Abstract |
Central Nervous System (CNS) injuries, such as spinal cord or optic nerve injuries (SCI, ONI), affect thousands
of individuals worldwide. Still no cure can handle the complex multifactorial nature of CNS injury. Along this
direction, the present thesis evaluates novel combinatorial treatments for CNS injuries that contain three
components: 1) Porous collagen-based scaffolds (PCS), biomaterials that provide structural support,
inflammation regulation, a substrate for cellular migration and axonal elongation as well as a delivery system
of therapeutic molecules or cells, 2) Neural Stem Cells (NSC), multipotent cells that can replace neuronal
cells lost during CNS injuries, 3) Microneurotrophins (MNT), small-molecule mimetics of endogenous
neurotrophins, that have demonstrated significant therapeutic effects on various animal models of human
neurological diseases, but have not been evaluated in rodent models of CNS injuries yet.
The first part of this thesis focuses on evaluating the effects of BNN27, the seminal MNT, on the mouse optic
nerve crush (ONC) model. Results provide the first evidence on the effects of BNN27 on animal models of
ONI. In particular, BNN27 administration significantly increased RGC survival and decreased microgliamediated
inflammation at 2 weeks post injury (wpi). BNN27 was delivered via eye drops or via a PCS graft.
Interestingly, this study presents the first administration of MNT via a biomaterial graft and it highlights a
more consistent and efficient neuroprotective effect provided by a targeted delivery at the injury site.
The second part of this thesis focuses on evaluating the effects of combinatorial treatments on the dorsal
column crush mouse SCI model. The first SCI study evaluated mouse embryonic NSC-seeded PCS grafts in
this SCI model. The second SCI study combined NSC-seeded PCS grafts with systemic administration of
BNN27. This thesis highlights PCS grafts as a promising delivery method of NSCs in SCI lesions, contrary to
the widely used method of delivering NSCs in suspension via injection. NSC-seeded PCS grafts decreased glial
scar and enhanced crucial events following SCI, such as neuron density, synaptogenesis, axonal elongation
and angiogenesis at 12 wpi. Notably, NSC-seeded PCS grafts also led to statistically significant locomotion
recovery starting at 9-10 wpi. This thesis also demonstrates the first evidence on the effects of BNN27 on
animal models of SCI. Systemic administration of BNN27 decreased astrogliosis and neuronal loss following
SCI. In addition, when BNN27 administration was combined with the implantation of NSC-seeded PCS grafts,
BNN27 significantly increased the density of implanted NSC-derived cells, possibly addressing a major
challenge of emerging NSC-based cell therapies.
In conclusion, this thesis presents novel combinatorial treatments that could cope with the complexity of
CNS injuries and could hopefully be new tools in regenerative medicine leading to the design of more
effective therapies with clinical application.
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