title: Vascular calcifying progenitor cells possess bidirectional differentiation potentials.
abstract: Vascular calcification is an advanced feature of atherosclerosis for which no effective therapy is available. To investigate the modulation or reversal of calcification, we identified calcifying progenitor cells and investigated their calcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1 and PDGFRα markers. Sca-1(+) (Sca-1(+)/PDGFRα(+) and Sca-1(+)/PDGFRα(-)) progenitor cells exhibited greater osteoblastic differentiation potentials than Sca-1(-) (Sca-1(-)/PDGFRα(+) and Sca-1(-)/PDGFRα(-)) progenitor cells. Among Sca-1(+) progenitor populations, Sca-1(+)/PDGFRα(-) cells possessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages, whereas Sca-1(+)/PDGFRα(+) cells differentiated into an osteoblastic lineage unidirectionally. When treated with a peroxisome proliferator activated receptor γ (PPARγ) agonist, Sca-1(+)/PDGFRα(-) cells preferentially differentiated into osteoclast-like cells. Sca-1(+) progenitor cells in the artery originated from the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1(+) calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate the modulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification. Computed tomography indicated that Sca-1(+) progenitor cells increased the volume and calcium scores of ectopic calcification. However, Sca-1(+)/PDGFRα(-) cells treated with a PPARγ agonist decreased bone formation 2-fold compared with untreated cells. Systemic infusion of Sca-1(+)/PDGFRα(-) cells into Apoe(-/-) mice increased the severity of calcified atherosclerotic plaques. However, Sca-1(+)/PDGFRα(-) cells in which PPARγ was activated displayed markedly decreased plaque severity. Immunofluorescent staining indicated that Sca-1(+)/PDGFRα(-) cells mainly expressed osteocalcin; however, activation of PPARγ triggered receptor activator for nuclear factor-κB (RANK) expression, indicating their bidirectional fate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cells offer a therapeutic target for the prevention of vascular calcification and that PPARγ activation may be an option to reverse calcification.
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Cho
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Myung-Kang
authors.initials: MK
authors.lastname: Song
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Seo
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Bae
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Whal
authors.initials: W
authors.lastname: Lee
authors.forename: Bon-Kwon
authors.initials: BK
authors.lastname: Koo
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology; D001854:Bone Marrow Cells / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D061205:Vascular Calcification / Q000473:pathology*
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha