title: Accelerated Chondrogenic Differentiation of Human Perivascular Stem Cells with NELL-1.
abstract: Osteoarthritis is the leading cause of disability in the US. Consequently, there is a pressing need for restoring the structural and functional properties of diseased articular cartilage. Yet the search for the right combination of proper target cells and growth factors for cartilage regeneration remains challenging. In this study, we first tested the intrinsic chondrogenic differentiation ability of human perivascular stem cells (hPSCs), a novel source of mesenchymal stem cells (MSCs) isolated by fluorescence-activated cell sorting (FACS) from human adipose tissue. A putative prochondrogenic growth factor, NEL-like molecule-1 (NELL-1), was added to the hPSC pellets to upregulate gene expression of chondrogenic markers, including AGGRECAN, COLLAGEN II, and COMP. Furthermore, the addition of NELL-1 to a transforming growth factor beta 3 (TGF-β3) + bone morphogenetic protein-6 (BMP-6) "cocktail" resulted in the best combinatorial stimulation in accelerating the chondrogenic differentiation of hPSCs, as evidenced by increased gene and protein expression of chondrogenic markers in a shortened induction time without elevating expression of hypertrophic, fibrotic, and osteogenic markers. Mechanistically, this acceleration rendered by NELL-1 may be partially attributed to NELL-1's upregulation of BMP receptors and TGF-β receptor type I in hPSCs for increased responsiveness to BMPs + TGF-βs. In conclusion, lipoaspirate-derived hPSCs present a novel and abundant cell source of MSCs for cartilage regeneration, and the combinatorial application of NELL-1, TGF-β3, and BMP-6 with hPSCs may remarkably enhance and accelerate cartilage repair.
authors.affiliation: 1 Department of Orthodontics, Peking University , School and Hospital of Stomatology, Beijing, P.R. China .|2 Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors.forename: Chen-Shuang
authors.initials: CS
authors.lastname: Li
authors.affiliation: 2 Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 3 UCLA Division of Plastic Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California , Los Angeles, Los Angeles, California.|4 Center for Cardiovascular Science and MRC Center for Regenerative Medicine, University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Bruno
authors.initials: B
authors.lastname: Péault
authors.affiliation: 2 Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: 2 Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.|3 UCLA Division of Plastic Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California , Los Angeles, Los Angeles, California.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: 2 Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.|3 UCLA Division of Plastic Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California , Los Angeles, Los Angeles, California.
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
authors.affiliation: 1 Department of Orthodontics, Peking University , School and Hospital of Stomatology, Beijing, P.R. China .
authors.forename: Yan-Heng
authors.initials: YH
authors.lastname: Zhou
mesh_terms: D000943:Antigens, Differentiation / Q000096:biosynthesis; D002135:Calcium-Binding Proteins; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000493:pharmacokinetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins