The role of stromal-immune cell interactions in the pathogenesis of tendinopathy

Crowe, Lindsay Alison Niven (2020) The role of stromal-immune cell interactions in the pathogenesis of tendinopathy. PhD thesis, University of Glasgow.

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Abstract

Background: Overuse injuries of the tendon—encompassed by the term ‘tendinopathy’—represent a largely underestimated group of musculoskeletal disorders associated with chronic inflammation and dysregulated tissue repair. Tendinopathies account for 30-50% of all sporting injuries and a high proportion of rheumatological and orthopaedic referrals from primary care physicians. Despite historical disagreement between ‘inflammation’ vs ‘degeneration’ hypotheses it is now widely accepted that inflammatory mechanisms elicited by persistent mechanical injury at a microscopic level disturb the intricate homeostatic balance that exists between stromal and immune cell compartments within the tendon during the initial stages of disease. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore this thesis sought to characterize mechanisms involved in activation of the innate immune system and subsequent development of persistent inflammation and aberrant matrix repair.

Key results: Gene expression analysis of tendon tissue identified the presence of myeloid associated alarmins S100A8 and S100A9 in early tendinopathy. Treatment of primary human tenocytes with exogenous S100A8 & A9 enhanced cytokine and chemokine release; however, no alterations in genes associated with matrix remodelling were observed indicating these alarmins act to exaggerate the inflammatory response in the early stages of disease. Extensive phenotyping of tendon stromal cells by flow cytometry identified the presence of novel subsets of tenocytes that are expanded under chronic inflammatory conditions. Furthermore, enhanced expression of markers associated with stromal cell activation was observed ex vivo in late tendinopathic tissue and in vitro in response to inflammatory stimuli. I next identified a contact dependent mechanism through which stromal cells influence immune cell phenotype and differentiation in a direct tenocyte-monocyte co-culture model. Finally, expression of stromal activation markers podoplanin and VCAM1 in tenocytes was silenced by siRNA mediated knockdown; however, no discernible alterations in tenocyte behaviour or changes in monocyte phenotype (induced by monocyte-tenocyte co-culture) were observed indicating alternate mechanisms are responsible for these interactions.
Conclusions: This study has identified novel stromal-immune cell crosstalk in tendinopathy and highlighted the significance of these interactions in the development of non-resolving chronic inflammation.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology
Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Supervisor's Name: Millar, Mr. Neal
Date of Award: 2020
Depositing User: Lindsay A N Crowe
Unique ID: glathesis:2020-79038
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 02 Mar 2020 17:18
Last Modified: 02 Mar 2020 17:22
URI: http://theses.gla.ac.uk/id/eprint/79038

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