Disease Progression After Bone Marrow Transplantation in a Model of Multiple Sclerosis Is Associated With Chronic Microglial and Glial Progenitor Response

Abstract

Multiple sclerosis (MS), the most common nontraumatic cause of neurologic disability in young adults in economically developed countries, is characterized by inflammation, gliosis, demyelination, and neuronal degeneration in the CNS. Bone marrow transplantation (BMT) can suppress inflammatory disease in a majority of patients with MS but retards clinical progression only in patients treated in the early stages of the disease. Here, we applied BMT in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), and investigated the kinetics of reconstitution of the immune system in the periphery and in the CNS using bone marrow cells isolated from syngeneic donors constitutively expressing green fluorescent protein. This approach allowed us to dissect the contribution of donor cells to the turnover of resident microglia and to the pathogenesis of observed disease relapses after BMT. BMT effectively blocked or delayed EAE development when mice were treated early in the course of the disease but was without effect in mice with chronic disease. We found that there is minimal overall replacement of host microglia with donor cells in the CNS and that newly transplanted cells do not appear to contribute to disease progression. In contrast, EAE relapses are accompanied by the robust activation of endogenous microglial and macroglial cells, which further involves the maturation of endogenous Olig2 glial progenitor cells into reactive astrocytes through the cytoplasmic translocation of Olig2 and the expression of CD44 on the cellular membrane. The observed maturation of large numbers of reactive astrocytes from glial progenitors and the chronic activation of host microglial cells have relevance for our understanding of the resident glial response to inflammatory injury in the CNS. Our data indicate that reactivation of a local inflammatory process after BMT is sustained predominantly by endogenous microglia/macrophages.

Evaluation of Bone Marrow- and Brain-Derived Neural Stem Cells in Therapy of Central Nervous System Autoimmunity

“…47,48 In the present study, we showed that BM cells did differentiate into NSCs, which, comparable to SVZ-NSCs, can differentiate into neural cells in vitro and in vivo and effectively suppress EAE. It has been found that transplantation of whole BM cells at early stage of disease effectively blocked or delayed EAE development 49 but without effect at chronic stage. 9,49 EAE mice treated with BM-derived mesenchymal stem cells (MSCs) 16,17,50,51 showed a significantly milder disease and fewer relapses compared with control mice, with decreased inflammation infiltrates, reduced demyelination, and axonal loss.…”

“…In a pilot clinical trail, autologous MSCs had been injected intrathecally to patients with MS, with a demonstrable benefit in some patients, 52 indicating that BM derived multipotential cells is likely to become a useful clinical tool. The effect of whole BM cells and MSCs on EAE is mainly the result of elimination of pathogenic cells 49 and interference with autoimmune responses, 16,50 but not transdifferentiation into neurons or oligodendrocytes. 16,50 Thus, the neural replacement and remyelination property of BM-NSCs, in addition to their immunoregulatory capacity, provides a significant advantage for these cells over MSCs and whole BM cells.…”

Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis

“…1 The etiology of this disease is still unclear, but based on altered immune responses in MS patients, the pathology of MS lesions, and its animal model, experimental autoimmune encephalomyelitis, the inflammatory element of MS pathogenesis is believed to be primarily T cell-mediated, possibly as the result of a breakdown in immune tolerance, in particular peripheral mechanisms. 2 Recent thymic emigrants that escape central tolerance can still be susceptible to peripheral tolerance checkpoints such as regulatory T cells (Tregs). Tregs, which are also thymic dependent, increasingly appear to be pivotal in the maintenance of selftolerance, with their elimination leading to the development of autoimmune diseases.…”

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

“…Moreover, by monitoring of tracking of transplanted green fluorescent protein-transduced cells, the endogenous origin of microglia in advanced disease was shown. Host macrophages/microglial cells demonstrated robust activation and their number was higher in the stage of disease progression [25]. The same demonstration of different local trigger mechanisms can be made for systemic sclerosis (SSc), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and other autoimmune diseases.…”