Cerebrospinal Fluid (CSF) Exchange with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Experimental Autoimmune Encephalomyelitis

Abstract

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a “cerebrospinal fluid (CSF) exchange” procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure (“CSF exchange therapy”) caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.

Emergence and Developmental Roles of the Cerebrospinal Fluid System

“…However, a similar EAE model in rats demonstrates immune cell (effector T cell) entry preferentially via leptomeninges through CCR5/CXCR3 signaling (Schl€ ager et al, 2016), suggesting potential species differences. Notably, exchanging diseased CSF with fresh enriched artificial CSF can ameliorate the EAE response in mice (Valitsky et al, 2019). Additional roles for the ChP in mediating immune cell responses likely exist.…”

Effect of Multiple Sclerosis Cerebrospinal Fluid and Oligodendroglia Cell Line Environment on Human Wharton’s Jelly Mesenchymal Stem Cells Secretome

“…Even in the case of conditioning of stem cells culture with CSF, a novel approach is proposed to replace endogenous potentially pathogenic CSF by artificial CSF enriched with MSCs secreted factors. The treatment of EAE with MSC-secretions enriched with artificial CSF caused amelioration of the clinical symptoms [56]. Our results indicated that conditioning of MSCs with healthy, or multiple sclerosis CSF, might change the Secretome of MSCs and its immunomodulatory potential; furthermore, transplantation of MSCs to patients with different/unknown inflammatory status might promote a response impossible to foresee.…”

The Immunomodulatory Potential Role of Mesenchymal Stem Cells in Diseases of the Central Nervous System

“…This disease has a more elevated incidence in women, between 18 and 55 years [22, 23]. Animal models have become one of the primary tools for the study of MS, being induced in different ways, including by the emulsion with Myelin Oligodendrocyte Peptide (MOG 35-55), a complete Freund adjuvant, and Mycobacterium tuberculosis [24], or with Pertussis Toxin [25, 26].…”

“…Many studies have been demonstrated the neuroprotective role of MSCs from different tissues in the treatment of MS models, being the EAE the most common model. Clinically, it was observed in treatment with MSCs a delay in the onset of symptoms [26, 33], improvement in motor functions [20, 34], clinical signs [24-26, 35-42], and recovery/maintenance of body weight [37, 41, 42]. The most efficient clinical response was observed when MSCs were administered during the onset of disease relative to the disease peak and in untreated animals [24, 39, 41, 43].…”

“…However, animals treated at the peak of the disease also showed an improvement in clinical conditions, especially about the stage of the disease evolution compared to animals without treatment [44]. Parallel to the clinical findings, in the morphophysiological analysis, was observed a decrease in brain atrophy [20, 26, 34, 35], demyelination [20, 26, 33, 34, 39, 40, 42, 43, 45], and a smaller amount of inflammatory infiltrate [33-35, 37-44].…”