title: Cross-Talk Between Human Tenocytes and Bone Marrow Stromal Cells Potentiates Extracellular Matrix Remodeling In Vitro.
abstract: Tendon and ligament (T/L) pathologies account for a significant portion of musculoskeletal injuries and disorders. Tissue engineering has emerged as a promising solution in the regeneration of both tissues. Specifically, the use of multipotent human mesenchymal stromal cells (hMSC) has shown great promise to serve as both a suitable cell source for tenogenic regeneration and a source of trophic factors to induce tenogenesis. Using four donor sets, we investigated the bidirectional paracrine tenogenic response between human hamstring tenocytes (hHT) and bone marrow-derived hMSC. Cell metabolic assays showed that only one hHT donor experienced sustained notable increases in cell metabolic activity during co-culture. Histological staining confirmed that co-culture induced elevated collagen protein levels in both cell types at varying time-points in two of four donor sets assessed. Gene expression analysis using qPCR showed the varied up-regulation of anabolic and catabolic markers involved in extracellular matrix maintenance for hMSC and hHT. Furthermore, analysis of hMSC/hHT co-culture secretome using a reporter cell line for TGF-β, a potent inducer of tenogenesis, revealed a trend of higher TGF-β bioactivity in hMSC secretome compared to hHT. Finally, hHT cytoskeletal immunostaining confirmed that both cell types released soluble factors capable of inducing favorable tenogenic morphology, comparable to control levels of soluble TGF-β1. These results suggest a potential for TGF-β-mediated signaling mechanism that is involved during the paracrine interplay between the two cell types that is reminiscent of T/L matrix remodeling/turnover. These findings have significant implications in the clinical use of hMSC for common T/L pathologies.
authors: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey.|MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.
authors: Emmanuel C
authors: EC
authors: Ekwueme
authors: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey.
authors: Jay V
authors: JV
authors: Shah
authors: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey.
authors: Mahir
authors: M
authors: Mohiuddin
authors: MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.
authors: Corina A
authors: CA
authors: Ghebes
authors: MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.
authors: João F
authors: JF
authors: Crispim
authors: MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.|Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Daniël B F
authors: DB
authors: Saris
authors: MIRA Institute for Biomedical Technology and Technical Medicine, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|UC-Biotech-Cantanhede, Cantanhede, Portugal.
authors: Hugo A M
authors: HA
authors: Fernandes
authors: Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey.
authors: Joseph W
authors: JW
authors: Freeman
mesh_terms: D002450:Cell Communication; D048430:Cell Shape; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D044968:Regenerative Medicine; D013710:Tendons / Q000166:cytology* / Q000378:metabolism; D023822:Tissue Engineering; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D003094:Collagen
keywords: CO-CULTURE; LIGAMENT; MESENCHYMAL STROMAL CELLS; PARACRINE SIGNALING; TENDON; TRANSFORMING GROWTH FACTOR BETA