The UK Multiple Sclerosis Tissue Bank

Fibrin clots – good guys and bad guys?
Dr Djordje Gveric
Institute of Neurology, University College London

Fibrinogen is a protein that circulates in the blood and that can be thought of as a member of a “rapid response team”. When a blood vessel wall is torn at a site of injury anywhere in the body, fibrinogen escapes from the blood and enters the surrounding tissue. Here single molecules of fibrinogen stick to one another and form a mesh called fibrin. Fibrin seals the tear and stops any further leakage from the blood vessel. It also attracts cells and molecules to the site where they play a role in the healing process. An essential step at the end of this procedure is the removal of the fibrin; this is achieved by an enzyme called tissue plasminogen activator (tPA) that dissolves away the fibrin mesh.

In multiple sclerosis lesions, fibrinogen escapes from the blood into brain tissue across a broken down blood-brain barrier. Dr Gveric has been looking to see whether the failure of successful repair (remyelination) of MS lesions could be due fibrin not being cleared away from the site. One of the ways in which the body controls the activity of tPA is with an enzyme inhibitor called plasminogen activator inhibitor-1 (PAI-1) which binds to tPA and inactivates it. When the group examined active MS lesions they found an increase in the activity of PAI-1, a resulting decrease in the activity of tPA, and an accumulation of fibrin around blood vessels and on axons.

In this photograph, fibrin is stained green and axons red - there is one running across the photograph. The arrowheads point to areas where fibrin has been laid down on the axon resulting in a yellow colour. The extended presence of fibrin would inhibit the repair process and may actually favour damage to axons by components of the immune system. Since the action of tPA is inhibited by PAI-1, hindering the action of PAI-1 would release tPA to dissolve the fibrin. Dr Gveric’s group is now trying to develop a strategy that will block the action of PAI-1 and so aid recovery and reduce further damage.

Could preventing scarring help repair?
Dr Nick Gutowski
Peninsula Medical School, Exeter

A part of the normal response of the body to damage is to form a scar; the characteristic grey, firm MS lesion in the white matter is actually a scar that has grown as the myelin and/or axons have been destroyed. These scars mainly consist of a meshwork of fibres that are the outgrowth of a cell resident in the normal CNS – the astrocyte. Could this normal response of astrocyte scarring actually be hampering remyelination?

Dr Gutowski’s group has been trying to find out what makes a normal resting astrocyte turn into cell that lays down a fibrous scar. The group first made “identikits” that would allow astrocytes at different stages along this process to be distinguished according to the proteins that were present on the surface of each cell. Using the identikits, the group were able to distinguish “scar” astrocytes that were present in MS lesions from resting astrocytes that were in MS brain tissue that did not contain a lesion and in tissue from people that did not have MS.

The panel on the left shows the edge of an MS lesion; scarring astrocytes in the lesion have been marked with the identikit (black dots in right half of picture).
Finding an accurate way to recognise scar astrocytes was essential to be able to answer the next question: “what signals make a resting astrocyte change into a scarring astrocyte?” Astrocytes were isolated from tissue donated by people that did not have MS, and grown in plastic dishes as shown in the photograph in the right panel above. These resting astrocytes can then be used to test the ability of chemical messengers to convert them into a scarring astrocyte as recognised by the identikit. It is hoped that this work will lead to developing ways of stopping scarring; and this combined with therapies that encourage remyelination may provide a means of allowing demyelinated axons to regain their function.

Emergency Donor Line Number: 07659 132 045
In January 2005, we had to change the number of our 24-hour Emergency Donor Line. This is the number that people should use if they need an immediate response from the Tissue Bank; for example, to inform us of the death of someone registered on our donor scheme. In the New Year we sent all registered donors a new Donor Card, like this…

…if you are a registered donor and do not have a card like this, please let us know. Please also update the number on all your paperwork and let all relevant people know of the change. We are very sorry for the inconvenience that this is going to cause.

Please let us know…if you do not wish to receive another newsletter
Please let us know…of any changes that we need to make to our copy of your consent forms, (eg change of address, next-of-kin or general practitioner)

Telephone:
020 8846 7324

Email:
ukmstissuebank@imperial.ac.uk

Post:
The UK Multiple Sclerosis Tissue Bank
Division of Neuroscience and Mental Health
Imperial College London
Charing Cross Campus
Fulham Palace Road
London W6 8RF

the Bank Statement was written by Abhi Vora (Manager of the Tissue Bank)

page 5

The UK Multiple SclerosisTissue Bank
Welcome Introduction How to register as a tissue donor Raising awareness of all those affected by MS Donation of Tissue Requesting tissue for research on multiple sclerosis Promoting the Tissue Bank in the research community The Bank Statement Issue One Issue Two Issue Three Articles MS Matters Insight - Banking on the future MS Frontiers - A very special bank MS Frontiers - Making a very special contribution Links: Department of Cellular and Molecular Neuroscience Department of Neuropathology Multiple Sclerosis Society of Great Britain and Northern Ireland International Federation of Multiple Sclerosis Societies E-mail: ukmstissuebank@imperial.ac.uk	the Bank Statement News from The UK Multiple Sclerosis Tissue Bank . (The Bank Statement is also available as a PDF document.) Fibrin clots – good guys and bad guys? Dr Djordje Gveric Institute of Neurology, University College London Fibrinogen is a protein that circulates in the blood and that can be thought of as a member of a “rapid response team”. When a blood vessel wall is torn at a site of injury anywhere in the body, fibrinogen escapes from the blood and enters the surrounding tissue. Here single molecules of fibrinogen stick to one another and form a mesh called fibrin. Fibrin seals the tear and stops any further leakage from the blood vessel. It also attracts cells and molecules to the site where they play a role in the healing process. An essential step at the end of this procedure is the removal of the fibrin; this is achieved by an enzyme called tissue plasminogen activator (tPA) that dissolves away the fibrin mesh. In multiple sclerosis lesions, fibrinogen escapes from the blood into brain tissue across a broken down blood-brain barrier. Dr Gveric has been looking to see whether the failure of successful repair (remyelination) of MS lesions could be due fibrin not being cleared away from the site. One of the ways in which the body controls the activity of tPA is with an enzyme inhibitor called plasminogen activator inhibitor-1 (PAI-1) which binds to tPA and inactivates it. When the group examined active MS lesions they found an increase in the activity of PAI-1, a resulting decrease in the activity of tPA, and an accumulation of fibrin around blood vessels and on axons. In this photograph, fibrin is stained green and axons red - there is one running across the photograph. The arrowheads point to areas where fibrin has been laid down on the axon resulting in a yellow colour. The extended presence of fibrin would inhibit the repair process and may actually favour damage to axons by components of the immune system. Since the action of tPA is inhibited by PAI-1, hindering the action of PAI-1 would release tPA to dissolve the fibrin. Dr Gveric’s group is now trying to develop a strategy that will block the action of PAI-1 and so aid recovery and reduce further damage. Could preventing scarring help repair? Dr Nick Gutowski Peninsula Medical School, Exeter A part of the normal response of the body to damage is to form a scar; the characteristic grey, firm MS lesion in the white matter is actually a scar that has grown as the myelin and/or axons have been destroyed. These scars mainly consist of a meshwork of fibres that are the outgrowth of a cell resident in the normal CNS – the astrocyte. Could this normal response of astrocyte scarring actually be hampering remyelination? Dr Gutowski’s group has been trying to find out what makes a normal resting astrocyte turn into cell that lays down a fibrous scar. The group first made “identikits” that would allow astrocytes at different stages along this process to be distinguished according to the proteins that were present on the surface of each cell. Using the identikits, the group were able to distinguish “scar” astrocytes that were present in MS lesions from resting astrocytes that were in MS brain tissue that did not contain a lesion and in tissue from people that did not have MS. The panel on the left shows the edge of an MS lesion; scarring astrocytes in the lesion have been marked with the identikit (black dots in right half of picture). Finding an accurate way to recognise scar astrocytes was essential to be able to answer the next question: “what signals make a resting astrocyte change into a scarring astrocyte?” Astrocytes were isolated from tissue donated by people that did not have MS, and grown in plastic dishes as shown in the photograph in the right panel above. These resting astrocytes can then be used to test the ability of chemical messengers to convert them into a scarring astrocyte as recognised by the identikit. It is hoped that this work will lead to developing ways of stopping scarring; and this combined with therapies that encourage remyelination may provide a means of allowing demyelinated axons to regain their function. Emergency Donor Line Number: 07659 132 045 In January 2005, we had to change the number of our 24-hour Emergency Donor Line. This is the number that people should use if they need an immediate response from the Tissue Bank; for example, to inform us of the death of someone registered on our donor scheme. In the New Year we sent all registered donors a new Donor Card, like this… …if you are a registered donor and do not have a card like this, please let us know. Please also update the number on all your paperwork and let all relevant people know of the change. We are very sorry for the inconvenience that this is going to cause. Please let us know…if you do not wish to receive another newsletter Please let us know…of any changes that we need to make to our copy of your consent forms, (eg change of address, next-of-kin or general practitioner) Telephone: 020 8846 7324 Email: ukmstissuebank@imperial.ac.uk Post: The UK Multiple Sclerosis Tissue Bank Division of Neuroscience and Mental Health Imperial College London Charing Cross Campus Fulham Palace Road London W6 8RF the Bank Statement was written by Abhi Vora (Manager of the Tissue Bank) page 5 page 1/ page 2/ page 3/ page 4/ page 5
	The UK Multiple Sclerosis Tissue Bank Division of Neuroscience and Mental Health Imperial College London Charing Cross Campus Fulham Palace Road London W6 8RF Tel: 020 8846 7324 Fax: 020 8846 7500 E-mail: ukmstissuebank@imperial.ac.uk
*The UK Multiple Sclerosis Tissue Bank is funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland, registered charity 207495.*