Biomedical Engineering Reference
In-Depth Information
spared axons and/or releasing a milieu of neuroprotective and neurotrophic factors
favoring endogenous cell plasticity and sprouting [
73
].
Adult or embryonic mammalian NPCs from different sources have been
transplanted into a wide range of SCI models with significant clinical improve-
ment. Although human embryonic or foetal cell sources also showed promising
results, ethics, and availability issues make from the recently discovered iPS cells
a promising alternative [
74
,
75
]. Recent studies have developed safe nontumori-
genic mouse [
76
] and human [
77
] iPS cell-derived NPCs which were able to
improve locomotor function recovery after contusive SCI. Most of the studies have
delivered NPCs focally to increase their viability at the injury site. However, also
alternative routes of administration (e.g., systemic) have been investigated to avoid
the damage to the spared cord tissue at the time of focal cell injection, as well as
other procedure-related complications, with the final aim to improve the chances
of translation into clinical practice. After injection in the tail vein of nude SCI
mice, human NPCs were able to reach the injury site [
78
]; and led to a significantly
better behavioral recovery, compared to SCI mice transplanted intraspinally with
NPCs [
79
]. In almost all cases, both the focal and systemic NPC transplantation
resulted in significant recovery of functions, which were highly specific for the
treatment applied, as they were completely abolished in human NPC-transplanted
SCI mice treated with diphtheria toxin (DT; as human cells are about 100,000
times more sensitive to DT, via the human DT receptor, than mouse cells) [
80
].
There is a growing belief that the severity (and type) of the injury, as well as the
time after injury at which cells are transplanted, are two major key factors influ-
encing the capability of grafted NPCs to affect the healing of the damaged spinal
cord tissue. As such, rat spinal cord-derived somatic NPCs failed to induce any
detectable functional recovery when transplanted hyperacutely at the level of
injury in a severe (35 gr.) clip-induced SCI model [
81
], but were indeed signifi-
cantly efficacious when transplanted as early as 9 days after injury in a milder
(27 gr.) SCI model [
82
].
Interestingly, NPCs survive, migrate, and generate functional remyelinating
oligodendrocytes, which promote functional recovery, when transplanted sub-
acutely (namely 2 weeks), but not chronically (namely 8 weeks) after SCI [
83
].
The transplantation of NPCs in experimental SCI has yielded a general low degree
of differentiation [
79
,
84
], most of which biased towards a glial fate [
85
-
87
].
When more lineage restricted neural precursors have been transplanted, a much
higher rate of neuronal differentiation has been achieved, presumably because
these latter cells are less sensitive than NPCs to inhibitory signals coming from the
environment [
88
,
89
].
Strategies to overcome the observed poor differentiation potential of trans-
planted NPCs have include the combination with valproic acid [
90
] or neurotro-
phic growth factors [
91
,
92
], which promoted neuronal differentiation and
achieved the establishment of functional synapses between host axons and graft
neurons at the injury site. Further, the use of engineered NPCs transduced with
transcription factors or survival genes [
93
,
94
], as well as the cotransplantation
with
'scaffold'
cells,
such
as
mesenchymal/stromal
stem
cells
or
olfactory
