title: Macrophage-Associated Osteoactivin/GPNMB Mediates Mesenchymal Stem Cell Survival, Proliferation, and Migration Via a CD44-Dependent Mechanism.
abstract: Although MSCs have been widely recognized to have therapeutic potential in the repair of injured or diseased tissues, it remains unclear how functional activities of mesenchymal stem cells (MSCs) are influenced by the surrounding inflammatory milieu at the site of tissue injury. Macrophages constitute an essential component of innate immunity and have been shown to exhibit a phenotypic plasticity in response to various stimuli, which play a central role in both acute inflammation and wound repair. Osteoactivin (OA)/Glycoprotein non-metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein that plays a role in cell differentiation, survival, and angiogenesis. The objective of this study was to investigate the potential role of OA/GPNMB in macrophage-induced MSC function. We found that reparative M2 macrophages express significantly greater levels of OA/GPNMB than pro-inflammatory M1 macrophages. Furthermore, using loss of function and rescue studies, we demonstrated that M2 macrophages-secreted OA/GPNMB positively regulates the viability, proliferation, and migration of MSCs. More importantly, we demonstrated that OA/GPNMB acts through ERK and AKT signaling pathways in MSCs via CD44, to induce these effects. Taken together, our results provide pivotal insight into the mechanism by which OA/GPNMB contributes to the tissue reparative phenotype of M2 macrophages and positively regulates functional activities of MSCs. J. Cell. Biochem. 117: 1511-1521, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, Ohio.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, Ohio.|School of Biomedical of Sciences, Kent State University, Kent, OH.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sondag
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, Ohio.
authors.forename: Christopher
authors.initials: C
authors.lastname: Malcuit
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, Ohio.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, Ohio.|School of Biomedical of Sciences, Kent State University, Kent, OH.
authors.forename: Fayez F
authors.initials: FF
authors.lastname: Safadi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: C476399:Cd44 protein, mouse; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins
keywords: CD44; M2 MACROPHAGES; MSC; OA/GPNMB