Microvesicles and the prevention of tissue wasting
Microvesicles, Stem Cells, Aging, Tissue wasting
Basic research; translational and applied research; Maintenance of colonies of genetically altered animals
The objective of the project is to explore the clinical benefit of stem cell secretory factors on age related degenerative diseases and those associated with cancer. To facilitate the safe translation of pre-clinical testing to human clinical testing, animal testing is necessary in this project.
Previously studies have shown that the fluid that stem cells are grown in in the lab (conditioned media), can have therapeutic uses. However most work has concentrated on degenerative illnesses including multiple sclerosis and injury conditions like joint damage.
This project will serve to explore stem cell conditioned media and expand the range of conditions that it could help. Specifically we will now focus on age related tissue loss and cancer. This will provide pre-clinical data on safety and efficacy to facilitate early clinical application of therapy in diseases which currently have few treatment options.
The clinical use of differentiated or undifferentiated stem cell conditioned media provides an attractive, less invasive, safer alternative (minimising cancer, reducing immunological risks) to stem cell transplantation.
The project will use both rats and mice (wild-type and transgenic). The project will last 5 years and use approximately 6,500 animals per year
The project will use an accelerated ageing model to study the effects of stem cell secretions on age related degenerative disease. As a consequence, animals will show some symptoms of age related decline. At the end of the studies animals will be euthanized. A further model will involve cancer cachexia where animals will show some muscle wastage, at the end of the studies animals will be euthanized at humane end points.
Stem cell secretory factors ameliorate disease by a variety of mechanisms thus experimental treatments are not suited to mathematical or computer simulations to replace the use of experimental animals.
Appropriate animal testing for optimization, safety and efficacy are needed before any form of clinical trial on human subjects.
With some aspects of the project, experimental animals can be replaced by in-vitro testing, and as outlined in the programme of work such in-vitro testing will replace intact animal experimentation where ever possible in the project.
Our use of in-vitro methods limits the number of animals required for the in-vivo investigation phases of the project.
The use of accelerated ageing (progeric) mouse models will greatly reduce the number of animals bred for the work due the issues related to maintaining wild-type animals to geriatric ages.
To further reduce the number of animals used in the project, the proposed methods of experimental designs and methods of analysis of the results have been discussed with our Consultant Statistician, reviewed by our scientific advisory board and reviewed by the University local ethical advisory board.
The mouse is the species of choice due to availability of appropriate genetically modified lines that phenotypically display progeria (accelerated ageing). Transgenic Ercc mice (Delta) are an excellent model of normal age related pathologies enabling analysis of key features of aging namely decline of endogenous stem cell function, build up of inter and intra cellular debris, tissue atrophy, cognitive decline. There shortened lifespan gives less variability on onset of such changes than in natural aged animals.
Rats are the species of choice since their metabolism and other clinical features, including sarcopenia (loss of skeletal mass) resemble the pathological presentations found in humans.