1. REGENERATIVE THERAPY IN SPINAL CORD INJURIES: TRANSPLANT OF OLFACTORY ENHANCED GLIA, STEM CELLS AND OVEREXPRESSING SCHWANN CELLS
G. Solcan 1., M. Musteaţă1, S. Iencean2
University of Agricultural Sciences and Veterinary Medicine,
Faculty of Veterinary Medicine, Iasi, Romania, 8 M. Sadoveanu Alley,
Nerosurgery Hospital “N. Oblu” Iasi

2. Introduction In veterinary clinics
acute SCI type I IVDD, vertebral fractures and luxation, vascular disease (e.g. fibrocartilaginous embolism (FCE) and haemorrhage), cervical stenotic myelopathy and congenital malformation causing instability. 
chronic diseases, such as neoplasia, discospondylitis and inflammatory or infectious spinal cord disease.
Acute onset of SC dysfunction = a combination of one or more events including concussion, compression, ischemia, or laceration of the spinal cord.

3. Patophysiology

4. Strategy following SC injury
1. Neuroprotection: Diminution of the secondary damage
2.Neurorestauration:
Remyelination, conduction
3. Neuroregeneration/Plasticity
Antagonization of inhibitoy farctors
Axonal growth factors (neurotrophyic)
4. Axonal guidance towards site of deafferation (specific regeneration)
5. Neurorectonstruction: Cell and tissue transplantation

5. Considerations for developing cell therapy for spinal cord regeneration
To successfully treat SCI by promoting functional recovery,
-cellular therapies must integrate into the injury site
and restore the lost neuronal circuitry or
promote plasticity of the spared neurons.
For this goal, cellular therapies should be designed
considering both the obstacles posed by the injury site
as well as sourcing and reproducibility issues associated with different cell culture systems.

6. Obstacles to regeneration presented by the injured spinal cord - Cavity formation
the initial injury + necrosis
loss of grey and white matter = fluid filled cavity
expand = additional cell death and increased loss of function
physical barrier to spontaneous regeneration.
bridge the lesion and restore signaling in the SC.
factors that promote regeneration of the damaged axons into the cavity while also providing the trophic support necessary for cell migration.
reduction of the cavity size = increase in functional recovery

7. Obstacles to regeneration presented by the injured spinal cord – Glial scar
Transplanted cells = counterbalance to the inhibitory effects of the glial scar
Secretion of the extracellular matrix and
cytokines that promote cell migration
Other therapy ± cell therapy
molecules that prevent CSPG synthesis
chondroitinases which degrade the CSPGs in vivo
Migration of macrophages, oligodendrocyte precursors, and meningeal cells
glial scar = predominantly reactive astrocyte
inhibitory molecules into their extracellular matrix (CSPGs)
inhibit axonal regeneration in 3D settings

8. Obstacles to regeneration presented by the injured spinal cord – Myelin based inhibitors
Strategies
Sialidase
Tenascin-R
genetic manipulation and antibodies
damaged oligodendrocytes release
myelin based inhibitors
Nogo, MAG, Omgp, tenascin

9. Study and therapy in SC injury
Cell type used
Embrionic cell stem
Mouse
Human
Neural cell stem
Bone marrow stromal cell
Mature cells
Schwan
OEG
Fibroblasts
Species consideration
Invertebrates
Small mammals
Rats
Mice
Large mammals
Cats
Dogs
Pigs
Primates
Contusions model
Transection model

10. Cells Sources Transplantable cells can be obtained from :
- the patient (autologous)
- genetically different individuals, embryos, or umbilical cords (allogeneic)
- different species (xenogeneic)
The undifferentiated nature of
embryonic and umbilical cells
minimizes immunological rejection.

11. Site of Transplantation
Donor cells are transplanted in
the spinal cord
cerebro-spinal fluid
intravenously
intramuscularly

12. Surgical practice in spinal cord injury
The surgical procedure consist of - remove of spinal cord scar - implanting of bone – marrow tissue into the spinal cord injury site.
The bone-marrow tissue transplantation
procedure has no complications.
Scar reduction make the post – injury scar more permeable to neuronal axons attempting to regrow through the injury site.

13. Bone-marrow derived stem cells
Dr. Tarcisio Barros (Sao Paulo) have infused bone-marrow-derived stem cells into the spinal artery closest to the injury site
Dr. Andrey Bryukhovetskiy (Moscow) has
transplanted both embryonic / fetal stem cells and autologous adult stem cells
Dr. K-S Kang (Seoul) injected stems cells
isolated from umbilical cord blood into the injury area
Dr. Yoon Ha (South Korea) has transplanted bone-marrow cells into the injury site of patients with acute SCI
Dr. Eva Sykova (Prague ) have harvested autologous, bone-marrow stem cells from the iliac bone and re-introduced intravenously
Dr. Yongfu Zhang (China) have transplanted autologous bone-marrow stem cells into patients with both acute and chronic SCI
Bone-marrow
derived stem cells

14. Olfactory Tissue and Cell Transplantation
Dr. Carlos Lima (Lisbon)
implant whole olfactory tissue from
the patient back into the injury site
Dr. Hongyun Huang (Beijing)
transplants OECs isolated from
fetal olfactory bulbs
Dr. Alan MacKay-Sim (Australia)
has implanted autologous OECs
back into the patient’s injured cord
Dr. Tiansheng Sun (Beijing)
have transplanted OECs into
patients with SCI

15. OTHER CELL TRANSPLANTATION
Dr. Fernando Ramirez (Mexico) has transplanted blue-shark, embryonic neuronal cells (xenogeneic transplantation)
The Diacrin Corporation (USA) sponsored another xenotransplantation clinical trial. Dr John McDonald (Missouri) and Dr Darryl DiRisio (Albany) injected immature fetal pig, myelin cells into the cord surrounding the injury site
Dr. Hui Zhu have transplanted fetal Schwann cells

16. Thank you!