Catherine L.R. Merry, PH.D.
Research authored by Dr. Merry
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List of Publications via PubMed
(NIH National Library of Medicine)
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, Catherine L.R. Merry and John T. Gallagher
The University of Manchester,
School of Materials,
Lecturer in Biomedical Materials

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.

Professional biography

Cathy Merry graduated in Biochemistry from The University of Manchester in 1995. As part of this course, she spent a year
working for Amgen Inc. in California. She obtained her Ph.D. from the University of Manchester (1999), transferring to the
Paterson Institute where she worked with Professor John Gallagher in Medical Oncology.

Following on from her Ph.D. studies, during which she developed and patented a novel method for sequencing heparan sulphate
(HS), she stayed within Medical Oncology to establish facilities for the culture and study of embryonic stem (ES) cells. Over the
next six years, Cathy was able to exploit the use of various developmental models with which to study the biological effects of
alteration of HS structure. As part of these studies, ES cells became a central focus, and three studentships, a Post Doc and a
senior technician within the Medical Oncology group were dedicated to this research area. The group published the first detailed
analysis of ES cell HS in early 2006.

In March 2006 Cathy joined the Biomaterials group in the School of Materials. Working within the Manchester Stem Cell
Network, her main interests are in the role of cell surface and extracellular matrix molecules in influencing cell fate. Glycobiology
remains a central theme, with glycosaminoglycans of particular interest. Future projects will focus on the use of various
biomaterials to provide scaffolds to promote the culture of ES cells, either to scale-up their growth in the pluripotent state or to
direct differentiation to specific cell types.
Dr. Merry's research
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2009 Conference abstract
Restoring Function to Heparan-Sulphate Deficient Cells

Kate Meade, Claire Johnson, Rebecca Holley, Catherine Merry
Stem Cell Glycobiology Group, Biomaterials, University of Manchester, UK.

e-mail:
Catherine.Merry @manchester.ac.uk

Embryonic stem (ES) cell differentiation is dependent on the presence of heparan sulphate (HS). We have demonstrated that
during differentiation, the evolution of specific cell lineages is associated with particular patterns of glycosaminoglycan (GAG)
expression with, for example, different HS epitopes synthesised during neural or mesodermal lineage formation. Cells deficient
in HS production (EXT1-/- and EXT1+/- ES cells) are able to be maintained as a stem cell population but are unable to
differentiate normally to various lineages. We have been using these cells to understand how cells lacking cell surface HS
coordinate multiple signalling pathways and have found that it is often the ability to switch off specific intracellular signals that is
at fault in these cells. We have also observed that the addition of soluble GAG saccharides to cells with or without cell surface
HS can influence the pace and outcome of differentiation, often correcting the deficiencies in intracellular signalling, again
highlighting specific pattern requirements for particular lineages.  We are combining this work with ongoing studies into the
design of artificial cell environments where we have optimised 3D scaffolds, generated by electrospining or by the formation of
hydrogels. By permeating these scaffolds with defined GAG oligosaccharides we can to control the mechanical environment of
the cells (via the scaffold architecture) as well as their biological signalling environment (using the oligosaccharides). Initially,
these scaffolds have been used to demonstrate that they can restore function to HS-deficient cells in vitro however; in the near
future we hope to use these scaffolds in vivo to present defined GAGs to HS deficient cells with the aim of influencing cell
behaviour. A focus of such studies will be the application of GAG-bearing scaffolds to the sites of exostosis removal with the
aim of reducing the reoccurrence of exostosis formation and the need for further surgery.
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