Human olfactory mesenchymal stromal cell transplantation ameliorates experimental autoimmune encephalomyelitis revealing an inhibitory role for IL16 on myelination

Aleksandra M. Molęda,Daniel E. McElroy,Susan C. Barnett,Lindsay M. MacLellan,Carl S. Goodyear,Siew Min Keh,Christopher Linington,Susan L. Lindsay

doi:10.1186/s40478-022-01316-9

Abstract

One of the therapeutic approaches for the treatment of the autoimmune demyelinating disease, multiple sclerosis (MS) is bone marrow mesenchymal stromal cell (hBM-MSCs) transplantation. However, given their capacity to enhance myelination in vitro, we hypothesised that human olfactory mucosa-derived MSCs (hOM-MSCs) may possess additional properties suitable for CNS repair. Herein, we have examined the efficacy of hOM-MSCs versus hBM-MSCs using the experimental autoimmune encephalomyelitis (EAE) model. Both MSC types ameliorated disease, if delivered during the initial onset of symptomatic disease. Yet, only hOM-MSCs improved disease outcome if administered during established disease when animals had severe neurological deficits. Histological analysis of spinal cord lesions revealed hOM-MSC transplantation reduced blood–brain barrier disruption and inflammatory cell recruitment and enhanced axonal survival. At early time points post-hOM-MSC treatment, animals had reduced levels of circulating IL-16, which was reflected in both the ability of immune cells to secrete IL-16 and the level of IL-16 in spinal cord inflammatory lesions. Further in vitro investigation revealed an inhibitory role for IL-16 on oligodendrocyte differentiation and myelination. Moreover, the availability of bioactive IL-16 after demyelination was reduced in the presence of hOM-MSCs. Combined, our data suggests that human hOM-MSCs may have therapeutic benefit in the treatment of MS via an IL-16-mediated pathway, especially if administered during active demyelination and inflammation.

Highlights

Multiple sclerosis (MS) is a chronic disease in which repeated episodes of inflammation in the central nervous system (CNS) result in widespread demyelination associated with varying degrees of irreversible axonal injurySeveral studies discuss pharmacological approaches to enhance remyelination by stimulating oligodendrocyteLindsay et al Acta Neuropathologica Communications (2022) 10:12 progenitor cell (OPC) proliferation, differentiation, and survival in the CNS mesenchymal stromal cell (MSC) transplantation provides an alternative strategy
MSCs were alternatively injected at a later time point when animals had developed at least partial hind limb paralysis. hOM- and hBM-MSCs ameliorated EAE to a similar extent compared to PBS injected controls when administered early (Fig. 1a), but only hOM-MSCs significantly improved recovery when cells were injected into animals with severe disease (Fig. 1b)
We reported the therapeutic benefit of MSCs from biopsies of human olfactory mucosa for CNS repair which have similar biological and antigenic characteristics as hBM-MSCs, and promote myelination in vitro [14, 15] and in vivo [22]

Summary

Introduction

Multiple sclerosis (MS) is a chronic disease in which repeated episodes of inflammation in the central nervous system (CNS) result in widespread demyelination associated with varying degrees of irreversible axonal injurySeveral studies discuss pharmacological approaches to enhance remyelination by stimulating oligodendrocyteLindsay et al Acta Neuropathologica Communications (2022) 10:12 progenitor cell (OPC) proliferation, differentiation, and survival in the CNS mesenchymal stromal cell (MSC) transplantation provides an alternative strategy. There are several reports demonstrating the beneficial effects of syngeneic [4, 6] or human [7, 8] MSC transplantation in experimental autoimmune encephalomyelitis (EAE), an animal model of MS These include reduced inflammation, demyelination, axonal loss, as well as corresponding increases in remyelination. There has been evidence of neuroprotection from structural and functional improvements, which strongly supports their future use as a treatment [10, 12, 13] These pre-clinical studies provide a functional basis for the beneficial effects of autologous MSC transplantation already reported in MS patients and support its future use as a routine intervention

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