A systematic investigation of the effect of neural injury on the survival, development and migration of adult neural ste

Lead Research Organisation: University of Cambridge
Department Name: Unlisted

Abstract

Our scientific and clinical attitudes to injury of the brain and spinal cord are changing. Human neural stem cells offer the potential for developing new therapies to replace lost cells and deliver biologically active substances, such as growth factors, to the central nervous system. Recent investigations have demonstrated that neural stem cells are not confined to embryos but are also present in the adult brain including man. These cells may have a limited capacity to replace lost cells in a process of self-repair. Unfortunately this response is normally overwhelmed by the inflammation and scarring associated with disease.

In order to utilise stem cells we need to (1) learn how to turn them into the cells we want to replace (e.g. dopamine cells in Parkinson‘s disease) and (2) help the cells get to the site of injury and circumvent any glial scarring process.

The four investigations proposed in this project aim to begin to address this second problem by characterising the effect of injury and scarring on a) stem cells already present in the mature adult brain and b) on implanted stem cells.

The project then goes on to begin to look at how we can obtain adult human neural stem cells and how they behave in response to injury. The results will increase our understanding of how stem cells respond to neural injury and how they might be manipulated to develop novel therapies to treat disease. This in turn would make the use of human embryonic tissue unnecessary and by using the bodies own cells avoid the need for immunosuppressive drugs.

Technical Summary

Objective: To characterise the effect of neural injury on adult stem cell behaviour and hence determine how adult stem cells may be incorporated into strategies to repair the damaged central nervous system.

An integrated series of 4 studies are proposed. The first will characterise the effect of excitotoxic and mechanical damage on the ability of endogenous adult neural progenitors to continue to proliferate and to be recruited into areas of neural injury. This in vivo study will use cell migration in the rostral migratory stream as a model system based upon previous studies in intact animals. Cells will be labelled with a reporter gene and their fate and distribution investigated over time. This will form the basis for the second study.

The second study will investigate the effect of neural injury on the survival and behaviour of implants of adult neural stem cells. Tissue will be expanded in vitro and labelled to enable the fate and distribution of the cells to be determined. The ability of stem cells to re-populate areas of neural damage will also be studied.

The third study involves a different experimental paradigm, which seeks to evaluate the interaction between reactive astrocytes and migrating progenitors in vitro. The effect of manipulation of cell adhesion molecules in the extracellular matrix on progenitor cell migration over astrocytes will be investigated. This will lead to studies in vivo to determine how stem cells react interact with areas of reactive astrocytes at different stages of maturity.

The final study will begin to characterise the behaviour of human adult neural stem cells derived from clinical material obtained during routine neurosurgical practice. Techniques for harvesting and expanding human adult progenitors in vitro will be developed based on reported data. The study then aims to go on to investigate their behaviour in vivo.

Publications

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Borg N (2011) Serum albumin and survival in glioblastoma multiforme. in Journal of neuro-oncology

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Jefferies SJ (2013) High grade glioma--the arrival of the molecular diagnostic era for patients over the age of 65 years in the UK. in Clinical oncology (Royal College of Radiologists (Great Britain))

 
Description Changing clinical practice
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Changes in process of care leading to reduced length of stay, enhanced patient care (shift from in-patient emergency-based practice to elective outpatient-based practice) and enhanced clinical trial recruitment (see Guilfoyle et al 2011)
 
Description BIDD Programme
Amount £189,908 (GBP)
Funding ID C9221/A16700 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2016
 
Description GALA-5
Amount £38,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2011 
End 06/2013
 
Description Project grant
Amount £176,900 (GBP)
Funding ID 10/136 
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2013 
End 06/2016
 
Title Glioma Stem Cell Derivation Protocol 
Description Development of highly efficient derivation protocol for glioma stem-like cells based on adapting protocols for adult neural stem cell derivation. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Industrial collaboration with Genzyme to identify cell surface epitopes suitable for diagnostic or therapeutic targeting. 
 
Description Clonal Evolutionary dynamics of GBM 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Derivation of cell lines from patients & use to generate orthotopic model of GBM. Sequential in vivo tumourigeneis Generation of material for FISH analysis
Collaborator Contribution FISH analysis of copy number aberrations to general clonal evolutionary tree.
Impact First confirmation of clonal evolution of solid human tumour Paper in preparation
Start Year 2011
 
Description Genzyme Phage Project 
Organisation Sanofi
Department Genzyme Corporation
Country United States 
Sector Private 
PI Contribution Generation of patient specific cell lines
Collaborator Contribution Phage analysis & validation of novel epitopes
Impact Data on novel epitopes held by genzyme. This has not been published or disclosed
Start Year 2009
 
Description Molecular Genetics of Glioblastoma 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Technique of Fluorescence-Guided Multiple Sampling (FGMS) developed to allow objective spatially discrete tumour sampling for molecular genetic analysis
Collaborator Contribution Bioinformatic analysis of molecular genetics of GBM
Impact Identification of sampling bias in generating molecular genetic data from surgical specimens 2 papers under review
Start Year 2010
 
Title Fluorescence-guided multiple sampling (FGMS) 
Description FGMS is a surgical technique designed to study spatial genomic heterogeneity in Glioblastoma 
Type Support Tool - For Fundamental Research
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Increased recognition of the importance of understanding spatial genomic heterogeneity and its role in the emergence of resistant disease 
 
Description APPG 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Prof Sir Mike Richards (National Clinical Director for Cancer) spoke to MPs and patient support groups at the Houses of Parliament highlighting some of the issues raised.

CRUK are planning to highlight brain cancer as a priority in their next strategic five year plan (2014-19).
Year(s) Of Engagement Activity 2010
 
Description Patient support group activity 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Health professionals
Results and Impact Successful application for clinical trial funding to CRUK

Enhanced Brain CSG clinical trial portfolio
Identification of barriers to recruitment to clinical trials
Year(s) Of Engagement Activity 2009