Tissue repair

Wound healing remains a major problem, particularly in diabetes where 100 people in the UK lose a limb each week. High rates of foot ulceration are also seen in inflammatory arthropathies such as rheumatoid arthritis. In diabetes this is associated with loss of intra-epidermal nerve fibres and significant co-morbidities, such as vascular impairment and kidney disease. At the molecular level, several mediators (called cytokines) are essential for the body to survive infections by killing bacteria (resistance) or withstanding the damage they cause (tolerance). We recently identified cytokines that stimulate repair and protect from damage, and termed them tissue-protective cytokines.

Project aims

Tissue-protective cytokines have been described mainly in the context of neurorepair. Here we plan to exploit their activities in wound and nerve injury.

We also plan to characterise tissue repair small molecules (peptides) derived from these cytokines that could be used as therapeutics, as such or onto biomaterials (e.g. dressings, nerve guides).

We are testing these cytokines, and their interaction with inflammation, in two models:

  1. in vitro model of wound healing; and
  2. an in vitro model of remyelination (nerve repair).

Project findings

We have identified one pro-myelinating cytokine. We are currently in the progress of performing a gene expression profiling experiment to show exactly which genes mediate the reparative action of tissue-protective cytokines. We have also identified their mechanism of action, that is what are the signalling mechanisms they activate in oligodendrocytes (the cell producing the myelin sheath).

Furthermore, we have set up an in vitro model of wound healing in endothelial cells and demonstrated a reparative function of tissue-protective cytokines. We will soon expand these studies to primary skin cells and, in the future, performing a gene expression profiling also in this model.

These studies will allow us to define tissue-protective cytokines, conceptually and at a molecular level, and their role in skin and nerve repair. The date obtained with small peptides might lead the way to new treatments.

We have also performed a bioinformatics analysis of several cytokines to help define a family of tissue-protective cytokines. This new research affords an opportunity to explore new models of tissue healing. More rapid healing would not only potentially reduce amputation rates but also improve patients’ quality of life, which is typically negatively affected by the impact of chronic wounds and peripheral neuropathies.

TPC-no-addition

in vitro wound healing is augmented by tissue-protective cytokines (L. Heikal)

TPC-with-cytokines

Research team

Professor Pietro Ghezzi

Professor Tony Metcalfe

Professor Gordon Ferns

Dr Manuela Mengozzi

Dr. Simon Otter

Dr Lamia Heikal

Georgina Gyetvay (PhD student).

Outputs

Mengozzi M, Ermilov P, Annenkov A, Ghezzi P, Pearl F. Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study. Front Immunol. 2014 Mar 17;5:115. doi: 10.3389/fimmu.2014.00115. eCollection 2014. PubMed PMID: 24672526; PubMed CentralPMCID: PMC3955874.

Cervellini I, Annenkov A, Brenton T, Chernajovsky Y, Ghezzi P, Mengozzi M. Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor. Mol Med. 2013 Aug 28;19:223-9. doi: 10.2119/molmed.2013.00013. PubMed PMID: 23821361; PubMed Central PMCID:PMC3769529.

Gyetvai G, Mengozzi M, Annenkov A, Ghezzi P “LIF increases myelination but inhibits the myelinating effect of EPO in oligodendrocyte precursor cells“. British Society of Immunology, Conference December 2014 (manuscript in preparation)

L.Heikal, P.Ghezzi, G.Ferns. The effects of Erythropoietin (EPO) and its carbamylated derivative (CEPO) are enhanced under hypoxic conditions in a wound injury model. Manuscript in preparation.

Partners

Blonde McIndoe Research Foundation