The role of endogenous stem cells in spontaneous repair in multiple sclerosis

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It is multifactorial with a multitude of neurological presentations. Equally there is a plethora of treatments for MS. Many offer relief from symptoms and reduce the number of relapses in the early phase of disease, but to date none have been shown to halt or slow disease progression. Recently the use of stem cell transplantation has been explored as a therapy for MS. Preliminary results are promising, but without knowledge of endogenous neural progenitor cells (NPC) within the CNS, and their response to MS disease it is difficult to tailor appropriate therapies to patients. Originally it was assumed that NPC were very restricted in the adult brain and only resided in specialised germinal zones. However, there is now gathering evidence that NPC are far more widespread in both normal and diseased adult brain. Several animal models of MS have shown that, in response to demyelination, NPC can migrate from germinal zones into demyelinated lesions where they differentiate into neurons, oligodenrocytes and astrocytes. This study aims to show that there are stem like cells within MS lesions in adult human brain and explore their role in repair within MS. Nestin is one of the most commonly used markers for NPc. This study quantifies nestin expressing cells within MS lesions, showing that there are more cells expressing nestin in lesion tissue than in normal appearing white matter or control. Many of the nestin expressing cells co-express musashi-l, an alternative marker for NPC, and some are proliferating consistent with a stem like cell. Demyelination leading to axonal damage is one of the main features of MS. Spontaneous remyelination is a common event in MS lesions. Remyelination is carried out primarily by oligodendrocyte progenitor cells (OPC). OPC are derived from NPC during development. As the neural tube develops, the NPC• differentiate into neurons, astrocyes and oligodendrocytes to form a complex brain network. Here the possibility that OPC may be replenished by NPC in the adult human brain is explored. The phenotype of nestin expressing cells has been assessed showing that nestin expressing NPC within MS lesions may differentiate into OPC which aid in remyelination and neurons which could replace lost or damaged axons. Apoptosis is seen in a wide variety of cells within MS lesions. To determine the fate of nestin expressing NPC within MS lesions, normal appearing white matter (NA WM) and control tissue a TUNEL assay was used. This study has shown that many nestin expressing NPC in MS lesions. are undergoing apoptosis, but some are not apoptotic and so could survive and possibly aid in the repair process. MS lesions are often characterised by a large amount of inflammation caused by the infiltration of circulating immune cells and activation of resident microglia. Inflammation has been shown to affect the proliferation and differentiation of NPC. There is a two and a half fold increase in the number of cells in the sub ventricular zone (SVZ) of MS patients compared to control tissue, suggesting that the MS disease state causes an increase in NPC. This study compares. the number of immune cells with the number of nestin expressing cells within control and MS tissue; identify a relationship between inflammation and NPc.EThOS - Electronic Theses Online ServiceGBUnited Kingdo