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Galactosaminoglycans - Role in Brittlestar Limb Regeneration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Dorothe Spillmann)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regeneration is, in simple terms, ‘to re-grow’ damaged or lost parts of the body (e.g. cells, tissues and organs) and is a natural phenomenon occurring throughout the life of an organism. The regenerative capacity varies in the animal kingdom. Invertebrates have high regenerative capacity in contrast to higher vertebrates. This raises several fundamental questions related to the regeneration potential, evolutionary selection and its cellular and molecular mechanisms. An in-depth knowledge in regeneration is warranted to answer the fundamental questions that are still a challenge in regenerative medicine.

 Glycosaminoglycans (GAGs) are known to be involved in various physiological processes. Of several GAG types galactosaminoglycans are the focus of this thesis. Galactosaminoglycans such as chondroitin sulfate/dermatan sulfate (CS/DS) are anionic linear polysaccharides covalently linked to core proteins so called proteoglycans (PGs), and form an integral part of both cell surface and extracellular matrix components. Although CS/DS have been associated with different cellular processes from development to homeostasis, not many studies have been carried out to understand their role in regeneration. In this thesis, we aim to study galactosaminoglycans, their structure, and interaction with growth factors of biological importance in the process of regeneration using simple invertebrate model organisms - brittlestars.

We have identified CS/DS as the major GAG present in brittlestars. Molecular characterization of these chains indicated a much higher level of sulfation in Amphiura filiformis than so far found in GAGs from invertebrates or vertebrates. This brittlestar CS/DS promotes FGF2 mediated cell signaling similar to heparin. Further, we studied the functional role of these CS/DS chains and their biosynthetic machinery during arm regeneration in A. filiformis. Regeneration is followed by an increase in GAG sulfation from blastema stage to the fully functional arm. Suppressing sulfation on the other hand by sodium chlorate treatment drastically affected the proliferation process and thereby regeneration. Thus our findings suggest a potential biological role of CS/DS in brittlestar limb regeneration that may have relevance to regenerative medicine in future.

 

 

 

 

 

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 791
Keyword [en]
Chondroitin sulfate, Dermatan sulfate, Brittlestar, Regeneration
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-179044ISBN: 978-91-554-8413-2 (print)OAI: oai:DiVA.org:uu-179044DiVA: diva2:543003
Public defence
2012-09-18, C2:301, BMC, Uppsala University, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-08-28 Created: 2012-08-06 Last updated: 2013-01-22Bibliographically approved
List of papers
1. Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling
Open this publication in new window or tab >>Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling
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2014 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 24, no 2, 195-207 p.Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans (GAGs) isolated from brittlestars, Echinodermata class Ophiuroidea, were characterized, as part of attempts to understand the evolutionary development of these polysaccharides. A population of chondroitin sulfate/dermatan sulfate (CS/DS) chains with a high overall degree of sulfation and hexuronate epimerization was the major GAG found, whereas heparan sulfate (HS) was below detection level. Enzymatic digestion with different chondroitin lyases revealed exceptionally high proportions of di- and trisulfated CS/DS disaccharides. The latter unit appears much more abundant in one of four individual species of brittlestars, Amphiura filiformis, than reported earlier in other marine invertebrates. The brittlestar CS/DS was further shown to bind to growth factors such as fibroblast growth factor 2 and to promote FGF-stimulated cell signaling in GAG-deficient cell lines in a manner similar to that of heparin. These findings point to a potential biological role for the highly sulfated invertebrate GAGs, similar to those ascribed to HS in vertebrates.

Keyword
Brittlestar, Chodroitin sulfate, Dermatan sulfate, Fibroblast growth factor-2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178989 (URN)10.1093/glycob/cwt100 (DOI)000330839300009 ()
Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2016-02-12Bibliographically approved
2. A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
Open this publication in new window or tab >>A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
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2017 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 27, no 5, 438-449 p.Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) and dermatan sulfate (DS) from various vertebrate and invertebrate sources are known to be involved in diverse cellular mechanisms during repair and regenerative processes. Recently, we have identified CS/DS as the major GAG in the brittlestar Amphiura filiformis, with high proportions of di- and tri-O-sulfated disaccharide units. As this echinoderm is known for its exceptional regeneration capacity, we aimed to explore the role of these GAG chains during A. filiformis arm regeneration. Analysis of CS/DS chains during the regeneration process revealed an increase in the proportion of the tri-O-sulfated disaccharides. Conversely, treatment of A. filiformis with sodium chlorate, a potent inhibitor of sulfation reactions in GAG biosynthesis, resulted in a significant reduction in arm growth rates with total inhibition at concentrations higher than 5 mM. Differentiation was less impacted by sodium chlorate exposure or even slightly increased at 1-2 mM. Based on the structural changes observed during arm regeneration we identified chondroitin synthase, chondroitin-4-O-sulfotransferase 2 and dermatan-4-O-sulfotransferase as candidate genes and sought to correlate their expression with the expression of the A. filiformis orthologue of bone morphogenetic factors, AfBMP2/4. Quantitative amplification by real-time PCR indicated increased expression of chondroitin synthase and chondroitin-4-O-sulfotransferase 2, with a corresponding increase in AfBMP2/4 during regeneration relative to nonregenerating controls. Our findings suggest that proper sulfation of GAGs is important for A. filiformis arm regeneration and that these molecules may participate in mechanisms controlling cell proliferation.

Keyword
Echinoderm, Brittlestars, Chondroitin sulfate, Dermatan sulfate, Sodium chlorate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178991 (URN)10.1093/glycob/cwx010 (DOI)000401003500007 ()28130266 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Research Council FormasWenner-Gren Foundations
Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2017-06-19Bibliographically approved
3. Gene expression of chondroitin sulfate/dermatan sulfate biosynthetic enzymes during regeneration in Amphiura filiformis.
Open this publication in new window or tab >>Gene expression of chondroitin sulfate/dermatan sulfate biosynthetic enzymes during regeneration in Amphiura filiformis.
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
Amphiura filiformis, Regeneration, Dermatan sulfate, Sulfotransferase, Biosynthesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178992 (URN)
Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2013-01-22

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