Stemming the MS tide
Research is ongoing, particularly in regenerative
cell therapy, for the effective treatment of
immune diseases. Thomas Vihtelic, director of
experimental therapeutics at MPI Research,
explains why mesenchymal stem cells might have
a role to play in treating multiple sclerosis.
Stem cells are critical during the development
of
regenerative cell therapy and migrate to different
locations in the organism, such as bone marrow.
Embryonic stem cells are pluripotent and are
found during
very early development, while adult stem cells
function to
maintain and repair their tissues of origin. Adult
bone marrow
contains at least three cell types:
- haematopoietic stem cells
- non-haematopoietic stem cells such as very
small
embryonic-like stem cells
- mesenchymal stromal cells (also known as mesenchymal
stem cells (MSCs).
MSCs were originally described as a non-haematopoietic
bone marrow component but were isolated from other
tissues,
such as adipose, synovial fluid, placenta, muscle
and articular
cartilage, as well as organs such as the lung,
liver and spleen.
These cells exhibit a number of surface antigens
but lack
haematopoietic markers such as CD34, CD45 and
CD11b.
MSCs influence a broad range of immune cell types
and
migrate to sites of tissue damage or inflammation.
Interestingly, the improvement levels observed
in different
animal disease models treated with MSCs do not
correlate
with the levels of cell engraftment and differentiation,
which
suggests MSC regenerative properties are due to
paracrine
influences on resident cellular repair processes,
including
activation of endogenous tissue progenitor cells.
Inflammatory disease treatment
The immunomodulating properties of MSCs indicate
this
cellular therapeutic class has application in
inflammatory
disease treatment. MSCs inhibit T and B cell proliferation
and differentiation, attenuate natural killer
cell activity, and
support T regulatory cell production. These activities
depend
on soluble factors released by the MSCs and direct
interactions of the MSCs with inflammatory cells
present at
tissue injury sites. Indoleamine 2,3-dioxygenase,
iNO
synthase, PGE2, TGF-1 and other regulatory proteins
mediate
MSC anti-inflammatory properties.
Recently, pro-inflammatory activities mediated
by toll-like
receptors were also identified for MSCs. A recent
hypothesis
suggests pro-inflammatory or immunosuppressive
phenotypes
of the MSC may result from different temporal
stimulation
related to either early tissue injury or the later
tissue resolution
responses. Regardless, the majority of current
findings support
the use of MSCs for treating inflammatory components
of
various diseases and autoimmune dysfunction.
Animal disease model
The use of animal disease models identified and
characterised potential therapeutic applications
for MSCs.
Experimental autoimmune encephalomyelitis (EAE),
a model
for human multiple sclerosis (MS), is induced
by
immunisation with peptides found within proteins
of the
axon myelin sheath, such as proteolipid protein
(PLP) or
myelin oligodendrocyte glycoprotein (MOG). These
models
exhibit ascending tail and limb paralysis, which
becomes
evident approximately ten days after immunisation.
Intravenous administration of mouse MSCs to C57BL/6J
mice
with MOG35-55-induced EAE before disease onset
significantly
reduced disease severity, based on clinical sign
scoring. Reduced
CNS demyelination and decreased T cell and macrophage
infiltration of the CNS parenchyma were also observed
in the
diseased animals compared with controls based
on
histopathology. Similarly, allogeneic transfer
of MSCs isolated
from C57BL/6J mice into PLP139-151-immunised SJL
recipients
at 12 days post-immunisation resulted in significantly
reduced
clinical and pathological scores, compared with
non-treated EAE
controls. Ex vivo analysis demonstrated decreased
T cell
proliferation, lower TNF and IFN production and
less PLP-specific
antibodies. Furthermore, eGFP-labelled MSC colonised
the
lymphoid organs and infiltrated the CNS, although
transdifferentiation of the MSCs into neural cells
was not detected.
The use of mouse EAE models sheds light on the
cellular and
molecular mechanisms responsible for MSC therapeutic
effects.
Studies in these models also validated the rationale
for
exploring the use of MSCs as a treatment option
for MS. Thus,
autologous or allogeneic MSCs were well tolerated
by human
patients, and new multicentre clinical trials
are being launched
to further characterise the safety and efficacy
of MSCs for the
treatment of some forms of MS.
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