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Towards an optimal microenvironment for nucleus pulposus regeneration: a glycobiology approach

Creator:

Collin, Estelle;

Subject Keywords: Glycobiology; Tissue Engineering; Hydrogel; Glycosaminoglycans; Nucleus pulposus;
Topic: Chronic Conditions
Conditions
Back pain
Chronic Conditions
Catalogue: Research and Evaluation
Report
Type: Report
Region: Republic of Ireland
Description:

Neck and low back pain are the two highest causes of job-related disability in
the UK and the USA. These pathologies are strongly related to intervertebral disc
degeneration (IVD). Disc degeneration diseases (DDD) are characterised by changes
in extracellular matrix (ECM) composition which lead to an important
disorganisation of IVD tissue. Better knowledge of IVD biology and DDD in the last
decades has promoted the development of new tissue engineering approaches to
restore the disc function from a biological viewpoint. The ultimate objective of this
thesis was to develop an optimal functionalized cell delivery system using an ECMmimicking
injectable hydrogel that enhances the production and the deposition of
newly synthesised ECM to aid the regeneration of NP tissue. It was hypothesised that
the modulation of the glycoenvironment of NP cells will promote the maintenance of
their phenotype.
In the first phase of this thesis, an injectable type II collagen hydrogel
stabilised with poly(ethylene glycol)ether tetrasuccinimidyl glutarate and
supplemented with hyaluronic acid was successfully developed. The hydrogel system
was stable in culture and had the capability to support cell growth. In addition, NP
cells maintained a low type I collagen expression and their cell morphology after
culture in the hydrogel. These characteristics, in addition to its injectable properties,
make this hydrogel a promising candidate as a carrier of cells for future translation in
vivo. The results obtained in this study highlighted the importance of ECM
composition on NP cell behaviour. Highly glycosylated, the ECM of IVD tissue
plays a crucial role on cell behaviour and IVD biology. Therefore, as a step forward,
the glycoenvironment of the IVD was mapped in an effort to understand IVD
glycoenvironment and its impact on IVD biology. A subset of specific and selective
histological markers to distinguish the cell and ECM phenotypes of NP, AF and
cartilage tissue and their stage of maturation was identified. The detailed CS
composition and quantity of chondroitin sulfates (CS) revealed a change in sulfation
pattern of CS with maturity. The depletion of CS has been shown to greatly affect
IVD biology of the intervertebral disc and CS were chosen for the investigations
conducted in the last part of this thesis. Therefore, the behaviour of GAGs,
specifically of CS, and xylosyltransferase I (XT-I) and glucuronyltransferase I (GTI),
two key enzymes involved at crucial points of CS synthesis, was evaluated in a bovine ageing IVD model. Important changes in GAGs composition during disc
ageing were highlighted in this study. CS, specifically, were affected at a structural
and quantitative levels with important changes in sulfated disaccharide composition
upon ageing. A correlation between the expressions of XT-I and GT-I and CS
content was shown in this study. The delivery via electroporation restored the
expression of both enzymes at a protein level. A trend, although not significant,
towards the increase of CS production after delivery of XT-I and GT-I was seen. In
accord with the results of this study, the best therapeutic approach to modulate the
expression of GAGs might be a dual delivery of XT-I and GT-I or in combination
with aggrecan protein core up-regulation.
Glycans were shown in this thesis to be essential to IVD biology. A better
understanding of their effects on cell behaviour will promote the development of new
biological tissue engineering approaches for IVD regeneration.

Suggested citation:

Collin, Estelle; . () Towards an optimal microenvironment for nucleus pulposus regeneration: a glycobiology approach [Online]. Available from: http://publichealthwell.ie/node/771355 [Accessed: 25th May 2019].

  

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