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Cell transplantation2018; 27(10); 1434-1450; doi: 10.1177/0963689718792203

Growth Factor-Mediated Tenogenic Induction of Multipotent Mesenchymal Stromal Cells Is Altered by the Microenvironment of Tendon Matrix.

Abstract: Age-related degenerative changes in tendon tissue represent a common cause for acute tendon pathologies. Although the regenerative potential of multipotent mesenchymal stromal cells (MSC) was reported to restore functionality in injured tendon tissue, cellular mechanisms of action remain partly unclear. Potential tenogenic differentiation of applied MSC is affected by various intrinsic and extrinsic factors. The current study presents an in vitro model to evaluate the combined extrinsic effects of decellularized equine tendon matrix, transforming growth factor beta 3 (TGFβ3) and bone morphogenetic protein 12 (BMP12) on the tenogenic fate of equine adipose tissue-derived MSC. Monolayer MSC cultures supplemented with TGFβ3 and BMP12 as well as MSC cultured on tendon matrix scaffolds preloaded with the growth factors were incubated for 3 and 5 days. Histological evaluation and real time reverse transcription polymerase chain reaction (RT-PCR) revealed that growth factor-mediated tenogenic induction of MSC was modified by the conditions of the surrounding microenvironment. While the gene expression pattern in monolayer cultures supplemented with TGFβ3 or TGFβ3 and BMP12 revealed an upregulation for collagen 1A2, collagen 3A1, tenascin c, scleraxis and mohawk ( p < 0.05 ), the presence of tendon matrix led to an upregulation of decorin and osteopontin as well as to a downregulation of smad8 ( p < 0.05). Preloading of scaffolds with either TGFβ3, or with TGFβ3 and BMP12 promoted a tenocyte-like phenotype and improved cell alignment. Furthermore, gene expression in scaffold culture was modulated by TGFβ3 and/or BMP12, with downregulation of collagen 1A2, collagen 3A1, decorin, scleraxis, smad8 and osteopontin, whereas gene expression of tenascin c was increased. This study shows that growth factor-induced tenogenic differentiation of equine MSC is markedly altered by topographical constraints of decellularized tendon tissue in vitro. While TGFβ3 represents an effective mediator for tenogenic induction, the role of BMP12 in tenogenesis may be of modulatory character and needs further evaluation.
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Publication Date: 2018-09-25 PubMed ID: 30251565PubMed Central: PMC6180728DOI: 10.1177/0963689718792203Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article investigates the role of growth factors and surrounding microenvironment on the transformation of multipotent mesenchymal stromal cells (MSCs) to tendon cells (tenogenic induction), using an in-vitro model. Particularly, it explores how decellularized equine tendon matrix and two growth factors – transforming growth factor beta 3 (TGFβ3) and bone morphogenetic protein 12 (BMP12) – influence this process.

Overview of the Study

The researchers aim to better understand the processes and factors that influence how multipotent mesenchymal stromal cells (MSCs) derived from equine adipose tissue can be directed towards becoming tendon cells (tenogenic differentiation). They use an in-vitro model for their experiments. Two growth factors (TGFβ3 and BMP12) and the tissue environment created by equine tendon matrix are manipulated to study their impact.

  • Cells were grown in two different set-ups – standard monolayer cultures supplemented with the growth factors, and on tendon matrix scaffolds preloaded with growth factors.
  • Cell cultures were incubated for 3 and 5 days, and the effects observed both histologically and at a gene expression level using RT-PCR.

Findings and Interpretations

The researchers found that the environment and the presence of growth factors significantly affect MSCs’ conversion into tendon cells.

  • In monolayer cultures, TGFβ3 (alone or with BMP12) led to upregulation of certain genes for collagen, tenascin, scleraxis, and mohawk – all implicated in tenogenesis.
  • In the presence of tendon matrix, however, there was up-regulation of decorin and osteopontin, and a downregulation of smad8, suggesting that the matrix also influences gene expression patterns.
  • The pre-loading of the tendon scaffolds with growth factors seemed to enhance their effects and promoted features of a tenocyte-like phenotype and better cell alignment.
  • Different gene expression patterns were observed in scaffold cultures with growth factors, showing a decrease in collagen, decorin, scleraxis, smad8, and osteopontin genes, but an increase in tenascin c (+).

Concluding Remarks

The study concludes that both growth factor signalling and the local tissue environment significantly impact the direction of MSC differentiation into tendon cells, and not just at a morphological level but at a gene expression level too, indicating deeper cellular changes. Specifically, TGFβ3 shows potential as a strong inductor of tenogenesis, while BMP12 seems to have a more modulatory function. More research needs to be done to confirm and expand upon these findings.

Cite This Article

APA
Roth SP, Schubert S, Scheibe P, Groß C, Brehm W, Burk J. (2018). Growth Factor-Mediated Tenogenic Induction of Multipotent Mesenchymal Stromal Cells Is Altered by the Microenvironment of Tendon Matrix. Cell Transplant, 27(10), 1434-1450. https://doi.org/10.1177/0963689718792203

Publication

Cell transplantation
ISSN: 1555-3892
NlmUniqueID: 9208854
Country: United States
Language: English
Volume: 27
Issue: 10
Pages: 1434-1450

Researcher Affiliations

Roth, Susanne Pauline
  • 1 Faculty of Veterinary Medicine, Veterinary Teaching Hospital Department for Horses, Universität Leipzig, Germany.
  • 2 Saxonian Incubator for Clinical Translation, Universität Leipzig, Germany.
Schubert, Susanna
  • 2 Saxonian Incubator for Clinical Translation, Universität Leipzig, Germany.
  • 3 Faculty of Veterinary Medicine, Institute of Veterinary Physiology, Universität Leipzig, Germany.
Scheibe, Patrick
  • 2 Saxonian Incubator for Clinical Translation, Universität Leipzig, Germany.
Groß, Claudia
  • 2 Saxonian Incubator for Clinical Translation, Universität Leipzig, Germany.
Brehm, Walter
  • 1 Faculty of Veterinary Medicine, Veterinary Teaching Hospital Department for Horses, Universität Leipzig, Germany.
Burk, Janina
  • 1 Faculty of Veterinary Medicine, Veterinary Teaching Hospital Department for Horses, Universität Leipzig, Germany.
  • 3 Faculty of Veterinary Medicine, Institute of Veterinary Physiology, Universität Leipzig, Germany.

MeSH Terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • Gene Expression
  • Horses
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Tendons / chemistry
  • Tendons / cytology
  • Tendons / ultrastructure
  • Tissue Engineering / methods
  • Tissue Scaffolds / chemistry
  • Transforming Growth Factor beta3 / metabolism

Conflict of Interest Statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Citations

This article has been cited 18 times.
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