BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo

We characterized the differentiation of rat bone marrow-derived mesenchymal stem cells (BM-MSCs) into tenocyte-like cells in response to bone morphogenetic protein-12 (BMP-12). BM-MSCs were prepared from Sprague-Dawley rats and cultured as monolayers. Recombinant BMP-12 treatment (10 ng/ml) of BM-MS...

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Published in:	PloS one Vol. 6; no. 3; p. e17531
Main Authors:	Lee, Jonathan Y, Zhou, Zuping, Taub, Peter J, Ramcharan, Melissa, Li, Yonghui, Akinbiyi, Takintope, Maharam, Edward R, Leong, Daniel J, Laudier, Damien M, Ruike, Takuya, Torina, Phillip J, Zaidi, Mone, Majeska, Robert J, Schaffler, Mitchell B, Flatow, Evan L, Sun, Hui B
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 11-03-2011 Public Library of Science (PLoS)
Subjects:	Adult Stem Cells - cytology Adult Stem Cells - drug effects Adult Stem Cells - metabolism Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Biology Biomarkers Biomedical engineering Bone marrow Bone Marrow Cells - cytology Bone morphogenetic proteins Bone Morphogenetic Proteins - pharmacology Calcaneus - drug effects Calcaneus - pathology Cell Differentiation - drug effects Cell Lineage - drug effects Cell number Cells, Cultured Collagen Collagen (type I) Collagen - pharmacology Colonies Differentiation Elongation Engineering Female Fractures Gene Expression Regulation - drug effects Growth factors Implants, Experimental Medicine Membrane Proteins - genetics Membrane Proteins - metabolism Mesenchymal stem cells Mesenchymal Stromal Cells - cytology Mesenchymal Stromal Cells - drug effects Mesenchymal Stromal Cells - metabolism Mesenchyme Monomolecular films Morphogenesis Nervous system Plastic surgery Progeny Proteins Rats Rats, Sprague-Dawley Reconstruction Scaffolds Skin & tissue grafts Stem cell transplantation Stem cells Surgical implants Tenascin Tenascin C Tendons Tendons - drug effects Tendons - pathology Tissue Engineering Tissue Scaffolds Transplantation Wound Healing - drug effects New York United States > US
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Summary:	We characterized the differentiation of rat bone marrow-derived mesenchymal stem cells (BM-MSCs) into tenocyte-like cells in response to bone morphogenetic protein-12 (BMP-12). BM-MSCs were prepared from Sprague-Dawley rats and cultured as monolayers. Recombinant BMP-12 treatment (10 ng/ml) of BM-MSCs for 12 hours in vitro markedly increased expression of the tenocyte lineage markers scleraxis (Scx) and tenomodulin (Tnmd) over 14 days. Treatment with BMP-12 for a further 12-hour period had no additional effect. Colony formation assays revealed that ~80% of treated cells and their progeny were Scx- and Tnmd-positive. BM-MSCs seeded in collagen scaffolds and similarly treated with a single dose of BMP-12 also expressed high levels of Scx and Tnmd, as well as type I collagen and tenascin-c. Furthermore, when the treated BM-MSC-seeded scaffolds were implanted into surgically created tendon defects in vivo, robust formation of tendon-like tissue was observed after 21 days as evidenced by increased cell number, elongation and alignment along the tensile axis, greater matrix deposition and the elevated expression of tendon markers. These results indicate that brief stimulation with BMP-12 in vitro is sufficient to induce BM-MSC differentiation into tenocytes, and that this phenotype is sustained in vivo. This strategy of pretreating BM-MSCs with BMP-12 prior to in vivo transplantation may be useful in MSC-based tendon reconstruction or tissue engineering.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Conceived and designed the experiments: JYL PJT MR YL RJM MBS ELF HBS. Performed the experiments: JYL PJT MR YL TA ERM DML TR PJT. Analyzed the data: JYL ZZ PJT TA DJL RJM MBS HBS. Contributed reagents/materials/analysis tools: JYL PJT MR YL. Wrote the paper: JYL ZZ MZ RJM MBS ELF HBS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0017531