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Home / Equine Research Bank / BMC Vet Res / Indicators of replicative damage in equine tendon fibroblast...
BMC veterinary research2013; 9; 180; doi: 10.1186/1746-6148-9-180

Indicators of replicative damage in equine tendon fibroblast monolayers.

Abstract: Superficial digital flexor tendon (SDFT) injuries of horses usually follow cumulative matrix microdamage; it is not known why the reparative abilities of tendon fibroblasts are overwhelmed or subverted. Relevant in vitro studies of this process require fibroblasts not already responding to stresses caused by the cell culture protocols. We investigated indicators of replicative damage in SDFT fibroblast monolayers, effects of this on their reparative ability, and measures that can be taken to reduce it. Results: We found significant evidence of replicative stress, initially observing consistently large numbers of binucleate (BN) cells. A more variable but prominent feature was the presence of numerous gammaH2AX (γH2AX) puncta in nuclei, this being a histone protein that is phosphorylated in response to DNA double-stranded breaks (DSBs). Enrichment for injury detection and cell cycle arrest factors (p53 (ser15) and p21) occurred most frequently in BN cells; however, their numbers did not correlate with DNA damage levels and it is likely that the two processes have different causative mechanisms. Such remarkable levels of injury and binucleation are usually associated with irradiation, or treatment with cytoskeletal-disrupting agents.Both DSBs and BN cells were greatest in subconfluent (replicating) monolayers. The DNA-damaged cells co-expressed the replication markers TPX2/repp86 and centromere protein F. Once damaged in the early stages of culture establishment, fibroblasts continued to express DNA breaks with each replicative cycle. However, significant levels of cell death were not measured, suggesting that DNA repair was occurring. Comet assays showed that DNA repair was delayed in proportion to levels of genotoxic stress. Conclusions: Researchers using tendon fibroblast monolayers should assess their "health" using γH2AX labelling. Continued use of early passage cultures expressing initially high levels of γH2AX puncta should be avoided for mechanistic studies and ex-vivo therapeutic applications, as this will not be resolved with further replicative cycling. Low density cell culture should be avoided as it enriches for both DNA damage and mitotic defects (polyploidy). As monolayers differing only slightly in baseline DNA damage levels showed markedly variable responses to a further injury, studies of effects of various stressors on tendon cells must be very carefully controlled.
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Publication Date: 2013-09-11 PubMed ID: 24025445PubMed Central: PMC3847935DOI: 10.1186/1746-6148-9-180Google 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.

This research explores why superficial digital flexor tendon (SDFT) injuries in horses often follow a pattern of gradual small-scale tissue damage, focusing on the reparative capabilities of tendon fibroblasts. The results indicate that significant replicative stress during cell culture cultivation might compromise the health and reparative abilities of these fibroblasts, which has potential implications for further studies and therapeutic applications.

Study Objectives and Methodology

  • The study primarily aimed to investigate signs of duplicative damage in SDFT fibroblast monolayers to understand how this impacts their abilities to repair damage.
  • The researchers looked for signs of replicative stress, including the presence of binucleate (BN) cells, a potential sign of cell damage, and the possible presence of the histone protein gammaH2AX (γH2AX) in cell nuclei.
  • The DNA damage repair process was also analyzed by looking at how frequently injury detection and cell cycle arrest factors p53 (ser15) and p21 occurred within BN cells.

Key Findings

  • Immediate substantial signs of replicative stress were found, manifested as large numbers of BN cells and a variable yet significant presence of numerous γH2AX puncta in nuclei, indicating DNA double-stranded breaks (DSBs).
  • Ongoing DNA damage was observed in fibroblasts in the early stages of culture establishment, continuing across each consequent replicative cycle, despite a lack of considerable cell death, suggesting DNA repair was occurring but may be delayed depending on the level of genotoxic stress inflicted.
  • DSBs and BN cells were most abundance in subconfluent (replicating) monolayers, co-expressing the replication markers TPX2/repp86 and centromere protein F.

Implications and Recommendations

  • The study concludes that researchers using tendon fibroblast monolayers should evaluate their health through γH2AX labelling, as pronounced initial levels of γH2AX puncta could potentially disrupt mechanistic studies and ex-vivo therapeutic applications.
  • The use of low-density cell culture should be discouraged since it escalates both DNA damage and mitotic defects (polyploidy).
  • This research stresses the need for careful controls over studies on the effects of various stress factors on tendon cells due to the observed significant variations in responses to further injury by monolayers with only slightly different baseline DNA damage levels.

Cite This Article

APA
Rich T, Henderson LB, Becker DL, Cornell H, Patterson-Kane JC. (2013). Indicators of replicative damage in equine tendon fibroblast monolayers. BMC Vet Res, 9, 180. https://doi.org/10.1186/1746-6148-9-180

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 9
Pages: 180

Researcher Affiliations

Rich, Tina
  • Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK. Tina.Rich@glasgow.ac.uk.
Henderson, Livia B
    Becker, David L
      Cornell, Hannah
        Patterson-Kane, Janet C

          MeSH Terms

          • Animals
          • Cell Culture Techniques / veterinary
          • Cell Death
          • DNA Damage
          • Fibroblasts / cytology
          • Fibroblasts / physiology
          • Horses
          • Mitosis / physiology
          • Tendons / cytology

          Grant Funding

          • BB/J000655/1 / Biotechnology and Biological Sciences Research Council

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