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Reduced Stress Responses: A Potential Problem for Autologous MSC-based Treatment of Multiple Sclerosis

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Review of “Dysregulation of Mesenchymal Stromal Cell Antioxidant Responses in Progressive Multiple Sclerosis” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Autologous mesenchymal stem cell (MSC) therapy represents a potentially interesting means to treat multiple sclerosis (MS), a neurodegenerative disease of the central nervous system characterized by inflammatory demyelination and the development of severe neurological disability. The anti‐inflammatory, immunomodulatory, and anti-oxidant activities of MSCs combined with their favorable safety profile has brought the hope of an effective stem cell therapy for MS patients; however, we lack a full understanding of how MS and the associated pro‐inflammatory environment affect MSC function. 

Unfortunately, recent studies have provided evidence that MS-MSCs suffer from an early aging-like phenotype [1] with reduced expansion potential and diminished paracrine neuroprotective abilities [2]. Now, a new STEM CELLS Translational Medicine report from the laboratory of Claire M. Rice (Southmead Hospital, Bristol, UK) describes how an increased susceptibility to nitrosative stress in combination with the diminished expression, activity, and secretion of antioxidants can contribute to the functional deficits observed in MS-MSCs [3]. Do reduced stress responses in MS-MSCs represent a potential problem for the autologous MSC-based treatment of MS?

When assessing for oxidative stress responses, the authors discovered that MS‐MSCs expressed and secreted lower levels of two essential anti-oxidants (superoxide dismutase 1 [SOD1] and glutathione S‐transferase P [GSTP]), leading to lower overall activity and, fascinatingly, this correlated negatively with MS progressive phase duration. Previous research also links nitrosative stress and MS [4, 5], so the current study next tested for susceptibility to nitric oxide‐induced cell death as determined by exposure to DETANONOate, a nitric oxide donor. They discovered that DETANONOate accelerated MS-MSC senescence, prompted further downregulation of SOD1 and GSTP, and reduced the expression of master regulators of antioxidant responses (nuclear factor erythroid 2‐related factor 2 [Nrf2] and peroxisome proliferator‐activated receptor gamma coactivator 1‐α [PGC1α]).

This new study suggests that the therapeutic application of MS-MSCs will require the potentiation or correction of oxidative- and nitrosative-stress defenses, and, interestingly, the authors also note that the dysfunction of stress defenses in MSCs may also contribute to the development of MS and/or its comorbidities, perhaps creating a new target for MS treatments. The team now aims to advance this research by describing Nrf2 and PGC1α target genes, assessing MS-related vascular stress, testing strategies that aim to boost stress defenses, and analyzing the bone marrow microenvironment and function in MS.

For more on stem cell therapies for MS and how disease-states can alter the regenerative capacities of stem cells, stay tuned to the Stem Cells Portal.

References

  1. Redondo J, Sarkar P, Kemp K, et al., Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro. Multiple Sclerosis Journal 2018;24:919-931.
  2. Sarkar P, Redondo J, Kemp K, et al., Reduced neuroprotective potential of the mesenchymal stromal cell secretome with ex vivo expansion, age and progressive multiple sclerosis. Cytotherapy 2018;20:21-28.
  3. Redondo J, Sarkar P, Kemp K, et al., Dysregulation of Mesenchymal Stromal Cell Antioxidant Responses in Progressive Multiple Sclerosis. STEM CELLS Translational Medicine 2018;7:748-758.
  4. Gironi M, Borgiani B, Mariani E, et al., Oxidative stress is differentially present in multiple sclerosis courses, early evident, and unrelated to treatment. J Immunol Res 2014;2014:961863.
  5. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, et al., Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol 2013;2013:708659.