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

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.

Development of Good Manufacturing Practice-Compatible Isolation and Culture Methods for Human Olfactory Mucosa-Derived Mesenchymal Stromal Cells

“…However, by completely removing our reliance on xeno-derived components in the culture medium and refining our sample preparation and culture methods to eliminate microbial contamination (without relying on antibiotics), we are confident that we have developed a process for the establishment of hOM-MSCs that is readily translatable to full GMP compliance. These cells have been thoroughly characterized, conform to ISCT criteria for identification as MSCs [34], demonstrate high expression of nestin and CXCL12 (a previously established trait of hOM-MSCs [29,30,33]), and so we would propose these as key release criteria for any future cell product developed from this method. Additionally, in 3/3 samples tested in a GMP-compliant QC lab, endotoxin levels within spent culture media from these cells were below the limit of detection for the assay (Appendix B).…”

“…Previous methods of generating hOM-MSCs utilized non-GMP-compliant CD271 bead sorting [29,30]. We have demonstrated elsewhere that CD271-sorted cells have superior promyelinating and neuroprotective properties compared with cells grown from the negative sort fraction and hBM-MSCs [29,30,32,33]. However, MSCs isolated from other tissues often do not require sorting and instead are developed into a homogenous population by culture methods alone [35,36].…”

“…Moreover, in the experimental autoimmune encephalitis (EAE) model, intravenous (IV) injection of hOM-MSCs was seen to reduce disease severity and recovery time compared with control animals and those injected with hBM-MSCs. Furthermore, animals injected with hOM-MSCs saw reduced immune cell infiltrate and axonal abnormalities, as well as improved blood-brain barrier integrity [33].…”

Low sulfated heparan sulfate mimetic differentially affects repair in immune‐mediated and toxin‐induced experimental models of demyelination

“…It has been reported that heparin mimetics have antiinflammatory effects when used therapeutically in respiratory diseases such as asthma and chronic obstructive pulmonary disease (Mohamed & Coombe, 2017 ). A further difference is that the BBB remains largely intact in the cuprizone model (Kondo et al, 1987 ) but is disrupted during EAE (Lindsay et al, 2022 ). Therefore, it cannot be discounted that the greater access to the CNS environment in EAE mice may facilitate a more robust effect since we have shown that LS‐mHep7 can bind negative factors released after demyelination.…”

Human nasal olfactory stem cells, purified as advanced therapy medicinal products, improve neuronal differentiation

“…The potential therapeutic benefits of OE-MSCs were also tested in animal models of various injuries/pathologies affecting the peripheral or central nervous system. Promising results have been reported in models replicating some of the symptoms/mechanisms observed in Alzheimer's disease (Hong et al, 2022), Parkinson's disease (Murrell et al, 2008;Farhadi et al, 2021;Simorgh et al, 2021), Huntington's disease (Bayat et al, 2021), multiple sclerosis (Lindsay et al, 2010(Lindsay et al, , 2022Wu et al, 2013), cerebellar ataxia (Moghaddam et al, 2022) ischemic stroke (Liu et al, 2020;Zhuo et al, 2021), spinal cord injury (Lindsay et al, 2017;Stamegna et al, 2018;Voronova et al, 2020;Hamidabadi et al, 2021), amnesia (Nivet et al, 2011), hearing loss (Pandit et al, 2011). In regard to mechanisms, it has been reported that OE-MSCs secrete trophic factors, modulate the inflammatory response, phagocyte inclusions or deleterious molecules, regulate oxidative stress.…”