Neurorepair with mesenchymal stem cells: hope or hype? The Lancet Neurology. 2012

Mark S Freedman, Antonio Uccelli
Mesenchymal stem cells are pluripotent cells that
can be derived and expanded from various tissues
from adults (eg, bone marrow or adipose tissue) or
fetuses (eg, placenta) and can differentiate into cells
of mesodermal origin (eg, bone, cartilage, or fat).
These stem cells possess unique immunomodulatory
properties and can control drug-resistant graftversus-
host disease in people; in animals, they
also seem to limit damage to, or mediate repair
of, CNS tissue via mechanisms other than cell
replacement or transdiff erentiation, probably via
their paracrine function.1 The potential to repair the
CNS or protect it from further damage is precisely
what is being sought as a treatment for progressive
forms of multiple sclerosis (MS). In this issue of
The Lancet Neurology, Peter Connick and colleagues2
assess the effects of a single intravenous dose of
autologous mesenchymal stem cells in the CNS of ten
patients with secondary progressive MS—a disorder
for which there is no proven therapy, despite many
successful agents being used to treat its predecessor,
relapsing-remitting MS.
How to measure repair in MS accurately in the
absence of pathological confi rmation3 has not
been established. Patients who improve after the
overt infl ammatory phase of a relapse and in whom
new lesion formation has stopped might simply
be recovering from these acute events rather than
undergoing active repair. It is also diffi cult to establish
whether lesions on MRI scans are truly improving or
shrinking because of repair or whether they are showing
resolution of infl ammation and oedema. Nevertheless,
evidence of repair with some newer techniques, such
as a change in lesional magnetisation transfer ratio on
MRI, does correlate with histological fi ndings.4 Rather
than looking for signs only of general repair, Connick
and colleagues concentrated on the visual pathway, a
system that can be assessed for structure and function
with validated imaging and neurophysiological
techniques. The investigators chose patients who had
a clear history and objective evidence of optic nerve
involvement due to demyelination, which they refer
to as the sentinel lesion. More importantly, the optic
nerve event was reasonably remote (at least 2 years
from the treatment), such that any acute repair from
the event would have been completed. To ensure
stability, Connick and colleagues assessed patients
several times before treatment, and although two
patients had what might have been an attack of MS,
neither had symptoms or signs involving the anterior
visual pathways.
So far, we have not really been convinced that
any treatment for MS is associated with repair.
Connick and colleagues might be showing the
early signs of this process, somehow mediated by
a single injection of mesenchymal stem cells. They
showed that over the course of 6–10 months after
a single infusion there was recovery of vision that
seemed functional (visual acuity and low contrast
sensitivity), neurophysiological (reduction of the
visual evoked response latency and improved visual
evoked response amplitudes), and structural (increase
in the optic nerve cross-sectional area). What can be
measured in the anterior visual pathway might be an
indicator of a more general process within the CNS,
which is suggested by the reduction in functional
disability (the expanded disability status score) as well
as large, but statistically non-significant, changes in
T1 lesion volume and magnetisation transfer ratio.
However, many measures did not show statistically
significant changes after treatment; particularly
disappointing were the results for optical coherence
tomography, which we all hoped might be a sensitive
index for repair. Nevertheless, this did not detract
from the important findings consistent with CNS
recovery, particularly in the anterior visual system.
Furthermore, there were no serious adverse events in
any patients.
This study is not defi nitive, and Connick and
colleagues have carefully pointed out some of the
caveats of a small non-randomised single-centre
study, such as pretest versus post-test design with no
control group to confi rm that changes after treatment
were directly attributable to treatment rather than
natural history. However, the signs of repair measured
in most of the patients with secondary progressive MS
less than a year after a single infusion of mesenchymal
stem cells raise substantial interest. The hope and
faith of stem-cell research has been to be able to
repair a failing nervous system—with a particular
focus on the use of mesenchymal stem cells.5 Most
investigators agree that these cells have the potential
to repair, but many thought they should fi rst seek to
prove the biological eff ect of modulating immune
responses to reduce infl ammation and explore for
repair signals before leaping into a clinical trial aimed
directly at showing repair.6 Connick and colleagues
have shown us that sometimes it might be better to
leap before looking.
Mark S Freedman, Antonio Uccelli
University of Ottawa Neurology Program, Ottawa, ON, Canada
(MSF); and Department of Neurosciences, Ophthalmology and
Genetics, University of Genoa, Italy (AU)
Articulo a trevés del HINARI