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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
16
VOLUME 12 NUMBER 1 • JULY 2015
application relative to other invasive methods of delivery such as
intrathecal or intraventricular injection.
However, Franchi
et al.’s
results are hindered by a number of
limitations. For example, other studies have found contradictory
results, namely, that NSC transplantation does not affect
neuropathic pain
42
and may somewhat paradoxically exacerbate
nociceptive symptoms.
43
Furthermore, the analgesic effects were
only demonstrated acutely for 28 days post-grafting, which
provides no information on: the utility of NSCs in the treatment
of chronic neuropathic pain; whether tolerance developed; and
whether the experimental models showed delayed anti-allodynic
effects. Leading on from this, during the study period repeated NSC
injections were required to sustain the analgesic effect, which could
be a potential hindrance to putative clinical translation in relation to
patient compliance with a multi-dose regime.
The pro-inflammatory milieu associated with neuropathic
pain may not be entirely harmful; in Franchi
et al.’s
study, anti-
nociceptive effects on pain-like behaviour were observed three days
post-NSC grafting. This coincides with the time to recruit
macrophages to the injury site to phagocytose myelin debris, which
would otherwise have contributed to neuropathic pain.
Franchi
et al.
reported that NSCs specifically homed towards
neuronal lesions. However, this has not been supported by other
studies on the biodistribution of NSCs following intravenous
administration.
44
Finally, Franchi
et al.’s
study results are restricted to the chronic
constriction injury model of peripheral neuropathic pain and can-
not be extrapolated to other neuropathic pain models.
In a separate study, NSCswere found to reduce allodynia in a central
neuropathic pain model of spinal cord injury if they preferentially
differentiated into oligodendrocytes rather than astrocytes.
45
Normally when NSCs are transplanted into the brain or spinal cord
they tend to differentiate into astrocytes.
46
However, NSCs derived
from the spinal cord that were virally transfected to co-express the
transcription factor neurogenin-2 and the marker GFP, differentiated
predominantly into oligodendrocytes post-transplantation. This was
somewhat unexpected;
in vitro
neurogenin-2 normally promotes
neuronal differentiation. In comparison, the naïve GFP-NSCs
predictablydifferentiatedintoastrocytes.
47
Inaspinalcordinjurymodel,
transplanted neurogenin-2 NSCs generated more oligodendrocytes
and significantly reduced allodynia relative to the naïve GFP-NSC
group. The neurogenin-2 NSC-grafted animals showed significantly
greater white matter area relative to the naïve GFP-NSC group,
which suggested the observed analgesic effects may be secondary
to increased remyelination of injured axons. Interestingly, in the naïve
GFP-NSC group an increased nociceptive effect was recorded. This
may be explained by a higher density of naïve GFP-NSC-derived
astrocytes; astrocytes in neuropathic injury models secrete trophic
factors such as NGF, which promote neurite outgrowth and cell
survival that facilitates locomotor and sensory recovery.
48
However,
the neurite outgrowth with associated nociceptive fibre sprouting
into inappropriate regions of the dorsal horn may account for the
pro-algesic effects observed.
43
The strengths of these findings are twofold, namely: the
importance of differentiating NSCs towards an oligodendrocytic
lineage prior to transplantation; and specifically targeting NSC
migration to precise regions of the spinal cord. This may reduce pro-
nociceptive effects associated with astrocyte-derived neurotrophic
factor induced neuronal sprouting into the dorsal horn.
However, in Klein
et al.’s
study no control group containing
animals without neuronal lesions that received astrocyte grafts were
used for comparison. This would have enabled the observers to
assess whether ‘healthy’ control animals developed a neuropathic
phenotype. Therefore, the observation that NSC-derived astrocytes
exacerbate neuropathic pain cannot be reliably concluded.
hMSCs have also demonstrated efficacy for the treatment of
neuropathic pain. Evidence suggests hMSCs may have the best
potential results for treating neuropathic pain
49
and, in contrast
to NSCs isolated from the SVZ, hMSCs are more readily accessible
and harvested. Evidence supporting this is derived from a study that
injected bone marrow derived hMSCs into the rodent tail vein of
the spared nerve injury model four days after sciatic nerve surgery
by which time neuropathic pain was firmly established.
50
The strength of Siniscalco
et al.’s
results is the novel observation
that hMSCs attenuate neuropathic pain through an anti-in-
flammatory restorative mechanism based on two components,
namely: a cell-to-cell contact activation mechanism – hMSCs drive
macrophages towards an anti-inflammatory neuroprotective M2
phenotype; and through down-regulation of pro-inflammatory
cytokines. These findings are supported by other studies.
51
No safety concerns were associated with the use of hMSCs. This
coupled with the non-invasive intravenous route of administration
providesforpotentiallyfavourableclinicaltranslation.Furthermore, the
inherently strong anti-inflammatory immunomodulatory properties
of hMSCs, which would negate the need for pharmacological
immunosuppression, adds weight to their clinical appeal. However,
somewhat paradoxically, exploiting pro-inflammatory chemotaxis
may also facilitate clinical translation; the chemokine driven
homing potential of hMSCs towards pro-nociceptive lesions could
be exploited as a bioactive site-specific delivery system, which would
avoid the dose-limiting adverse effects associated with systemic
administration of current licensed drugs.
However, the effects of hMSCs in Siniscalco
et al.’s
study are
limited in their application by methodological flaws. For example,
during the progression of neuropathic pain, time-course tracking
of intravenous hMSCs was not performed, thus homing of hMSCs
towards areas involved in neuropathic pain modulation cannot be
reliably elucidated. Leading on from this, there is contradictory
evidence on the homing capabilities of hMSCs towards sites
of neuropathy, for example, evidence has shown that hMSCs
transplanted into themouse tail vein are predominantly sequestrated
in the lung.
52
Furthermore, the utility of hMSCs for the treatment
of neuropathic pain was only assessed for 90 days, thus providing
no information in relation to attenuating chronic neuropathic pain
or reducing associated complications such as deconditioning e.g.
reduced mobility, muscle atrophy and contractures.
In summary, there is an emerging body of preclinical data
based on exploiting the multipotency, self-renewing capacity, high
expansion potential and genetic stability of adult stem cells that
supports their utility for the treatment of neuropathic pain. The
mainstay of evidence has honed in on the immunomodulatory and
trophic effects of adult stem cells. The progression on to clinical
trials would be the next stage in defining the potential utility of
adult stem cells for the treatment of neuropathic pain.
Evidence on the utility of iPS cells for the treatment
of neuropathic pain
There are no published data on the utility of iPS cells for the
treatment of neuropathic pain; however, there has been a lot of