Transcript Obstacles to regeneration presented by the injured spinal cord

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,
[email protected]
Nerosurgery Hospital “N. Oblu” Iasi
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.
Patophysiology
Strategy following SC injury
1. Neuroprotection: Diminution of the
secondary damage
2.Neurorestauration:
Remyelination, conduction
3. Neuroregeneration/Plasticity
a) Antagonization of inhibitoy farctors
b) Axonal growth factors
(neurotrophyic)
4. Axonal guidance towards site of
deafferation (specific regeneration)
5. Neurorectonstruction: Cell and tissue
transplantation
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.
Obstacles to regeneration presented by the
injured spinal cord - Cavity formation
the initial injury + necrosis
loss of grey and white matter
= fluid filled cavity

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
expand = additional cell death
and increased loss of function
physical barrier to
spontaneous regeneration.
Obstacles to regeneration presented by the
injured spinal cord – Glial scar
Migration of macrophages,
oligodendrocyte precursors,
and meningeal cells

◦ Secretion of the extracellular matrix
and
glial scar = predominantly
reactive astrocyte
inhibitory molecules into
their extracellular matrix
(CSPGs)
inhibit axonal regeneration
in 3D settings
Transplanted cells =
counterbalance to the
inhibitory effects of the glial scar
◦ cytokines that promote cell
migration

Other therapy ± cell therapy
◦ molecules that prevent CSPG
synthesis
◦ chondroitinases which degrade the
CSPGs in vivo
Obstacles to regeneration presented by the
injured spinal cord – Myelin based inhibitors
damaged
oligodendrocytes
release
myelin based inhibitors

Strategies

Sialidase
Tenascin-R
genetic manipulation and antibodies


Nogo, MAG, Omgp,
tenascin
Study and therapy in SC injury
Cell type used
Species consideration
Embrionic cell stem
Invertebrates
Mouse
Small mammals
Human
Rats
Neural cell stem
Mice
Bone marrow stromal cell
Large mammals
Mature cells
Cats
Schwan
Dogs
OEG
Pigs
Fibroblasts
Primates
Contusions model
Transection model
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.
Site of Transplantation
Donor cells are transplanted in
the spinal cord
 cerebro-spinal fluid
 intravenously
 intramuscularly

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.
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
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
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
Thank you!