by nearly 90% compared with control-treated cells (P<0.001). Differentiation to osteoblasts by PEDF resulted in a common pathway that involved PPARγ suppression (P<0.01). Canonical Wnt-β-catenin signaling results in a MSC differentiation pattern analogous to that seen with PEDF. Thus, adding PEDF enhanced Wnt-β-catenin signal transduction in human MSCs, demonstrating a novel Wnt agonist function. In PEDF knockout (KO) mice, total body adiposity was increased by >50% compared with controls, illustrating its systemic role as a negative regulator of adipogenesis. Bones from KO mice demonstrated a reduction in mineral content recapitulating the OI type VI phenotype. These results demonstrate that the human diseases associated with PEDF reflect its ability to modulate MSC differentiation.
authors.affiliation: 1Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, 1080 LMP, New Haven, CT, USA. chuhan.chung@yale.edu.
authors.forename: Arijeet K
authors.initials: AK
authors.lastname: Gattu
authors.forename: E Scott
authors.initials: ES
authors.lastname: Swenson
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Iwakiri
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Nancy
authors.initials: N
authors.lastname: Troiano
authors.forename: Ryan
authors.initials: R
authors.lastname: Berry
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Church
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Rodeheffer
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D015519:Bone Density; D002460:Cell Line; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D052242:Adiponectin; D005136:Eye Proteins; D009414:Nerve Growth Factors; D047495:PPAR gamma; D015843:Serpins; D051153:Wnt Proteins; D000099174:Pigment Epithelium-Derived Factor
keywords: metabolic syndrome; osteogenesis imperfecta type VI