Musculoskeletal

Multinucleated human skeletal muscle cells developed in culture and stained with an anti-sarcomeric myosin (red). Nuclei are stained in blue with DAPI.  Image Courtesy of G. Cossu.

Musculoskeletal – intro text

Manchester possesses substantial academic and clinical strengths in musculoskeletal research, ranging from the generation of ESC and iPS-derived chondrocytes and research into the degeneration and regeneration of intervertebral discs, to the treatment of Duchenne muscular dystrophy through novel cell therapy techniques, and the reconstruction of tendons.

In order to accelerate the translation of novel research findings the National Institute for Health Research (NIHR) has funded the Manchester Musculoskeletal Biomedical Research Unit (BRU) which brings together leading researchers from Central Manchester University Hospitals NHS Foundation Trust and The University of Manchester, to take promising early stage biomedical research and translate it into patient benefit.

Orthopaedics

Musculoskeletal – Cartilage/IVD (Academic)

Academic

Professor Sue Kimber

Professor of Stem Cells and Development
Faculty of Biology, Medicine and Health
sue.kimber@manchester.ac.uk
Professor Kimber’s University Profile

iPSC/ESCs and Differentiation to Chondrocytes

Professor Kimber’s research involves studying targeted differentiation, particularly to mesodermal lineages and most successfully, to cartilage (with Tim Hardingham). Her group can derive chondrocytes from hESCs and iPSCs (reprogrammed from adult fibroblasts); these cells are able to repair osteochondral defects in immunocompromised mice. This technology is being used to produce new disease models for cartilage related diseases. Her group is also deriving new hES cell lines from human oocytes and embryos (collaborator Daniel Brison). So far she has derived 9 research grade hES cell lines; RCM1 and Man1-8.  Professor Kimber is also a director of the  North West Embryonic Stem Cell Centre, whose goal is to derive hES cell lines under cGMP,  for use in clinical therapies.

Professor Judith Hoyland

Professor of Molecular Pathology
Faculty of Biology, Medicine and Health
judith.hoyland@manchester.ac.uk
Professor Hoyland’s University Profile

Regeneration and Repair of Intervertebral Disc

Professor Hoyland’s research focusses on the development of modern molecular technologies for application in the pathological study of disease mechanisms in human “hard” tissues (cartilage, IVD, bone etc.). Currently her research group is applying these techniques to: i) investigate the cell and matrix biology of normal and diseased (degenerate) cervical and lumbar intervertebral discs (IVD), in order to develop clinically viable novel cell based (adult stem cells) tissue engineering/ regenerative medicine therapies for the degenerate IVD; ii) study adult mesenchymal stem cells (derived from bone marrow, adipose tissue and umbilical cord), their differentiation and regulation, and their interactions with novel biomaterials (including graphene based materials) for musculoskeletal tissue engineering strategies; iii) define the molecular pathology of the regenerate “niche” in which tissue regeneration will occur; iv) design and utilise ex-vivo models for exploration of cell function in normal, degenerate and tissue engineered tissues. Through collaboration with several academics and colleagues with skills in biomaterial design (both in Manchester and external national and international institutions), clinicians and industrial partners members of her group are applying new knowledge gained from this research to develop unique strategies for regenerating the degenerate intervertebral disc and other musculoskeletal tissues (including bone and cartilage).

Dr Qing-Jun Meng

Arthritis Research UK Senior Research Fellow
Faculty of Biology, Medicine and Health
qing-jun.meng@manchester.ac.uk
Dr Meng’s University Profile

Circadian Rhythms in Tissue Degeneration and Repair of the Musculoskeletal System

Circadian rhythms are the endogenous 24 hour cycles governing nearly all aspects of physiology and behaviour. In mammals (including humans), this rhythm is generated by the master clock (suprachiasmatic nucleus, SCN) in the brain, which entrains to the light/dark environment and co-ordinates the peripheral clocks in most major body organs and cells. Circadian clocks control ~10% of our transcriptome in a tissue-specific manner and disrupted circadian rhythms (e.g. during ageing) have been linked with various diseases, including metabolic syndrome, obesity, diabetes, osteoarthritis and increased tumorigenesis.
Research in this group focuses on the interface between ageing and circadian biology. We aim to 1) Identify the mechanisms underlying age-related changes in circadian rhythms in musculoskeletal tissues (cartilage, intervertebral disc, tendon and bone); 2) Establish the functional significance of various skeletal clocks in coordinating local physiology (tissue homeostasis and repair); 3) Explore the possibility of targeting body clocks in order to ameliorate disease progression and promote stem cell based tissue regeneration.

Dr Stephen Richardson

Lecturer in Cell and Tissue Engineering
Faculty of Biology, Medicine and Health
s.richardson@manchester.ac.uk
Dr Richardson’s University Profile

Orthopaedic Engineering and Stem Cells

Dr. Richardson’s primary interest is adult human mesenchymal stem cells (MSCs) and their application in clinically and commercially viable regenerative medicine therapies. This work has involved the development of novel tissue engineering therapies for musculoskeletal tissues, including intervertebral disc, articular cartilage and bone; the comparison of the efficacy of bone marrow and adipose derived MSCs for musculoskeletal tissue engineering/regenerative medicine applications; and the elucidation of the effects of MSC ageing on tissue regeneration. In addition to his work on MSCs, Dr Richardson is also interested in the isolation, characterisation and culture of human notochordal cells, and the development of methods to differentiate induced pluripotent stem cells towards notochordal cells. To achieve this work he has established collaborations with clinicians, companies and academics around the world to develop novel biomaterials and strategies for regeneration of musculoskeletal tissues. The work has demonstrated promising results which suggest a regenerative medicine treatment for IVD degeneration is a possibility in the near future. Current work is aiming to transfer this technology to pre-clinical trials.

Professor Tony Freemont

Professor of Osteoarticular Pathology
Faculty of Biology, Medicine and Health
tony.freemont@manchester.ac.uk
Professor Freemont’s University Profile

Osteochondral Molecular pathology and Regenerative Medicine

Over the years, Professor Freemont’s group has pioneered the development of molecular pathology techniques required to understanding disease mechanisms at the cellular level in human hard tissues (eg. bone, cartilage). Examples include being the first to use in-situ RT PCR to detect low copy number transcripts (eg. IL-1 and oestrogen receptors) in bone, and in-situ zymography to identify active matrix degrading enzymes in osteoarthritic cartilage.
Currently his primary research focuses on identifying molecular mechanisms underlying discogenic low back pain and designing novel therapies using regenerative medicine techniques (eg. tissue engineering, stem cell manipulation, gene therapy). Key discoveries include: 1) showing that imbalances in the IL-1 superfamily drive the intervertebral disc (IVD) pathology underlying back pain, 2) that IL-1RA, delivered by gene therapy, reverses the cellular dysfunction causing this pathology and 3) that autologous mesenchymal stem cells can be differentiated into IVD cells.
In addition, because it is difficult to reproduce the disease conditions of IVD degeneration in animal models, they have developed a novel tissue culture bioreactor systems that mimics the human disease situation in a controlled environment.  This has advanced the understanding of the factors precipitating IVD degeneration and preclinical evaluation of novel therapies.

Professor Ray Boot-Handford

Professor of Biochemistry
Faculty of Biology, Medicine and Health
ray.boot-handford@manchester.ac.uk
Professor Boot-Handford’s University Profile
Professor Boot-Handford’s Wellcome Trust Centre for Cell Matrix Research Profile

ER Stress as a Pathogenic Factor in Cartilage Disorders

Professor Boot-Handford’s research centres on two questions relating to the structure and function of cartilage in development and disease:
1) What is the role of ER stress in the pathogenesis of diseases mediated by chondrocytes, such as chondrodysplasias and osteoarthritis? Professor Boot-Handford’s group have shown an association of ER stress with disease pathology using cell culture and in-house generated knock-in mouse models of chondrodysplasia, caused by mutations in cartilage ECM genes such as collagen X, COMP and matrilin 3. Furthermore, by generating novel transgenic mouse lines, in which elevated ER stress (caused by the expression of a non-secreted, ER stress-inducing protein) is targeted to relevant chondrocytes in vivo, by use of the collagen X or II promoter, they have demonstrated the capability of ER stress to induce chondrodysplasia. Their current efforts are focused on genetically dissecting the roles of different ER stress pathways in disease pathogenesis using a series of conditional ER stress-related mouse lines crossed with their own chondrodysplasia lines. They are also characterising the consequences of elevated ER stress in the pathogenesis of osteoarthritis using a mechanically-induced disease model.
2) Does alleviating ER stress by various pharmacological interventions reduce disease severity? These approaches may lead to novel therapeutic opportunities for treating a variety of chondrodysplasias and osteoarthritis.

Professor Tony Day

Professor of Biochemistry
Faculty of Biology, Medicine and Health
anthony.day@manchester.ac.uk
Professor Day’s University Profile
Professor Day’s Wellcome Trust Centre for Cell Matrix Research Profile

Understanding Endogenous Tissue Protective Pathways

Tony Day’s group is interested in the role of TSG-6 as an endogenous protector of tissues during inflammation. With Dr Caroline Milner he is investigating how TSG-6’s protective properties (e.g. anti-inflammatory, chondroprotective and anti-bone resorptive) can be harnessed for the treatment of musculoskeletal conditions such as osteoarthritis and osteoporosis, and together they are developing a biological drug based on the TSG-6 protein.

Work in the Day lab has identified that TSG-6 interacts with glycosaminoglycans such as hyaluronan and chondroitin sulphate and can thereby reorganise extracellular matrix through the crosslinking of these ubiquitous polysaccharides, e.g. enhancing the interaction of hyaluronan with its major cell surface receptor CD44. It has also recently been discovered that TSG-6 can regulate the binding of the chemokine CXCL8 to heparan sulphate proteoglycans providing a mechanism for how TSG-6 inhibits neutrophil migration.

Tony’s other main interest is age-related macular degeneration, a major form of blindness that results from dysregulation of complement, i.e. part of the innate system. He has defined how a common AMD-associated polymorphism in complement factor H (FH) alters its specificity/binding to heparan sulphate proteoglycans at the interface between an epithelial cell layer and a complex extracellular matrix, which is known to be the site of disease initiation. This combined with an age-dependent decrease in the amount of heparan sulphate within the matrix likely impairs the ability of FH to protect host tissues from self attack, leading to local inflammation and damage. On-going work is investigating how age-related changes in the retinal matrix of the human eye might contribute to AMD pathology.

Dr Caroline Milner

Senior Research Fellow
Faculty of Biology, Medicine and Health
caroline.milner@manchester.ac.uk
Dr Milner’s University Profile

Understanding Endogenous Protective Pathways in Joint Tissues

Research in Caroline Milner’s group is focussed on the endogenous protective role of TSG-6 during inflammation. With Professor Tony Day, she is investigating how TSG-6’s anti-inflammatory and tissue-protective properties (i.e. as an inhibitor of cartilage breakdown and bone resorption) might be harnessed for the treatment of musculoskeletal conditions such as osteoarthritis and osteoporosis; together they are developing a biological drug based on the TSG-6 protein.

Understanding the mechanisms underlying TSG-6’s protective effects is an important goal. The protein has been shown to act directly on chondrocytes and osteoclasts to modulate cell phenotype and work is on-going to determine the molecular interactions and signalling pathways involved. It was recently discovered that TSG-6 is a chemokine-binding protein, with the potential to regulate migration of specific leukocyte populations. For example, TSG-6 can suppress the binding of CXCL8 to heparan sulphate proteoglycans, providing a mechanism for its inhibition of neutrophil migration. TSG-6 also binds to several bone morphogenetic proteins (BMPs) that have key roles in bone and cartilage homeostasis; the contributions of these interactions to the protective effects of TSG-6 in joint tissues are being investigated.

Professor Karl Kadler

Professor of Biochemistry
Faculty of Biology, Medicine and Health
karl.kadler@manchester.ac.uk
Professor Kadler’s University Profile
Professor Kadler’s Wellcome Trust Centre for Cell Matrix Research Profile

Tendon Biology and Repair

Professor Kadler’s research is focused on understanding how cells synthesise an extracellular matrix containing organised collagen fibrils. The fibrils account for 30% of the mass of vertebrates and are the mechanical framework for all fibrous and hard tissues, as well as organs such as skin, gut and muscle. Collagen fibrils are the end-point of fibrosis (of heart, liver, skin and kidney) in which functional tissue is replaced by dense collagen. The Kadler group want to understand how and where collagen fibrils are assembled with the aim of controlling this process in the treatment of fibrotic disease. They have shown that the circadian clock regulates gene expression in fibrous tissues leading to collagen pathologies including calcific tendinopathy.

Professor Sarah Cartmell

Professor of Bioengineering
Faculty of Science and Engineering
sarah.cartmell@manchester.ac.uk
Professor Cartmell’s University Profile

Novel Tendon Attachment and Repair Strategy

Currently, only 60% of tendon injuries result with an effective repair; this is because scar tissue forms that is not the same as its original tissue, making the hand stiff and difficult to move properly. Professor Cartmell’s group is working towards a novel approach to tendons repair, by allowing mechanical loads to be transferred across the healing tendon which, will promote new healthy tissue repair and reduce scar formation. Previously her group has demonstrated how state of the art polymer nano-fibres can be used in tendon repair in small rodents, however her laboratory is currently working on a MRC DPFS funded project, to perform larger animal model studies to translate this product development to the clinic.

Professor Julie Gough

Professor of Biomaterials and Tissue Engineering
Faculty of Science and Engineering
j.gough@manchester.ac.uk
Prof Gough’s University Profile

Tissue Engineering of Mechanically Sensitive Connective Tissues such as Bone, Cartilage, Skeletal Muscle and the Intervertebral disc

Her research includes controlling cell responses at the cell-biomaterial interface by engineering defined surfaces. This includes analysis and control of cells such as osteoblasts, chondrocytes, fibroblasts, keratinocytes, myoblasts and macrophages on a variety of materials and scaffolds. Her research also involves development of scaffolds for tissue repair, such as novel hydrogels and various porous and fibrous materials.

Professor Brian Saunders

Professor of Polymer and Colloid Chemistry
Faculty of Science and Engineering
brian.saunders@manchester.ac.uk
Professor Saunders’s Univerity Profile

Injectable Microparticle Gels

The Saunders group is running projects involving using microgels, which are swellable polymer colloids, to repair damaged intervertebral discs (IVDs).  The Saunders group have shown that injection of a pH-responsive microgel into degenerated IVDs result in an increase in disc height under biomechanically meaningful loads. This research has resulted in ESPRC Established Career Funding (for BRS) and a Spin Out (Gelexir Healthcare).

Musculoskeletal – Cartilage (Academic/Clinical)

Academic-Clinical

Dr Jason Wong

Honorary Senior Clinical Lecturer in Plastic and Reconstructive Surgery
Subject Lead for Acute Tissue Injury and Trauma Speciality; MAHSC Inflammation and Repair Domain
Clinical Lead for Plastic Surgery Major Trauma and Complex Wounds UHSM
Faculty of Biology, Medicine and Health
University Hospital of South Manchester
jason.k.wong@manchester.ac.uk
Dr Wong’s University Profile

Composite Tissue Allotransplantation, Tendon Repair and Major Trauma

Dr Wong’s interests lie in repair and regeneration of injuries to the musculoskeletal system, which includes hand injuries, sports injuries and major limb trauma. He maintains a specialist interest in tendon biology, iatrogenic tendon injury, tissue engineering, tendon regeneration, revascularisation, and tissue engraftment.

Musculoskeletal – Cartilage (Clinical)

Clinical

Professor Tim Board

Consultant Orthopaedic Surgeon; Hip and Knee Specialist
Wrightington, Wiggan and Leigh NHS Trust
Tim Board’s PA
Mr Board’s NHS Profile

Bone Grafting and Revision Hip Surgery

Professor Board is a Consultant Hip Surgeon at Wrightington Hospital in Lancashire, one of the largest specialist Orthopaedic Hospitals in the country. His clinical interests are complex hip problems including primary and revision arthroplasty and arthroscopy of the hip. He has an active interest in research and undertook an MD at the University of Manchester, investigating bone grafting techniques in revision hip surgery. His research interests include bone grafting and tissue engineering, hip impingement and arthroscopy, computer modelling and biomechanics of hip disease, infection and outcomes of hip arthroplasty.

Professor Board is a Visiting Professor in the Department of Materials and an Honorary Professor in the Department of Heath Sciences, University of Salford.

Professor Phil Turner

Consultant Orthopaedic Surgeon; Knee Specialist
Stepping Hill Hospital, Stockport NHS Trust
philip.turner@stockport.nhs.uk
Professor Turner’s MAHSC Profile

Biological Joint Reconstruction

Professor Phil Turner is a consultant orthopaedic surgeon based at Stepping Hill Hospital in Stockport and is the domain clinical lead for Inflammation and Repair at the Manchester Academic Health Science Centre.

His practice is entirely related to the knee with interests in articular cartilage regeneration, meniscus preservation, the unstable knee, off-loading the degenerate knee with osteotomy and the more general management of the young patient with arthritis of the knee often related to trauma or sports injury.

Professor Turner also has a particular interest in teaching and training; he holds an honorary chair in the Department of Health Sciences at the University of Salford.

Mr Sanj Anand

Consultant Orthopaedic Surgeon; Knee Specialist
Stepping Hill Hospital, Stockport NHS Trust
sanjayanand@doctors.org.uk
Dr Anand’s Profile

Orthopaedic Surgery; Cartilage Injuries

Mr Anand’s practice covers all aspects of knee surgery, from sports injuries to arthritis of the knee. He commonly performs arthroscopic (keyhole) surgery, cruciate ligament reconstruction and both total and partial knee replacements. His specialist areas of interest include cruciate ligament injuries and other sports-related trauma including cartilage injuries.

Mr Bilal Barkatali

Consultant Orthopaedic Surgeon; Knee Specialist
Salford Royal Foundation Trust
Bilal.Barkatali@srft.nhs.uk
Mr Barkatali’s NHS Profile

Knee specialist; Orthopaedic Surgery; Joint Replacement; Soft Tissue Reconstruction and Arthroplasty

Mr Barkatali specialist interest is the full spectrum of knee surgery from sports injuries e.g. ACL reconstruction, to joint preservation surgery e.g. HTO (high tibial osteotomy), cartilage regeneration and meniscal transplantation to joint replacement surgery.  He also has an interest in Orthopaedic Trauma Surgery. His interest in Regenerative Medicine encompasses the use of Graphene and Graphene Oxide hydeogells for the use of cartilage repair.
“knee specialist” and “soft tissue reconstruction and arthroplasty

Orthopaedics

Musculoskeletal – Cartilage/IVD (Academic)

Academic

Professor Sue Kimber

Professor of Stem Cells and Development
Faculty of Biology, Medicine and Health
sue.kimber@manchester.ac.uk
Professor Kimber’s University Profile

iPSC/ESCs and Differentiation to Chondrocytes

Professor Kimber’s research involves studying targeted differentiation, particularly to mesodermal lineages and most successfully, to cartilage (with Tim Hardingham). Her group can derive chondrocytes from hESCs and iPSCs (reprogrammed from adult fibroblasts); these cells are able to repair osteochondral defects in immunocompromised mice. This technology is being used to produce new disease models for cartilage related diseases. Her group is also deriving new hES cell lines from human oocytes and embryos (collaborator Daniel Brison). So far she has derived 9 research grade hES cell lines; RCM1 and Man1-8.  Professor Kimber is also a director of the  North West Embryonic Stem Cell Centre, whose goal is to derive hES cell lines under cGMP,  for use in clinical therapies.

Professor Judith Hoyland

Professor of Molecular Pathology
Faculty of Biology, Medicine and Health
judith.hoyland@manchester.ac.uk
Professor Hoyland’s University Profile

Regeneration and Repair of Intervertebral Disc

Professor Hoyland’s research focusses on the development of modern molecular technologies for application in the pathological study of disease mechanisms in human “hard” tissues (cartilage, IVD, bone etc.). Currently her research group is applying these techniques to: i) investigate the cell and matrix biology of normal and diseased (degenerate) cervical and lumbar intervertebral discs (IVD), in order to develop clinically viable novel cell based (adult stem cells) tissue engineering/ regenerative medicine therapies for the degenerate IVD; ii) study adult mesenchymal stem cells (derived from bone marrow, adipose tissue and umbilical cord), their differentiation and regulation, and their interactions with novel biomaterials (including graphene based materials) for musculoskeletal tissue engineering strategies; iii) define the molecular pathology of the regenerate “niche” in which tissue regeneration will occur; iv) design and utilise ex-vivo models for exploration of cell function in normal, degenerate and tissue engineered tissues. Through collaboration with several academics and colleagues with skills in biomaterial design (both in Manchester and external national and international institutions), clinicians and industrial partners members of her group are applying new knowledge gained from this research to develop unique strategies for regenerating the degenerate intervertebral disc and other musculoskeletal tissues (including bone and cartilage).

Dr Qing-Jun Meng

Arthritis Research UK Senior Research Fellow
Faculty of Biology, Medicine and Health
qing-jun.meng@manchester.ac.uk
Dr Meng’s University Profile

Circadian Rhythms in Tissue Degeneration and Repair of the Musculoskeletal System

Circadian rhythms are the endogenous 24 hour cycles governing nearly all aspects of physiology and behaviour. In mammals (including humans), this rhythm is generated by the master clock (suprachiasmatic nucleus, SCN) in the brain, which entrains to the light/dark environment and co-ordinates the peripheral clocks in most major body organs and cells. Circadian clocks control ~10% of our transcriptome in a tissue-specific manner and disrupted circadian rhythms (e.g. during ageing) have been linked with various diseases, including metabolic syndrome, obesity, diabetes, osteoarthritis and increased tumorigenesis.
Research in this group focuses on the interface between ageing and circadian biology. We aim to 1) Identify the mechanisms underlying age-related changes in circadian rhythms in musculoskeletal tissues (cartilage, intervertebral disc, tendon and bone); 2) Establish the functional significance of various skeletal clocks in coordinating local physiology (tissue homeostasis and repair); 3) Explore the possibility of targeting body clocks in order to ameliorate disease progression and promote stem cell based tissue regeneration.

Dr Stephen Richardson

Lecturer in Cell and Tissue Engineering
Faculty of Biology, Medicine and Health
s.richardson@manchester.ac.uk
Dr Richardson’s University Profile

Orthopaedic Engineering and Stem Cells

Dr. Richardson’s primary interest is adult human mesenchymal stem cells (MSCs) and their application in clinically and commercially viable regenerative medicine therapies. This work has involved the development of novel tissue engineering therapies for musculoskeletal tissues, including intervertebral disc, articular cartilage and bone; the comparison of the efficacy of bone marrow and adipose derived MSCs for musculoskeletal tissue engineering/regenerative medicine applications; and the elucidation of the effects of MSC ageing on tissue regeneration. In addition to his work on MSCs, Dr Richardson is also interested in the isolation, characterisation and culture of human notochordal cells, and the development of methods to differentiate induced pluripotent stem cells towards notochordal cells. To achieve this work he has established collaborations with clinicians, companies and academics around the world to develop novel biomaterials and strategies for regeneration of musculoskeletal tissues. The work has demonstrated promising results which suggest a regenerative medicine treatment for IVD degeneration is a possibility in the near future. Current work is aiming to transfer this technology to pre-clinical trials.

Professor Tony Freemont

Professor of Osteoarticular Pathology
Faculty of Biology, Medicine and Health
tony.freemont@manchester.ac.uk
Professor Freemont’s University Profile

Osteochondral Molecular pathology and Regenerative Medicine

Over the years, Professor Freemont’s group has pioneered the development of molecular pathology techniques required to understanding disease mechanisms at the cellular level in human hard tissues (eg. bone, cartilage). Examples include being the first to use in-situ RT PCR to detect low copy number transcripts (eg. IL-1 and oestrogen receptors) in bone, and in-situ zymography to identify active matrix degrading enzymes in osteoarthritic cartilage.
Currently his primary research focuses on identifying molecular mechanisms underlying discogenic low back pain and designing novel therapies using regenerative medicine techniques (eg. tissue engineering, stem cell manipulation, gene therapy). Key discoveries include: 1) showing that imbalances in the IL-1 superfamily drive the intervertebral disc (IVD) pathology underlying back pain, 2) that IL-1RA, delivered by gene therapy, reverses the cellular dysfunction causing this pathology and 3) that autologous mesenchymal stem cells can be differentiated into IVD cells.
In addition, because it is difficult to reproduce the disease conditions of IVD degeneration in animal models, they have developed a novel tissue culture bioreactor systems that mimics the human disease situation in a controlled environment.  This has advanced the understanding of the factors precipitating IVD degeneration and preclinical evaluation of novel therapies.

Professor Ray Boot-Handford

Professor of Biochemistry
Faculty of Biology, Medicine and Health
ray.boot-handford@manchester.ac.uk
Professor Boot-Handford’s University Profile
Professor Boot-Handford’s Wellcome Trust Centre for Cell Matrix Research Profile

ER Stress as a Pathogenic Factor in Cartilage Disorders

Professor Boot-Handford’s research centres on two questions relating to the structure and function of cartilage in development and disease:
1) What is the role of ER stress in the pathogenesis of diseases mediated by chondrocytes, such as chondrodysplasias and osteoarthritis? Professor Boot-Handford’s group have shown an association of ER stress with disease pathology using cell culture and in-house generated knock-in mouse models of chondrodysplasia, caused by mutations in cartilage ECM genes such as collagen X, COMP and matrilin 3. Furthermore, by generating novel transgenic mouse lines, in which elevated ER stress (caused by the expression of a non-secreted, ER stress-inducing protein) is targeted to relevant chondrocytes in vivo, by use of the collagen X or II promoter, they have demonstrated the capability of ER stress to induce chondrodysplasia. Their current efforts are focused on genetically dissecting the roles of different ER stress pathways in disease pathogenesis using a series of conditional ER stress-related mouse lines crossed with their own chondrodysplasia lines. They are also characterising the consequences of elevated ER stress in the pathogenesis of osteoarthritis using a mechanically-induced disease model.
2) Does alleviating ER stress by various pharmacological interventions reduce disease severity? These approaches may lead to novel therapeutic opportunities for treating a variety of chondrodysplasias and osteoarthritis.

Professor Tony Day

Professor of Biochemistry
Faculty of Biology, Medicine and Health
anthony.day@manchester.ac.uk
Professor Day’s University Profile
Professor Day’s Wellcome Trust Centre for Cell Matrix Research Profile

Understanding Endogenous Tissue Protective Pathways

Tony Day’s group is interested in the role of TSG-6 as an endogenous protector of tissues during inflammation. With Dr Caroline Milner he is investigating how TSG-6’s protective properties (e.g. anti-inflammatory, chondroprotective and anti-bone resorptive) can be harnessed for the treatment of musculoskeletal conditions such as osteoarthritis and osteoporosis, and together they are developing a biological drug based on the TSG-6 protein.

Work in the Day lab has identified that TSG-6 interacts with glycosaminoglycans such as hyaluronan and chondroitin sulphate and can thereby reorganise extracellular matrix through the crosslinking of these ubiquitous polysaccharides, e.g. enhancing the interaction of hyaluronan with its major cell surface receptor CD44. It has also recently been discovered that TSG-6 can regulate the binding of the chemokine CXCL8 to heparan sulphate proteoglycans providing a mechanism for how TSG-6 inhibits neutrophil migration.

Tony’s other main interest is age-related macular degeneration, a major form of blindness that results from dysregulation of complement, i.e. part of the innate system. He has defined how a common AMD-associated polymorphism in complement factor H (FH) alters its specificity/binding to heparan sulphate proteoglycans at the interface between an epithelial cell layer and a complex extracellular matrix, which is known to be the site of disease initiation. This combined with an age-dependent decrease in the amount of heparan sulphate within the matrix likely impairs the ability of FH to protect host tissues from self attack, leading to local inflammation and damage. On-going work is investigating how age-related changes in the retinal matrix of the human eye might contribute to AMD pathology.

Dr Caroline Milner

Senior Research Fellow
Faculty of Biology, Medicine and Health
caroline.milner@manchester.ac.uk
Dr Milner’s University Profile

Understanding Endogenous Protective Pathways in Joint Tissues

Research in Caroline Milner’s group is focussed on the endogenous protective role of TSG-6 during inflammation. With Professor Tony Day, she is investigating how TSG-6’s anti-inflammatory and tissue-protective properties (i.e. as an inhibitor of cartilage breakdown and bone resorption) might be harnessed for the treatment of musculoskeletal conditions such as osteoarthritis and osteoporosis; together they are developing a biological drug based on the TSG-6 protein.

Understanding the mechanisms underlying TSG-6’s protective effects is an important goal. The protein has been shown to act directly on chondrocytes and osteoclasts to modulate cell phenotype and work is on-going to determine the molecular interactions and signalling pathways involved. It was recently discovered that TSG-6 is a chemokine-binding protein, with the potential to regulate migration of specific leukocyte populations. For example, TSG-6 can suppress the binding of CXCL8 to heparan sulphate proteoglycans, providing a mechanism for its inhibition of neutrophil migration. TSG-6 also binds to several bone morphogenetic proteins (BMPs) that have key roles in bone and cartilage homeostasis; the contributions of these interactions to the protective effects of TSG-6 in joint tissues are being investigated.

Professor Karl Kadler

Professor of Biochemistry
Faculty of Biology, Medicine and Health
karl.kadler@manchester.ac.uk
Professor Kadler’s University Profile
Professor Kadler’s Wellcome Trust Centre for Cell Matrix Research Profile

Tendon Biology and Repair

Professor Kadler’s research is focused on understanding how cells synthesise an extracellular matrix containing organised collagen fibrils. The fibrils account for 30% of the mass of vertebrates and are the mechanical framework for all fibrous and hard tissues, as well as organs such as skin, gut and muscle. Collagen fibrils are the end-point of fibrosis (of heart, liver, skin and kidney) in which functional tissue is replaced by dense collagen. The Kadler group want to understand how and where collagen fibrils are assembled with the aim of controlling this process in the treatment of fibrotic disease. They have shown that the circadian clock regulates gene expression in fibrous tissues leading to collagen pathologies including calcific tendinopathy.

Professor Sarah Cartmell

Professor of Bioengineering
Faculty of Science and Engineering
sarah.cartmell@manchester.ac.uk
Professor Cartmell’s University Profile

Novel Tendon Attachment and Repair Strategy

Currently, only 60% of tendon injuries result with an effective repair; this is because scar tissue forms that is not the same as its original tissue, making the hand stiff and difficult to move properly. Professor Cartmell’s group is working towards a novel approach to tendons repair, by allowing mechanical loads to be transferred across the healing tendon which, will promote new healthy tissue repair and reduce scar formation. Previously her group has demonstrated how state of the art polymer nano-fibres can be used in tendon repair in small rodents, however her laboratory is currently working on a MRC DPFS funded project, to perform larger animal model studies to translate this product development to the clinic.

Professor Julie Gough

Professor of Biomaterials and Tissue Engineering
Faculty of Science and Engineering
j.gough@manchester.ac.uk
Prof Gough’s University Profile

Tissue Engineering of Mechanically Sensitive Connective Tissues such as Bone, Cartilage, Skeletal Muscle and the Intervertebral disc

Her research includes controlling cell responses at the cell-biomaterial interface by engineering defined surfaces. This includes analysis and control of cells such as osteoblasts, chondrocytes, fibroblasts, keratinocytes, myoblasts and macrophages on a variety of materials and scaffolds. Her research also involves development of scaffolds for tissue repair, such as novel hydrogels and various porous and fibrous materials.

Professor Brian Saunders

Professor of Polymer and Colloid Chemistry
Faculty of Science and Engineering
brian.saunders@manchester.ac.uk
Professor Saunders’s Univerity Profile

Injectable Microparticle Gels

The Saunders group is running projects involving using microgels, which are swellable polymer colloids, to repair damaged intervertebral discs (IVDs).  The Saunders group have shown that injection of a pH-responsive microgel into degenerated IVDs result in an increase in disc height under biomechanically meaningful loads. This research has resulted in ESPRC Established Career Funding (for BRS) and a Spin Out (Gelexir Healthcare).

Musculoskeletal – Cartilage (Academic/Clinical)

Academic-Clinical

Dr Jason Wong

Honorary Senior Clinical Lecturer in Plastic and Reconstructive Surgery
Subject Lead for Acute Tissue Injury and Trauma Speciality; MAHSC Inflammation and Repair Domain
Clinical Lead for Plastic Surgery Major Trauma and Complex Wounds UHSM
Faculty of Biology, Medicine and Health
University Hospital of South Manchester
jason.k.wong@manchester.ac.uk
Dr Wong’s University Profile

Composite Tissue Allotransplantation, Tendon Repair and Major Trauma

Dr Wong’s interests lie in repair and regeneration of injuries to the musculoskeletal system, which includes hand injuries, sports injuries and major limb trauma. He maintains a specialist interest in tendon biology, iatrogenic tendon injury, tissue engineering, tendon regeneration, revascularisation, and tissue engraftment.

Musculoskeletal – Cartilage (Clinical)

Clinical

Professor Tim Board

Consultant Orthopaedic Surgeon; Hip and Knee Specialist
Wrightington, Wiggan and Leigh NHS Trust
Tim Board’s PA
Mr Board’s NHS Profile

Bone Grafting and Revision Hip Surgery

Professor Board is a Consultant Hip Surgeon at Wrightington Hospital in Lancashire, one of the largest specialist Orthopaedic Hospitals in the country. His clinical interests are complex hip problems including primary and revision arthroplasty and arthroscopy of the hip. He has an active interest in research and undertook an MD at the University of Manchester, investigating bone grafting techniques in revision hip surgery. His research interests include bone grafting and tissue engineering, hip impingement and arthroscopy, computer modelling and biomechanics of hip disease, infection and outcomes of hip arthroplasty.

Professor Board is a Visiting Professor in the Department of Materials and an Honorary Professor in the Department of Heath Sciences, University of Salford.

Professor Phil Turner

Consultant Orthopaedic Surgeon; Knee Specialist
Stepping Hill Hospital, Stockport NHS Trust
philip.turner@stockport.nhs.uk
Professor Turner’s MAHSC Profile

Biological Joint Reconstruction

Professor Phil Turner is a consultant orthopaedic surgeon based at Stepping Hill Hospital in Stockport and is the domain clinical lead for Inflammation and Repair at the Manchester Academic Health Science Centre.

His practice is entirely related to the knee with interests in articular cartilage regeneration, meniscus preservation, the unstable knee, off-loading the degenerate knee with osteotomy and the more general management of the young patient with arthritis of the knee often related to trauma or sports injury.

Professor Turner also has a particular interest in teaching and training; he holds an honorary chair in the Department of Health Sciences at the University of Salford.

Mr Sanj Anand

Consultant Orthopaedic Surgeon; Knee Specialist
Stepping Hill Hospital, Stockport NHS Trust
sanjayanand@doctors.org.uk
Dr Anand’s Profile

Orthopaedic Surgery; Cartilage Injuries

Mr Anand’s practice covers all aspects of knee surgery, from sports injuries to arthritis of the knee. He commonly performs arthroscopic (keyhole) surgery, cruciate ligament reconstruction and both total and partial knee replacements. His specialist areas of interest include cruciate ligament injuries and other sports-related trauma including cartilage injuries.

Mr Bilal Barkatali

Consultant Orthopaedic Surgeon; Knee Specialist
Salford Royal Foundation Trust
Bilal.Barkatali@srft.nhs.uk
Mr Barkatali’s NHS Profile

Knee specialist; Orthopaedic Surgery; Joint Replacement; Soft Tissue Reconstruction and Arthroplasty

Mr Barkatali specialist interest is the full spectrum of knee surgery from sports injuries e.g. ACL reconstruction, to joint preservation surgery e.g. HTO (high tibial osteotomy), cartilage regeneration and meniscal transplantation to joint replacement surgery.  He also has an interest in Orthopaedic Trauma Surgery. His interest in Regenerative Medicine encompasses the use of Graphene and Graphene Oxide hydeogells for the use of cartilage repair.
“knee specialist” and “soft tissue reconstruction and arthroplasty

Muscle

Musculoskeletal – Muscle (Academic)

Academic

Dr Urmas Roostalu

BBSRC Research Fellow
Faculty of Biology, Medicine and Health
urmas.roostalu@manchester.ac.uk
Dr Roostalu’s University Profile

Pericyte Mediated Muscle Repair

Dr Roostalu’s research is focused on blood vessel associeated cells and their role in tissue regeneration. Our blood vessels are lined by pericytes, these small cells can regulate blood flow, the formation of new blood vessels and guide the migration of immune cells through the blood vessel wall. Accumulating evidence indicates that pericytes can leave the vascular niche and give rise to various other cell types in our body. The full differentiation potential of pericytes and the underlying molecular mechanisms are still poorly understood. By using novel transgenic models Dr Roostalu studies pericyte fate in various tissues and the signalling networks that can activate pericyte differentiation into diverse cell types. A particular focus of his work is on the repair of skeletal muscle injuries and how it can be enhanced in muscular dystrophies.

Musculoskeletal – Muscle (Academic/Clinical)

Academic-Clinical

Professor Giulio Cossu

Constance Thornley Professor of Regenerative Medicine
Faculty of Biology, Medicine and Health
giulio.cossu@manchester.ac.uk
Professor Cossu’s University Profile

Stem Cell Therapy for Muscular Dystrophies

In collaboration with M. Buckingham’s laboratory, Professor Cossu has elucidated the hierarchy of the different myogenic regulatory factors (Tajbakhsh et al. Cell 2007) and also identified the unexpected expression of one of these factors, Myf5, in non-somitic progenitors such as the neuroectoderm (Tajbakhsh et al. Neuron 1994) and the lateral mesoderm (Salvatori et al. J. Cell Sci. 2005). These observations led to the identification of a bone-marrow derived, circulating myogenic progenitor cell in adult mice (Ferrari et al. Science 1998) whose embryonic precursors were later identified in the dorsal aorta (De Angelis et al. J Cell Biol. 1999). These cells, named mesoangioblasts, are able to proliferate in vitro and contribute to mesoderm tissues upon transplantation (Minasi et al. 2002). Mesoangioblasts were used for the first successful cell therapy protocols of muscular dystrophy in mice and dogs (Sampaolesi et al. Science 2003; Nature, 2006). After characterization of human mesoangioblasts as a subset of muscle pericytes (Dellavalle et al. Nature Cell Biol. 2007) whose lineage was traced in mice (Dellavalle et al. Nature Comm. 2011), these cells were used by GC for a first in man phase I/II clinical trial based upon allo-transplantation of donor mesoangioblasts from an HLA-identical donor in patients affected by Duchenne muscular dystrophy.

Musculoskeletal – Muscle (Clinical)

Clinical

Dr Imelda Hughes

Central Manchester Foundation Trust
Imelda.Hughes@cmft.nhs.uk

Muscular Dystrophy Treatments

Dr Imelda Hughes is a consultant paediatric neurologist at the Royal Manchester Children’s Hospital with an interest in neuromuscular disease.  She is currently involved in a PhI/IIa cell therapy trial for Duchenne Muscular Dystrophy.

Dr Gary McCullagh

Consultant Paediatric Neurologist
Central Manchester NHS Foundation Trust
Gary.McCullagh@cmft.nhs.uk

Muscular Dystrophy Treatments

Dr Gary McCullagh is a consultant paediatric neurologist at the Royal Manchester Children’s Hospital with an interest in neuromuscular disease.  He is currently involved in a PhI/IIa cell therapy trial for Duchenne Muscular Dystrophy.