Research Programmes
- Stroke
- Cardiac Repair
- Tissue Repair
- Blood Disorders
- Cystic Fibrosis and other Inherited Disorders
- Immune Diseases
- Transplantation Research
- Developmental Biology
Stroke Research Program
Our main research objective is to understand the biology of neural stem cells (NSC) and how these unique cells may be used in cellular therapies to improve clinical outcome after stroke. Over the last ten years we have investigated the factors that generate neurons and how they wire-up the brain to form a functioning nervous system during embryonic development and disease.
Each year 53,000 Australians suffer a stroke and one third have significant residual functional disabilities; indeed, stroke is the leading cause of disability in the Australian community. The financial burden is estimated to be greater than $2 billion per annum and the psychological and emotional burden is immeasurable. Stem cell therapy may provide a therapeutic strategy to overcome this burden.
In collaboration with Prof. Richard Faull, Auckland University, NZ, we will investigate the neural stem cell response of the human brain following stroke. To our knowledge we have set-up a world first initiative under the auspices of the SA Brain Bank to have patients who die from stroke donate their brain for investigation.
A/Professor Simon Koblar
Head, Stroke Research Programme
Schools of Medicine & Molecular Biomedical Science, University of Adelaide Academic Clinician
Neurologist/Stroke Physician, The Queen Elizabeth Hospital
Tel: +61 8 8222 6125
Email: simon.koblar@adelaide.edu.au
Cardiac Repair
Heart failure resulting from weakened heart muscle remains a major cause of ill health and death in our society despite improvements in current clinical therapies. Two major types of heart failure exist. Ischaemic heart failure makes up about 60% of cases and is caused by narrowing of coronary arteries depriving the heart muscle of necessary blood supply. Non-ischaemic heart failure accounts for the remainder of cases and has various causes including viruses, certain drugs and toxins, and some hereditary and metabolic diseases. Recently, different types of stem cells taken from bone marrow have been studied as a way of regenerating and repairing injured cardiac tissue. Mesenchymal stem cells (MSC) are a rare type of cell found in adult bone marrow that have the ability to divide and renew themselves and the potential to develop into different types of mature cells, including bone, cartilage, blood vessel cells and heart cells.
Professor Stephen Worthley
Helpman Professor of Cardiology, School of Medicine
Director Cardiac Catheterization Laboratories
Director Cardiovascular MRI
Royal Adelaide Hospital
Tel: +61 8 8222 5608
Email: stephen.worthley@adelaide.edu.au
Tissue Repair
- Characterisation and Application of Postnatal Stromal Stem Cells
- Periodontal Repair
- The Treatment of Brain Diseases Associated with Lysosomal Storage Disorders
- Understanding Neural Development in Mice and Man using Stem Cells
- Vascular Biology and Cellular Recruitment
Characterisation and Application of Postnatal Stromal Stem Cells
Adult bone marrow contains a non-haematopoietic, stromal stem cell population with the ability to form clonogenic, adherent colonies comprised of fibroblast-like cells (CFU-F: colony forming units-fibroblast). The ex vivo expanded progeny of CFU-F have been shown to develop into different stromal cell lineages (myelosupportive stroma, adipocytes, smooth muscle cells, myoblasts, chondrocytes and osteoblasts) and are thought to arise from a common, self-replicating multi-potential stem cell referred to as mesenchymal stem cells (MSC) or bone marrow stromal stem cells. Our stem cell isolation technology has recently been used to identify MSC-like cells from adipose tissue and dental tissues that exhibit similar growth properties and gene expression profiles to that described for bone marrow derived MSC. This work has resulted in the generation of several patents encompassing the isolation and expansion technologies and use of different MSC preparations for various tissue engineering based applications. These patents have now been licensed to two sister companies, Angioblast Inc. New York, NY. and Mesoblast Ltd., Melbourne Vic.
Professor Stan Gronthos
Head, Mesenchymal Stem Cell Group and Regenerative Medicine Program
Division of Haematology,
SA Pathology
Tel: +61 8 8222 3460
Email: stan.gronthos@imvs.sa.gov.au
Periodontal Repair
To date repair of damaged periodontal tissues relies on implantation of structural substitutes with little or no reparative potential. More recently, tissue-engineering, based on an understanding of the cell and molecular biology of the periodontium, has emerged as an interesting alternative to existing therapies for periodontal regeneration.
We have established the presence of mesenchymal stem-like cells (PDLSC) in both human and ovine periodontal tissues capable of sustained renewal and tissue regeneration. We now hypothesize that PDLSC can be used for cellular based therapies to treat damaged periodontal tissues.
Professor Mark Bartold
Director, Colgate Australian Clinical Dental Research Centre
School of Dentistry, University of Adelaide
Tel: +61 8 8303 3436
Email: mark.bartold@adelaide.edu.au
The Treatment of Brain Diseases Associated with Lysosomal Storage Disorders
More than 40 diseases are classified as lysosomal storage disorders (LSDs). Each results from an inherited genetic defect that causes an enzymatic deficiency or malfunction, in the cell's lysosomes. The lysosome is involved in the breakdown and removal of waste from the cell. When loss of activity of an enzyme of the lysosome occurs, it impairs waste trafficking, causing cellular dysfunction.
Patients suffering from lysosomal storage disorders suffer from heart problems, breathing difficulties, stiff joints, skeletal deformities, enlarged heads and a characteristic facial appearance. Further, in some patients, this leads to the development of brain disease, causing mental impairment (leading to hyperactivity, aggressiveness and loss of learned skills such as walking and talking).
While individually most of these diseases are rare, as a group their incidence is about 1 in 7,700 live births.
Research into lysosomal storage disorders that affect the CNS has also proposed the use of stem cells to treat these diseases.
The wider objective of this group is the ‘early diagnosis and effective therapy for all lysosomal storage disorder (LSD) patients’. To this end, a number of genes have been systematically isolated that are involved in LSDs and characterised mutations that effect their efficient expression. This has lead to a number of studies to investigate the pathophysiology of these storage disorders, evaluation of a number of potential therapies and the development of technology to enable newborn screen for these conditions.
Professor John Hopwood
Head, Lysosomal Diseases Research Unit
Department of Genetic Medicine,
Women’s and Children’s Hospital, CYWHS
Tel: +61 8 8161 7101
Email: john.hopwood@adelaide.edu.au
Dr Kim Hemsley
Lysosomal Diseases Research Unit
Department of Chemical Pathology
Women's and Children's Hospital
72 King William Road
North Adelaide SA 5006
Tel: +61 8 8161 6153
Email: kim.hemsley@adelaide.edu.au
Understanding Neural Development in Mice and Man using Stem Cells
Mental Retardation (MR) affects 2-3% of the population and is the most frequent cause of serious disability in children and young adults. In many cases, MR results from changes (mutations) in genes that are critical for the formation of the Central Nervous System (CNS) during embryonic development. We have identified a new causative gene for MR, termed SOX3, that is associated with a MR syndrome in which affected boys also have growth hormone deficiency (X-linked Hypopituitarism or XH). Importantly, SOX3 is active in the neural stem cells that give rise to the entire central nervous system and is generally downregulated during neuronal differentiation.
Our overall aim of our stem cell research programme is to understand how SOX3 controls the ability of neural stem cells to differentiate into neurons and to self-renew.
Our established Sox3 knock-out and transgenic mouse models provide an ideal platform technology for developing new therapeutic strategies for hypopituitarism/mental retardation, including the use of stem cells to restore neural function.
A/Prof Paul Thomas
Discipline of Biochemistry
Pfizer Australia Research Fellow and Senior Lecturer
School of Molecular and Biomedical Science
University of Adelaide
Tel: +61 8 8303 7047
Email: paul.thomas@adelaide.edu.au
Vascular Biology and Cellular Recruitment
Endothelial progenitor cells (EPCs) directly contribute to blood vessel formation (vasculogenesis) in physiological ‘repair' processes and the pathological settings of cardiovascular disease, cancer, wound healing, diabetes, arthritis and ischemia/reperfusion injury. The significant contribution that EPCs make to pathological vasculogenesis is gaining momentum with over 100 human clinical trials currently targeting EPCs. However, initial results have not been promising with their lack of success likely due to the lack of distinct EPC markers for identification as well as insufficient EPC differentiation, survival and retention.
To overcome the problems that preclude the clinical investigation of EPCs, we recently developed a protocol for human and rodent EPC isolation, culture and expansion and have made key discoveries in EPC differentiation (Bonder C et al Blood 2009). The overall objective of our program is to identify discrete genetic profile which specifically regulates human EPC differentiation, survival and recruitment. Our preliminary data suggest that human EPCs (i) express significantly greater levels of specific transcription factors which upregulates the progenitor markers CD34 and VEGFR2, (ii) exhibit increased surface expression of activated integrins for a pro-survival phenotype and (iii) express activated adhesion molecules for recruitment to vascular endothelium under shear flow.
Our program on human EPCs provides a single cell system to combat, for the first time, the two major killers in the Western world, cancer and cardiovascular disease. Our vision of identifying what controls EPC differentiation, survival and recruitment will target vasculogenesis and as such come closer to long lasting therapies and perhaps a cure.
Dr Claudine Bonder
Head, Vascular Biology and Cellular Recruitment Laboratory
Centre for Cancer Biology, SA Pathology
Tel: +61 8222 3504
email: claudine.bonder@health.sa.gov.au
Blood Disorders
- Leukaemia Program
- Blood Cell Growth and Differentiation and the Changes Associated with Leukaemia
- Myeloma Research
Leukaemia Program
Our major focus is into understanding the mechanisms underlying normal blood cell growth and differentiation, and the changes associated with leukaemia. We are using novel systems to dissect chemical signaling pathways that control cytokine-induced cell survival, proliferation, differentiation and self-renewal. Aberrant cytokine receptor signaling occurs frequently in acute myeloid leukaemia (AML) and identification of key downstream events will allow development of targeted therapies with reduced toxicity. We also utilising molecular and proteomic approaches to identify factors that contribute to the therapeutic response and relapsed diseases.
Myeloproliferative disease (MPD) occurs as a result of changes acquired in the haemopoietic stem cell compartment which induce aberrant growth factor responses and over-production of mature myeloid and erythoid cells. Through molecular and genetic cohort studies of patients with MPD we aim to understand the nature of the changes that are associated with disease initiation and long-term maintenance of disease in these patients.
We are also collaborating with A/Prof. Simon Barry (Discipline of Paediatrics) to investigate the mechanisms controlling the regulatory T cell linage and with A/Prof Andrew Zannetinno to study molecular mechanisms that contribute to bone differentiation.
Associate Professor Richard D’Andrea
Chief Medical Scientist
Division of Haematology
Centre for Cancer Biology, SA Pathology
and
Department of Haematology and Oncology
The Queen Elizabeth Hospital
Tel: +61 8 8222 8695 and +61 8 8222 8695
Email: richard.dandrea@health.sa.gov.au
Blood Cell Growth and Differentiation and the Changes Associated with Leukaemia
Umbilical cord blood (CB) is a proven alternative source of haemopoietic stem cells (HSC) for transplantation. The major limiting factor to more widespread use of CB is the characteristic delay in engraftment.
MSCs are derived from the non-haemopoietic elements of BM and are capable of in vitro differentiation into multiple mesodermal tissue types including osteoblasts, chondrocytes, myocytes and adipocytes. It has been postulated that MSCs may promote HSC engraftment by enhancement of haemopoietic progenitor proliferation, haemopoietic growth factor production or facilitating homing of transplanted cells through adhesion molecules. MSCs have also been shown to be immunosuppressive and thus may promote engraftment by reducing the recipient alloimmune response.
In this project we have characterised MSCs derived from human placenta and assessed their role in CB transplantation in a non-obese diabetic/severely immuno-deficient (NOD/SCID) mouse model and compared outcomes to transplantation using two umbilical cord blood units.
Acute myeloid leukaemia (AML) is a clonal, neoplastic proliferation of immature myeloid cells of the haemopoietic system, characterised by aberrant or arrested differentiation. Immunological characterisation of leukaemic cells is important in the diagnosis and prognosis of AML and is increasingly being used in the monitoring of the disease. The presence of Minimal Residual Disease (MRD) in the bone marrow (BM) of patients with AML following chemotherapy is strongly associated with relapse of leukaemia. Identification of patients with a high risk of relapse by MRD techniques may enable new therapeutic strategies to be offered to these individuals.
Dr Ian Lewis
Senior Consultant Haematologist, Division of Haematology, &
Medical Manager, Therapeutic Products Facility,
SA Pathology (IMVS)
and
Head, Clinical Haematology and Bone Marrow Transpantation
Royal Adelaide Hospital
Tel: +61 8 8222 3022
Email: ian.lewis@health.sa.gov.au
Myeloma Research Laboratory
Multiple myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of malignant plasma cells (PC) within the bone marrow (BM). MM is the second most common haematological malignancy after non-Hodgkin's Lymphoma, with approximately 1,400 newly-diagnosed patients each year in Australia. Despite recent advances in treatment, MM remains almost universally fatal with a 10 year survival rate of approximately 17%. The main clinical manifestations of MM are the development of osteolytic bone lesions, bone pain, hypercalcaemia, renal insufficiency, suppressed immunoglobulin production and increased BM angiogenesis. It is now widely accepted that most, if not all, MM is preceded by a premalignant MGUS (monoclonal gammopathy of uncertain significance) stage. However, the genetic factors which trigger the progression from asymptomatic MGUS to overt malignant MM remain to be determined. Current projects are focused on (a) Identifying key genetic changes that that "drive" the progression from asymptomatic MGUS to overt malignant MM; (b) Identifying novel BM microenvironmental factors which contribute to MM disease progression, and (c) Identifying novel signalling pathways with roles in mesenchymal stem cell differentiation which may be manipulated to increase bone formation in MM patients.
Professor Andrew Zannettino
Head, Myeloma Research Laboratory
School of Medical Science,
Faculty of Health Science,
University of Adelaide
Tel: +61 8 8222 3455
Email: andrew.zannettino@adelaide.edu.au
Cystic Fibrosis and other Inherited Disorders
Life Long Gene Therapy for Cystic Fibrosis
The Adelaide Cystic Fibrosis Gene Therapy Group, headed by Dr David Parsons and Dr Don Anson, is developing a safe and effective airway gene therapy to cure the early-fatal genetic lung disease in Cystic Fibrosis.
In vivo mouse studies using reported genes already show near lifetime gene expression after a single dosing, suggesting in situ transduction of stem/progenitor cells.
This approach also has clear potential for eventual use in humans to detect and monitor airway disease, and any successful treatment, in the smallest airways (< 100um dia).
Our group also attracts strong community support, with significant untied donations allowing rapid pilot studies of new approaches, and the core funds for construction of new CF research laboratories on the WCH campus.
Dr David Parsons
Principal Medical Scientist
Department of Pulmonary Medicine, &
Discipline of Paediatrics, School of Paediatrics and Reproductive Health
Women’s and Children’s Hospital, CYWHS
Tel: +61 8 8161 7004
Email: david.parsons@adelaide.edu.au
Immune Diseases
The Barry lab is focused on using cord blood stem cells for function based gene discovery using genome wide expression arrays followed by gene validation with viral vectors. We are developing tools for gene discovery, gene delivery and gene ablation, and applying them in immunological cell settings. The lab uses cellular and molecular approaches to identify and characterize genes involved in the function of a subset of the regulatory T cell population. We are attempting to identify novel proteins on the surface of regulatory T cells, which may be useful as diagnostic or functional markers for autoimmune diseases. We have established an in vitro differentiation system that can generate Treg from cord blood stem cells, and can use this to investigate the developmental contribution that different genes make to the differentiation of these cells.
Associate Professor Simon Barry
Head, Cord Blood Group
Discipline of Paediatrics
School of Paediatrics and Reproductive Health
University of Adelaide
Tel: +61 8 8161 6562
Email: simon.barry@adelaide.edu.au
Transplantation Research
Research in the laboratory is focused on the induction of immunological tolerance for the treatment of organ transplant rejection. Haematopoietic stem cells are a significant and important source of pre-cursor cells for the generation of dendritic cells. The major focus of our laboratory has been the development of novel pre-clinical transplantation models in which we can test tolerogenic therapies.
Projects also include work on the role of tolerance induction via mesenchymal stem cells in a variety of animal and human models which will allow the tolerance inducting properties of these cells to be tested.
The future direction for research includes the application of this technology for pancreatic islet transplantation as well as other solid organ transplants.
Gene Therapy projects to modify both mesenchymal Stem Cells and Dendritic Cells are avaiable in Tolerance and regection models.
A/Prof Toby Coates
Renal Transplant Nephrologist
Department of Nephrology and Transplantation Services
Royal Adelaide Hospital
Tel: +61 8 8222 0900
Email: toby.coates@health.sa.gov.au
Developmental Biology
- Isolation & Characterisation of Porcine Embryonic Stem Cells
- Ovarian Follicular Stem Cells
- Cyclic Regeneration of Ovarian Thecal Cells
Isolation and Characterisation of Mammalian Stem Cells
Work in our lab has increasingly focused on the isolation of porcine embryonic and adult stem cells to improve cloning and gene targeting efficiencies for various research programs. Recent research highlights include:
- the isolation and (ongoing) characterisation of porcine embryonic stem cells using novel methodology.
- the isolation and characterisation of porcine mesenchymal stem cells from bone marrow as well as blood
- the isolation and characterisation of porcine adult stem cells.
- The application of novel methodology for the isolation and expansion of embryonic stem cells to other species. Currently pluripotent cells are yet to be isolated from any of the domestic species. The isolation of embryonic stem cells for laboratory (eg rat) and domestic species (eg cattle) would greatly facilitate research as well as commercial applications.
- Currently there is considerable interest in the possibility of generating sperm or eggs from infertile couples using stem cells. Given the Groups background in reproductive biology and its many collaborations in this general area a long term goal for Group could be in this area namely the generation of gametes from infertile individuals using a number of different approaches including the use of adult stem cells.
Associate Professor Mark Nottle
Head, Reproductive Biotechnology Group
School of Paediatrics and Reproductive Health
Discipline of Obstetrics and Gynaecology
University of Adelaide
Tel: +61 8 8303 4087
Email: mark.nottle@adelaide.edu.au
Dr Michelle Lane
Early Development Group
Discipline of Obstetrics and Gynaecology
School of Paediatrics and Reproductive Health
University of Adelaide
Tel: +61 8 8303 8176
Email: michelle.lane@adelaide.edu.au
Ovarian Follicular Stem Cells
Ovaries are responsible for producing both eggs and hormones such as oestrogen and progesterone. How ovaries produce hormones is unlike that of any other endocrine organ because the pattern of hormone secretion by the ovary changing on a day-to-day basis.
We hypothesized that granulosa cells arise from a population of stem cells, that their progeny can divide (transit amplifying population of cells), and that they differentiate into at least two lineages, cumulus and mural cells. We provided key evidence of stem cells.
My established laboratory focuses on the biology of ovarian follicles and its regulation by extracellular matrix. Extracellular matrix is the final set of regulatory molecules other than hormones and growth factors to be examined in the ovary.
Our studies we believe will lead to methods for in vitro culture of follicles and maturation of their oocytes, and the regulation by matrix. Our studies may also lead us to understand ovarian tumourogenesis and premature menopause.
Professor Raymond Rodgers
Ovarian Biology Group
Discipline of Obstetrics and Gynaecology
School of Paediatrics and Reproductive Health
University of Adelaide
Tel 08 8303 3932
email raymond.rodgers@adelaide.edu.au
