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A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Dorothe Spillmann)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Dorothe Spillmann)
Department of Biological and Environmental Sciences, University of Gothenburg .
Department of Biological and Environmental Sciences, University of Gothenburg .
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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.

Place, publisher, year, edition, pages
2017. Vol. 27, no 5, 438-449 p.
Keyword [en]
Echinoderm, Brittlestars, Chondroitin sulfate, Dermatan sulfate, Sodium chlorate
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-178991DOI: 10.1093/glycob/cwx010ISI: 000401003500007PubMedID: 28130266OAI: oai:DiVA.org:uu-178991DiVA: diva2:543814
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
In thesis
1. Galactosaminoglycans - Role in Brittlestar Limb Regeneration
Open this publication in new window or tab >>Galactosaminoglycans - Role in Brittlestar Limb Regeneration
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
Chondroitin sulfate, Dermatan sulfate, Brittlestar, Regeneration
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179044 (URN)978-91-554-8413-2 (ISBN)
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
2. Brittlestars Galactosaminoglycans and Tools to Study their Structure
Open this publication in new window or tab >>Brittlestars Galactosaminoglycans and Tools to Study their Structure
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In all living organisms, biological activities such as proper functioning and co-ordination of different organs will depend on different cells and molecular interactions. In some organisms the loss of functional organs or damage of organs can be lethal, whereas in others a special process called regeneration can retrieve lost organs. The molecular details of regeneration are still not completely understood in many organisms. Echinoderms are close to vertebrates in the evolutionary tree and are well known for their amazing regeneration capacity. So we chose to investigate the molecular processes of regeneration mechanism with an interest towards our favorite groups of molecules, glycosaminoglycans (GAGs). GAGs are linear polysaccharides, expressed on all cell surfaces and extracellular space and are also known to be involved in many cellular activities. We aimed to characterize the GAGs present in Echinodermata species Amphiura filiformis and investigated their role during arm regeneration.

In Paper I we characterized the structure and function of GAGs from A. filiformis and identified that A. filiformis contains CS/DS type of GAGs, but no HS. The sulfation degree of these CS/DS is close to the one of heparin, i.e. they are highly sulfated. These chains are able to bind FGF-2 growth factor and induce FGF-2 mediated cell signaling. In Paper II we further characterized these GAGs for their localization and for their role in arm regeneration in A. filiformis. Immuno- and histochemical stainings on arm sections revealed that CS/DS GAGs are localized around the podia, surrounding the water vascular system, and around the muscle tissues. Inhibition of sulfated GAG biosynthesis by chlorate treatment affected the regeneration efficiency of the arms, which may be an indication of the importance of CS/DS structures in A. filiformis arm regeneration. We also characterized some bacterial sulfatases in Paper III and a lyase in Paper IV from human and canine gut symbiotic bacteria. Here we sought to find the substrate specificity and optimal conditions for these enzymes’ activities. Our findings suggest that these polysaccharide lyase and sulfatases can be used as potential tools to characterize different GAG structures and their application could further add knowledge on diseases mechanisms related to host pathogen interactions.

 

 

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1172
Keyword
Chondroitin sulfate, Brittlestars, Gut bacteria, H. bizzozeronii, B.thetaiotaomicron
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Research subject
Biochemistry; Microbiology; Molecular Biology
Identifiers
urn:nbn:se:uu:diva-271559 (URN)978-91-554-9449-0 (ISBN)
Public defence
2016-02-26, A1: 107, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-02-02 Created: 2016-01-10 Last updated: 2016-02-12

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Namburi, Ramesh BabuLindahl, UlfSpillmann, Dorothe

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