Reduced neuroprotective potential of the mesenchymal stromal cell secretome with ex vivo expansion, age and progressive multiple sclerosis

Abstract

BackgroundClinical trials using ex vivo expansion of autologous mesenchymal stromal cells (MSCs) are in progress for several neurological diseases including multiple sclerosis (MS). Given that environment alters MSC function, we examined whether in vitro expansion, increasing donor age and progressive MS affect the neuroprotective properties of the MSC secretome.MethodsComparative analyses of neuronal survival in the presence of MSC-conditioned medium (MSCcm) isolated from control subjects (C-MSCcm) and those with MS (MS-MSCcm) were performed following (1) trophic factor withdrawal and (2) nitric oxide–induced neurotoxicity.ResultsReduced neuronal survival following trophic factor withdrawal was seen in association with increasing expansion of MSCs in vitro and MSC donor age. Controlling for these factors, there was an independent, negative effect of progressive MS. In nitric oxide neurotoxicity, MSCcm-mediated neuroprotection was reduced when C-MSCcm was isolated from higher-passage MSCs and was negatively associated with increasing MSC passage number and donor age. Furthermore, the neuroprotective effect of MSCcm was lost when MSCs were isolated from patients with MS.DiscussionOur findings have significant implications for MSC-based therapy in neurodegenerative conditions, particularly for autologous MSC therapy in MS. Impaired neuroprotection mediated by the MSC secretome in progressive MS may reflect reduced reparative potential of autologous MSC-based therapy in MS and it is likely that the causes must be addressed before the full potential of MSC-based therapy is realized. Additionally, we anticipate that understanding the mechanisms responsible will contribute new insights into MS pathogenesis and may also be of wider relevance to other neurodegenerative conditions.

Dysregulation of Mesenchymal Stromal Cell Antioxidant Responses in Progressive Multiple Sclerosis

“…We have recently demonstrated that MSC isolated from patients with progressive MS (MS‐MSC) have reduced ex vivo proliferation and clonogenic potential , premature senescence, and accelerated shortening of telomere terminal restriction fragments . We have also shown that the MS‐MSC secretome has reduced in vitro neuroprotective potential . Recently, others have demonstrated abnormalities in MSC isolated from patients with progressive supranuclear palsy (PSP) .…”

Autologous Hematopoietic Cell Transplantation in Multiple Sclerosis: Changing Paradigms in the Era of Novel Agents

“…In line with this hypothesis, MSCs from MS patients have demonstrated similar growth in culture, differentiation potential, surface antigen expression, and immunomodulatory properties with MSCs from non-MS individuals [63–65]. Nevertheless, other studies have shown functional differences of MSCs [66, 67].…”

Restoring aged stem cell functionality: Current progress and future directions

“…42 MSCs are known to modulate their tissue micro-environment through their highly diverse secretomic profiles, 43,44 which are drastically altered with age. [45][46][47] As a result, the secretomes from aged bone-marrow derived MSCs have decreased immune-modulatory properties and can impede HSC differentiation and proliferation. 46…”