title: Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms.
abstract: Distraction osteogenesis (DO) successfully induces large-scale skeletal tissue regeneration, but it involves an undesirably long treatment period. A high-speed DO mouse model (H-DO) with a distraction speed twice that of a control DO model failed to generate new bone callus in the distraction gap. Here we demonstrate that the local administration of serum-free conditioned medium from human mesenchymal stem cells (MSC-CM) accelerated callus formation in the mouse H-DO model. Secretomic analysis identified factors contained in MSC-CM that recruit murine bone marrow stromal cells (mBMSCs) and endothelial cells/endothelial progenitor cells (EC/EPCs), inhibit inflammation and apoptosis, and promote osteoblast differentiation, angiogenesis, and cell proliferation. Functional assays identified MCP-1/-3 and IL-3/-6 as essential factors in recruiting mBMSCs and EC/EPCs. IL-3/-6 also enhanced the osteogenic differentiation of mBMSCs. MSC-CM that had been depleted of MCP-1/-3 failed to recruit mBMSCs, and consequently failed to promote callus formation. Taken together, our data suggest that MSCs produce a broad repertoire of trophic factors with tissue-regenerative activities that accelerate healing in the DO process.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kohki
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Fujio
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Shohara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hibi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: akihito@med.nagoya-u.ac.jp.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D019857:Osteogenesis, Distraction / Q000379:methods*
chemical_list: D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins
keywords: Bone marrow stromal cells; Cell recruitment; Distraction osteogenesis; Endothelial progenitor cells; Secretome; Stem cell-conditioned medium