title: Pyrintegrin Induces Soft Tissue Formation by Transplanted or Endogenous Cells.
abstract: Focal adipose deficiency, such as lipoatrophy, lumpectomy or facial trauma, is a formidable challenge in reconstructive medicine, and yet scarcely investigated in experimental studies. Here, we report that Pyrintegrin (Ptn), a 2,4-disubstituted pyrimidine known to promote embryonic stem cells survival, is robustly adipogenic and induces postnatal adipose tissue formation in vivo of transplanted adipose stem/progenitor cells (ASCs) and recruited endogenous cells. In vitro, Ptn stimulated human adipose tissue derived ASCs to differentiate into lipid-laden adipocytes by upregulating peroxisome proliferator-activated receptor (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), with differentiated cells increasingly secreting adiponectin, leptin, glycerol and total triglycerides. Ptn-primed human ASCs seeded in 3D-bioprinted biomaterial scaffolds yielded newly formed adipose tissue that expressed human PPARγ, when transplanted into the dorsum of athymic mice. Remarkably, Ptn-adsorbed 3D scaffolds implanted in the inguinal fat pad had enhanced adipose tissue formation, suggesting Ptn's ability to induce in situ adipogenesis of endogenous cells. Ptn promoted adipogenesis by upregulating PPARγ and C/EBPα not only in adipogenesis induction medium, but also in chemically defined medium specifically for osteogenesis, and concurrently attenuated Runx2 and Osx via BMP-mediated SMAD1/5 phosphorylation. These findings suggest Ptn's novel role as an adipogenesis inducer with a therapeutic potential in soft tissue reconstruction and augmentation.
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.|Department of Biomedical Engineering, Columbia University, 500 W. 120th St., Mudd 510, New York, NY 10027, USA.
authors.forename: Bhranti S
authors.initials: BS
authors.lastname: Shah
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Mildred
authors.initials: M
authors.lastname: Embree
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Kimi
authors.initials: K
authors.lastname: Kong
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.|Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.|Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Lusai
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ahn
authors.affiliation: Gladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94122, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St.-PH7E, New York, NY 10032, USA.|Department of Biomedical Engineering, Columbia University, 500 W. 120th St., Mudd 510, New York, NY 10027, USA.|Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
mesh_terms: D017667:Adipocytes / Q000473:pathology*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000502:physiology* / Q000637:transplantation; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D006801:Humans; D006912:Hydroxyquinolines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000473:pathology*; D013449:Sulfonamides / Q000378:metabolism*; D054457:Tissue Scaffolds / Q000706:statistics & numerical data; D016378:Tissue Transplantation
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D006912:Hydroxyquinolines; D047495:PPAR gamma; D013449:Sulfonamides; C000605137:pyrintegrin