Nanchahal Group | Treating Fibrosis and Improving Tissue Regeneration
Our work focusses on promoting the regeneration of tissues and reducing fibrosis. Tissue injury often results in sub-optimal repair and impaired function. Persistent low grade inflammation leads to fibrosis and long-term morbidity. Unraveling the mechanisms of that underlie repair and fibrosis using the laboratory facilities at the Kennedy Institute of Rheumatology combined with the knowledge of the natural history of the processes and access to surgical specimens provides an unparalleled opportunity. Our studies based on diseased and normal human tissues have revealed novel therapeutic targets that are the subject of early stage clinical trials.
Fibroproliferative disorders are estimated to contribute to 45% of deaths in the USA. The magnitude of the unmet clinical need has resulted in intense efforts to develop novel therapeutic strategies. Despite this, success remains elusive for a multitude of reasons:
- Detection: Fibrosis is the end stage of a process that develops over many years, often decades, and patients usually present late, once organ function has been significantly compromised. Early predictors and biomarkers are scarce.
- Reversibility: Whilst it may be possible to reverse the process during the early stages of the disease, it becomes much more challenging at later stages
- Matrix: Late-stage fibrotic tissues are relatively acellular, leaving few cells to target and a densely cross-linked matrix that is barely susceptible to proteolysis.
- Tissue availability: The study of primary cells from diseased human tissues has proven to be highly successful in the identification of therapeutic targets, as exemplified by TNF in inflammatory arthritis. In fibrotic diseases human samples are available in very limited quantities and, even when they can be accessed, have failed to provide insights that have translated to successful clinical trials.
- Cell and animal models: Consequently, investigators have turned to the study of cells in culture to identify and study potential new targets in fibrosis. The main effector cells in fibrosis are myofibroblasts. However, it is difficult to emulate in cell culture the mechanical and biochemical conditions found in vivo. Animal models of fibrosis have provided useful information but also have significant weaknesses and invariably involve the administration of toxins or other insults that are rarely encountered in clinical practice. Consequently, many targets identified in cell culture and tested in animal models have failed to translate to the clinic.
We have been studying Dupuytren's disease, a local fibrotic condition of the hand that affects approximately 8% of the general UK and US populations. The cell responsible for the matrix deposition and contraction in all fibrotic diseases is the myofibroblast and surgically excised specimens from patients with Dupuytren's disease provide an abundant supply of material to develop assays that can be applied to other fibrotic conditions where primary early disease stage human tissues are less readily available.
We found that TNF is the primary driver for development and maintenance of myofibroblasts in Dupuytren's disease. There is no approved therapeutic to prevent progression of early disease and we have shown that local administration of adalimumab is efficacious.
We have shown that there are similarities between Dupuytren’s disease and lung fibrosis and we continue to work with colleagues at Bristol Myers Squibb to investigate these pathways.
Unravelling the signalling pathways promoting fibrosis in dupuytren's disease reveals TNF as a therapeutic target
Verjee LS. et al, (2014), British journal of surgery, 101, 41 - 41
Layton T. and Nanchahal J., (2019), F1000res, 8
Izadi D. et al, (2019), Sci adv, 5
Layton TB. et al, (2020), Nat commun, 11
- Marco Fritzsche, Kennedy Institute of Rheumatology
- Glenda Trujillo, Celgene Corporation / Bristol-Myers Squibb
- Dr Wei-Yu Lu, University of Edinburgh
The RIDD trial aims to test whether the progression of Dupuytren’s disease can be halted or slowed by treatment with anti-TNF injection. Currently, Dupuytren’s disease is left to progress until the finger deformity is severe enough to warrant a surgical procedure in hospital. If successful, anti-TNF treatment would prevent loss of hand function and the need for surgery, and would allow patients to be treated conveniently and quickly.
Find out more here.
Frozen shoulder is a common condition affecting approximately 9% of people aged 25–64 years. During the early phasethe pain is usually unbearable and the later restriction in movement is severely limiting. The pain can be very severe and lasts 3–9 months, followed by a 4–12 month period of increasing stiffness, after which the condition usually improves. Frozen shoulder often affects a person’s ability to sleep, carry out everyday activities, and work. Current treatments include rest, painkillers, anti-inflammatories, physiotherapy and steroid injections. If stiffness persists, surgery is sometimes recommended. However, there is no evidence that any of these treatments lead to significant benefit in the long term, with many being ineffective. Steroid injections only help in the short term. The pathophysiology of frozen shoulder has similarities to Dupuytren’s disease and approximately 50% of patients with Dupuytren’s disease also develop frozen shoulder. The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder.
TISSUE REGENERATION AND HEALING
Adult stem cells have indispensable roles in both physiological tissue renewal and tissue repair following injury. Exogenous stem cell therapy has become standard of care for some haematological disorder. In contrast, there has been comparatively little clinical impact on enhancing the regeneration of solid organs. Strategies that rely on ex vivo expansion of autologous stem cells on an individual patient basis are prohibitively expensive and success in animal models has often failed to translate in late phase clinical trials. Furthermore, successful engraftment of exogenous stem cells to sites of tissue injury requires a supportive inductive niche and the typical proinflammatory scarred bed in damaged recipient tissues is sub-optimal.
An attractive alternative strategy, which overcomes many of the limitations described above, is to promote repair by harnessing the regenerative potential of the body's endogenous stem cells. We have discovered that HMGB1, which is present in the nuclei of all cells and is released on cell injury, orchestrates healing by acting on endogenous stem cells to transition then from G0 to GAlert, thereby priming them to rapidly enter G1 on exposure to the appropriate activating factors. Usually quiescent stem cells in G0 take several days to enter G1 and effect tissue repair. We found that administration of exogenous fully-reduced HMGB1, which is the form present in cell nuclei, either locally or systemically, accelerated healing of fractures, injury to skeletal muscle and blood following chemotherapy. It was even effective if administered 2 weeks before injury. We showed that the HMGB1 formed a heterocomplex with the chemokine CXCL12 and acted on CXCR4+ stem cells. We are now investigating whether HMGB1 will also work in other tissues, such as the heart following myocardial infarction and developing HMGB1 as a therapeutic.
Read the following paper in the Editor’s Choice of Science Translational Medicine.
Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert.
Lee G. et al, (2018), Proc natl acad sci u s a, 115, E4463 - E4472
Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response.
Chan JK. et al, (2015), Embo mol med, 7, 547 - 561
TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells.
Glass GE. et al, (2011), Proc natl acad sci u s a, 108, 1585 - 1590
- Marco Fritzsche, Kennedy Institute Of Rheumatology
- Paul Riley (DPAG)
- Carolyn Carr (DPAG),
- Wyatt Yue (CMD)
- Nicola Burgess-Brown (CMD)
- Robin Choudhury (Radcliffe Dept of Medicine)
- Wei-Yu Lu (Edinburgh)
- Chas Bountra, Professor of Translational Medicine, Director of the Centre for Medicines Discovery, University of Oxford.
SYSTEMATIC AND OTHER REVIEWS
Systematic reviews are crucial for evidence based medicine. The group is particularly interested in the management of open fractures of the lower limb
Managing missed lower extremity compartment syndrome in the physiologically stable patient: A systematic review and lessons from a Level I trauma center.
Glass GE. et al, (2016), J trauma acute care surg, 81, 380 - 387
Glass GE. et al, (2014), Br j surg, 101, 1627 - 1636
Glass GE. and Nanchahal J., (2012), J plast reconstr aesthet surg, 65, 903 - 910
Glass GE. and Nanchahal J., (2012), J plast reconstr aesthet surg, 65, 989 - 1001
Gardiner MD. and Nanchahal J., (2010), J plast reconstr aesthet surg, 63, e665 - e673
The microbiological basis for a revised antibiotic regimen in high-energy tibial fractures: preventing deep infections by nosocomial organisms.
Glass GE. et al, (2011), J plast reconstr aesthet surg, 64, 375 - 380
The ortho-plastic management of Gustilo grade IIIB fractures of the tibia in children: a systematic review of the literature.
Glass GE. et al, (2009), Injury, 40, 876 - 879