Dr. Vernique Mirn, PhD. The University of Edinburgh (MRC) And MS

Transcription

1 NEW STRATEGY FOR BRAIN REPAIR IN MULTIPLE SCLEROSIS By Dr. Vernique Mirn, Ph.D. Pstdctral fellw, MRC Centre fr Regenerative Medicine, The University f Edinburgh Multiple sclersis is caused by damage t the insulatin arund nerves, myelin. Multiple sclersis (MS) is the mst cmmn disease causing disability in yung adults, affecting ver 100,000 peple in the UK and 2.5 millin peple wrldwide. In MS the prtective layer that surrunds nerves in the brain and spinal crd, called myelin, is destryed. This causes nerves t degenerate leading t prblems with visin, mvement, and speech. In MS, myelin, the layer arund nerves, is damaged disrupting functin f the brain and spinal crd. Damaged myelin Nerve Regeneratin f myelin fllwing damage fails in prgressive frms f multiple sclersis. The creatin f new myelin ( remyelinatin ) is a regenerative prcess driven by cells called ligdendrcytes that make the new myelin. Hwever, remyelinatin ften fails as MS prgresses. This failure leads t the damage f nerves which cannt regrw, causing the lss f functin in peple with MS. All currently apprved therapies fr MS nly slw disease prgressin by reducing myelin injury; these are nt aimed at prmting remyelinatin. Thus, understanding what stimulates remyelinatin can lead t the discvery f prteins that may be develped int regenerative therapies fr the recvery f lst functins in peple with MS. Myelin regeneratin ( remyelinatin ) is carried ut by cells called ligdendrcytes. Remyelinatin fails in prgressive MS. Oligdendrcyte

2 Abut multiple sclersis Multiple sclersis (MS) is the mst cmmn cause f disability in yung adults (mstly aged 15-40), affecting peple in the UK and 2.5 millin peple wrldwide. MS is mre prevalent in wmen than in men (estimated t be a 3:1 rati). The prevalence f MS increases in areas further away frm the equatr, e.g. Canada and Sctland have high rates f MS. Symptms include prblems with visin, hearing, mvement, sensatin, speech, memry, fatigue, pain, bladder and bwels. The cause f MS is unknwn but likely invlves a cmplex interactin between the envirnment and genes. There are different types f MS: Mst peple with MS are diagnsed with Relapse-Remitting MS, where symptms appear fr sme time (called a relapse) then imprve (called remissin). Relapse-remitting MS can develp int Secndary Prgressive MS where symptms gradually get wrse ver time. A small number f MS patients shw steady accumulatin f disability frm diagnsis, with r withut relapses (Primary Relapsing r Primary Prgressive MS). Immune cells called macrphages are needed fr regeneratin. Previus studies have shwn that immune cells called macrphages are needed fr remyelinatin t ccur. Interestingly, anti-inflammatry macrphages (called M2 macrphages ) are required fr the regeneratin f skin and muscle. In a cllabrative study between the University f Edinburgh s MRC Centre fr Regenerative Medicine and the University f Cambridge s MRC Cambridge Stem Cell Institute, Immune cells called macrphages are needed fr remyelinatin. Macrphages we examined whether macrphages needed t be anti-inflammatry (M2) t drive myelin regeneratin. We tested whether a prtein released by M2 macrphages culd stimulate remyelinatin, which culd lead t the develpment f a new strategy fr regeneratin in peple with MS. \

3 Anti-inflammatry macrphages are required fr remyelinatin. T ask whether M2 macrphages are present during remyelinatin, we used muse mdels f myelin damage and regeneratin. We fund that M2 macrphages were present and that they increased in number at the start f remyelinatin, suggesting that these macrphages may cntrl the regeneratin prcess. Given that ligdendrcytes are the cells that nrmally make myelin in the brain and spinal crd, we asked whether M2 macrphages n their wn are able t stimulate ligdendrcytes t start making myelin by expsing them t prteins released by M2 macrphages in the labratry. These prteins did prmte mre ligdendrcytes t make myelin. In the labratry, prteins released by M2 macrphages stimulated ligdendrcytes t start making myelin. T bserve whether remyelinatin culd cntinue in the absence f M2 macrphages, these cells were eliminated fllwing myelin damage. In a muse mdel withut M2 macrphages, remyelinatin was dramatically reduced indicating that M2 macrphages are needed fr remyelinatin. Analysis f muse mdels f remyelinatin and brain tissue frm peple with MS shwed that numbers f M2 macrphages are high when remyelinatin is efficient, but nt when remyelinatin is pr. In a muse mdel withut M2 macrphages, remyelinatin was dramatically reduced Macrphages stimulate ligdendrcytes t make myelin by releasing activin-a. We then tested whether a prtein called activin-a, which is prduced by macrphages, cntributes t the regenerative effects f M2 macrphages. Activin-A was present at very high levels in M2 macrphages as remyelinatin was starting, and additin f activin-a t ligdendrcytes in the labratry stimulated them t make myelin. By blcking the effect f activin-a n ligdendrcytes fllwing myelin injury, we fund that the M2 macrphages had a reduced ability t prmte ligdendrcytes t make myelin. M2 macrphages stimulated ligdendrcytes t make myelin by releasing a prtein called activin-a In summary, we shwed that M2 macrphages release activin-a which causes ligdendrcytes t make myelin, a key step in myelin regeneratin.

4 Oligdendrcytes in the absence f activin-a are nt making myelin. Oligdendrcytes expsed t prteins released by macrphages including activin-a making myelin These are ur micrscpe images f ligdendrcytes in the labratry withut activin-a and after treatment with prteins released by macrphages, including activin-a. Oligdendrcytes that are nt making myelin are in green. Oligdendrcytes that are starting t make myelin are in red. Treatment f ligdendrcytes with activin-a stimulates them t start making myelin. Hw des myelin regeneratin happen and why des it fail? The damage t the brain and spinal crd in peple with MS is directed at the insulating layer surrund nerves, called myelin. Areas f damage are called lesins r plaques. Creatin f new myelin t replace the damaged myelin, called remyelinatin, ccurs at different levels f efficiency in different patients. Usually it is quite effective in early phases f MS (relapse-remitting MS), but ften fails in prgressive frms f MS. Remyelinatin starts by cells (called prgenitr cells) mving int the lesin frm surrunding areas, becming new ligdendrcytes, and then creating new myelin arund nerves. Previus studies suggest that remyelinatin fails in prgressive MS because prgenitr cells can t mve int the lesins, and als can t becme ligdendrcytes. This may be caused by prteins in the lesin that prevent ligdendrcytes frm mving in and making myelin, r the absence f prteins that allw ligdendrcytes t d these things.

5 What des this mean fr patients? The results in this study suggest that studying M2 macrphages and activin-a might ffer exciting new pprtunities fr the develpment f regenerative therapies fr multiple sclersis. In cmbinatin with a drug t reduce the initial myelin damage, therapies develped frm these new findings may supprt regeneratin f the central nervus system and restre lst functins in multiple sclersis patients. Future wrk is needed t understand hw activin-a affects ligdendrcytes and t determine the likely safety and effectiveness f ptential therapies in humans befre any clinical trial fr multiple sclersis culd take place. Publicatin details Mirn VE, Byd A, Zha J-W, Yuen TJ, Ruckh JM, Shadrach JL, v.wijngaarden P, Wagers AJ, Williams A, Franklin RJM & ffrench-cnstant C M2 micrglia/ macrphages drive ligdendrcyte differentiatin during CNS remyelinatin. Nature Neurscience, epub ahead f print. DOI: /nn.3469.