Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro

Abstract

Background:Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised.Objectives:To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS.Methods:Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken.Results:In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro.Conclusion:Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS.

Dysregulation of Mesenchymal Stromal Cell Antioxidant Responses in Progressive Multiple Sclerosis

“…The negative association between antioxidant responses (SOD1 and GSTP1 secretion) and duration of progressive MS raises the possibility that chronic exposure to disease adversely affects MSC function with functional consequences for the bone marrow microenvironment including, for example, alterations in regulatory and pro‐inflammatory T‐cell populations. While this may, in turn, contribute to disease pathophysiology, the finding adds to our previous work, demonstrating changes consistent with accelerated ageing in MS bone marrow and has clear implications for both MSC‐based and autologous haematopoietic stem cell therapy for MS and other conditions where oxidative stress plays a role in disease . It would suggest that bone marrow‐derived cell therapy is more likely to be effective in MS patients with a shorter phase of progressive disease although, based on currently available data, we are unable to speculate regarding a cut‐off in terms of age or disease duration for consideration of therapy.…”

Characterization of Mesenchymal Stem Cells Derived from Patients with Cerebellar Ataxia: Downregulation of the Anti-Inflammatory Secretome Profile

“…Moreover, MSCs can be primed by preexposure to noxious stimuli [44], implying that prolonged stimulation under pathological conditions might be associated with a loss of the putative disease-ameliorating capacity of MSCs. In addition, the age of donors has been considered as a factor that might limit the effectiveness of MSC-based therapy [45,46], particularly autologous MSC therapy. Senescence affects various functions of MSCs [47,48], reduces the capacity for migration and homing [49], and impairs the immunosuppressive potential [50].…”

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“…Previous studies from the laboratory of Claire M. Rice (Southmead Hospital, Bristol, UK) revealed that MSCs derived from MS patients suffered from an early aging‐like phenotype, displaying reduced expansion and neuroprotective activity and premature senescence in vitro, indicating a potential problem for their in vivo therapeutic application. In a new STEM CELLS Translational Medicine article, Redondo et al now establish that MSCs derived from MS patients display an elevated sensitivity to nitrosative stress (as determined by exposure to DETANONOate, a nitric oxide donor) and the diminished expression, activity, and secretion of antioxidants such as superoxide dismutase 1 (SOD1) and glutathione S‐transferase P (GSTP1). The authors linked the reduced expression of antioxidants to a decrease in expression of master regulators of antioxidant responses (NRF2 and PGC1α) and negatively correlated this downregulation with the duration of the progressive phase of MS.…”

“…The anti‐inflammatory, immunomodulatory, and antioxidant activities of MSCs combined with their favorable safety profile have brought hope of an effective stem cell therapy for MS patients; however, we lack a full understanding of how MS and the associated proinflammatory environment affect MSC function. Unfortunately, very recent studies have provided evidence that MSCs derived from MS patients suffer from an early aging‐like phenotype with diminished paracrine neuroprotective abilities . Our second Featured Article from Redondo et al describes how an increased susceptibility to nitrosative stress in combination with the reduced expression, activity, and secretion of antioxidants can contribute to the functional deficits observed in MSCs derived from MS patients.…”