John T. Gallagher, PH.D.
Embryonic Stem Cells can be used to investigate the role of Heparan Sulphate in Development and Disease
Abstract 2005 MHE Conference
Claire E. Johnson, Rebecca Baldwin, Annie Wat, Graham Rushton,
John T. Gallagher and Catherine L.R. Merry
Cancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital Research
Centre, Manchester, UK.
For several years now, work using model organisms has demonstrated that heparan sulphate (HS) in association with specific
core proteins is a downstream effecter of several regulatory molecules that modulate changes in the morphology, mobility and
proliferation of developing cells. The genetic analysis of inherited diseases such as HME has revealed the importance of HS in cell
growth regulation and tissue-specific patterning during human development.
In addition to our on-going study of the role of HS at the molecular level, we have established the novel approach of using
murine and human embryonic stem (ES) cells to provide in vitro model systems for the study of the developmental biology of
HS. ES cells undergo symmetrical self-renewal in culture whilst retaining the ability to differentiate into all foetal and adult
lineages.
There are three alternative fates for ES cells; they can remain pluripotent, they can differentiate or they can undergo apoptosis.
The signalling molecules that control this decision process are complex, and consist of a subtle interplay of secreted factors,
cell-autonomous factors and cell-adhesion molecules. Many of these signalling proteins are familiar to the proteoglycan (PG)
field, being HS-dependent growth factors, morphogens or matrix-resident PGs secreted by the ES cells, or by the fibroblasts
used as a feeder layer. ES cells therefore present an experimentally tractable in vitro system in which the role of HS in multiple
interacting signalling processes can be assessed.
The major benefit of the system is that we can monitor cells as they transform from a pluripotent phenotype to differentiated
lineages. This enables us to study the relationship between developmentally-regulated expression of HS-biosynthetic enzymes
(such as EXT-1) and the structural and functional attributes of HS. This has become a hotly debated issue in the field as
evidence has emerged concerning the deleterious effects of mutations in these enzymes on embryogenesis and the functions of
HS in the adult.
We are currently using an ext1 knock-out mouse ES cell line (from Prof. Esko, UCSD) to detail the role of cell-surface HS in the
earliest stages of differentiation and lineage commitment. This work will enable us to better understand the function of HS in
co-ordinating the multiple interacting pathways influencing cell development and differentiation in the normal and disease state.
Abstract 2005 MHE Conference
Claire E. Johnson, Rebecca Baldwin, Annie Wat, Graham Rushton,
John T. Gallagher and Catherine L.R. Merry
Cancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital Research
Centre, Manchester, UK.
For several years now, work using model organisms has demonstrated that heparan sulphate (HS) in association with specific
core proteins is a downstream effecter of several regulatory molecules that modulate changes in the morphology, mobility and
proliferation of developing cells. The genetic analysis of inherited diseases such as HME has revealed the importance of HS in cell
growth regulation and tissue-specific patterning during human development.
In addition to our on-going study of the role of HS at the molecular level, we have established the novel approach of using
murine and human embryonic stem (ES) cells to provide in vitro model systems for the study of the developmental biology of
HS. ES cells undergo symmetrical self-renewal in culture whilst retaining the ability to differentiate into all foetal and adult
lineages.
There are three alternative fates for ES cells; they can remain pluripotent, they can differentiate or they can undergo apoptosis.
The signalling molecules that control this decision process are complex, and consist of a subtle interplay of secreted factors,
cell-autonomous factors and cell-adhesion molecules. Many of these signalling proteins are familiar to the proteoglycan (PG)
field, being HS-dependent growth factors, morphogens or matrix-resident PGs secreted by the ES cells, or by the fibroblasts
used as a feeder layer. ES cells therefore present an experimentally tractable in vitro system in which the role of HS in multiple
interacting signalling processes can be assessed.
The major benefit of the system is that we can monitor cells as they transform from a pluripotent phenotype to differentiated
lineages. This enables us to study the relationship between developmentally-regulated expression of HS-biosynthetic enzymes
(such as EXT-1) and the structural and functional attributes of HS. This has become a hotly debated issue in the field as
evidence has emerged concerning the deleterious effects of mutations in these enzymes on embryogenesis and the functions of
HS in the adult.
We are currently using an ext1 knock-out mouse ES cell line (from Prof. Esko, UCSD) to detail the role of cell-surface HS in the
earliest stages of differentiation and lineage commitment. This work will enable us to better understand the function of HS in
co-ordinating the multiple interacting pathways influencing cell development and differentiation in the normal and disease state.
Research authored by Dr. Gallagher
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
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