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Age Related Decline in ASC Therapeutic Function in MS Model



 Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and scarring throughout the central nervous system (CNS) which currently has no cure (Jadasz et al). Mesenchymal stem cell (MSC) transplantation is a potential therapy, due to their ability to migrate to areas of damage, release trophic factors and exert neuroprotective and immunomodulatory effects (Bai et al and Freedman et al). Clinical trials have also confirmed the safety of MSC therapy (Connick et al, and Uccelli et al). However, one question which remains unanswered is that of any correlation of MSC functionality with the age of the donor (Lassmann et al). Now, in a report in Stem Cells Translational Medicine, researchers from the laboratory of Bruce A. Bunnell at the Tulane University School of Medicine, New Orleans, Louisiana, USA have used an experimental mouse model of MS to analyse the functionality of MSCs derived from human adipose tissue (ASCs) from donors of different ages (Scruggs et al).

The researchers used myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6J mice as a model system for MS, and analysed the effects of "young" (less than 35 years old) and "old" (more than 65 years old) ASC injections through scoring of tail and hind limb paralysis. Recipients of young ASCs had improved scores (less paralysis) relative to a non-ASC injected control; however, recipients of old ASCs showed no improvements over the control. Indeed, while EAE control and old ASC injected mice exhibited a significant decrease in mobility, young ASC injected mice were highly mobile. However all EAE induced mice displayed characteristic chronic disease progression.

Histological analysis of the spinal cord found a similar low level of myelin and infiltrating cells in the spinal cord in the EAE control and old ASC injected mice, but the mice injected with young ASCs presented with increased levels of myelin and infiltrating cells within the spinal cord similar to that of a naïve non-affected mouse. Analysis of splenocyte (monocytes, macrophages etc.) growth isolated from sacrificed mice from each group found that splenocytes from recipients of young ASCs proliferated at a higher rate than old ASC recipients or EAE control, even in a stimulatory environment (CD3 and CD28 anti-body exposure). While pro-inflammatory cytokine (IL-12, IL-17, IFN-γ, and TNF-α) levels in the sera of mice displayed a complex response to old and young ASCs the levels of cytokines/growth factors from young and old cultured ASCs were similar. However upon stimulation with macrophage-conditioned media, younger ASCs exhibited significantly higher expression of IL-1a, and, importantly, Hepatocyte growth factor (HGF). HGF has been noted to be an important therapeutic factor released by MSCs in the EAE MS model (Bai et al), and subsequent analysis in aged ASCs found alterations to the HGF-related signaling pathway which leads to a lower HGF response as previously reported (Pandey et al).

In conclusion, the authors note that this proof-of-concept study is the first demonstration of a reduced effect of a mesenchymal stem cell type (ASCs) in the EAE mouse model of MS. This in itself is perhaps not a surprising finding, although this type of study is required for delineating parameters for clinical trials. Furthermore, the study of model systems such as this may give us some potentially interesting data - can we study model systems such as this to delineate altered signalling processes and thereby provide a method of rejuvenating old ASCs which have a lower therapeutic effect? Studying the signalling pathways, as was initiated in this study, may provide a drugable target allowing aged ASC to be made useful in the treatment of numerous diseases/disorders.

Bai L et al. (2012)
Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models.
Nat Neurosci 15:862–870.

Connick P et al. (2012)
Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: An open-label phase 2a proof-of-concept study.
Lancet Neurol 11:150–156

Freedman MS et al. (2010)
The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: Consensus report of the International MSCT Study Group.
Mult Scler 16:503–510

Jadasz JJ et al. (2012)
The remyelination Philosopher's Stone: Stem and progenitor cell therapies for multiple sclerosis.
Cell Tissue Res 349:331–347

Lassmann H et al (2012)
Progressive multiple sclerosis: Pathology and pathogenesis.
Nat Rev Neurol 8:647–656

Pandey AC et al (2011)
MicroRNA profiling reveals age-dependent differential expression of nuclear factor κB and mitogen-activated protein kinase in adipose and bone marrow-derived human mesenchymal stem cells.
Stem Cell Res Ther 2:49

Uccelli A et al (2013)
Mesenchymal stem cells as treatment for MS: Progress to date.
Mult Scler 19:515–519

Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.