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. Whilst this huge number includes atherosclerosis, the biggest killer in the developed world, less common conditions such as idiopathic pulmonary fibrosis, fibrosis of the liver and kidney and systemic sclerosis are also associated with high mortality. Localised fibrotic conditions, which receive much less attention, including endometriosis, abdominal adhesions, frozen shoulder and Dupuytren's disease, also cause considerable morbidity and together affect more than 10% of the population. 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: Elimination of the initiating insult such as hepatitis B viral infection results in regression of fibrosis and restoration of function in the liver. However, in the majority of organs and even other liver disorders such as non-alcoholic steatohepatitis, this process is irreversible.
- 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 derived from a heterogeneous pool of precursors to produce and remodel collagen matrix into scar tissue. 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 4% 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 commenced a phase II clinical trial funded by the Health Innovation Challenge Fund (Wellcome Trust and Department of Health) to assess the efficacy of local injection of the anti-TNF drug adalimumab. The persistent localised inflammation in Dupuytren's disease would necessitate repeated injections of anti-TNF. We have now identified a potential target to overcome this.
We are working with Somalogic and Celgene to identify novel therapeutic targets for fibrotic diseases using Somascan and Quanticel single cell RNAseq. In parallel, we are developing new assays to study the phenotype of primary myofibroblasts from clinical samples of early stage fibrosis. Our aim is to use these techniques to identify and validate novel therapeutic targets in a variety of fibrotic disorders
Nanchahal J. and Hinz B., (2016), Proceedings of the National Academy of Sciences of USA, 113, 7291 - 7293
Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target.
Verjee LS. et al, (2013), Proc Natl Acad Sci U S A, 110, E928 - E937
Isometric contraction of Dupuytren's myofibroblasts is inhibited by blocking intercellular junctions.
Verhoekx JSN. et al, (2013), J Invest Dermatol, 133, 2664 - 2671
Optimal functional outcome measures for assessing treatment for Dupuytren's disease: a systematic review and recommendations for future practice.
Ball C. et al, (2013), BMC Musculoskelet Disord, 14
- Marco Fritzsche, Kennedy Institute of Rheumatology
- Kim Midwood, Kennedy Institute of Rheumatology
- Chris Buckley, Professor of Rheumatology, University of Birmingham
- Dominic Furniss, University Research Lecturer and Honorary Consultant Surgeon
- Wei Lin, Celgene Corporation, USA
- Glenda Trujillo, Celgene Corporation / Bristol-Myers Squibb
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.
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 ddministration 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
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
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
Ball CE. et al, (2016), Biomedcentral Musculoskeletal Disorders
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