REGENERATIVE THERAPY IN SPINAL CORD REGENERATIVE THERAPY IN SPINAL CORD INJURIES: TRANSPLANT OF OLFACTORY INJURIES: TRANSPLANT OF OLFACTORY

ENHANCED GLIA, STEM CELLS AND ENHANCED GLIA, STEM CELLS AND OVEREXPRESSING SCHWANN CELLSOVEREXPRESSING 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, gsolcan@uaiasi.roNerosurgery Hospital “N. Oblu” Iasi

IntroductionIntroduction

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 Patophysiology

Strategy following SC injuryStrategy 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 Considerations for developing cell therapy for spinal cord therapy for spinal cord regenerationregeneration

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 Obstacles to regeneration presented by the injured spinal cord - by the injured spinal cord - Cavity Cavity formationformation

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

Obstacles to regeneration presented Obstacles to regeneration presented by the injured spinal cord – by the injured spinal cord – Glial scarGlial 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

Strategies

Sialidase Tenascin-R genetic manipulation and

antibodies

Obstacles to regeneration presented Obstacles to regeneration presented by the injured spinal cord – by the injured spinal cord – Myelin Myelin based inhibitorsbased inhibitors

Study and therapy in SC injuryStudy 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 Species consideration consideration

Invertebrates

Small mammals

Rats

Mice

Large mammals

Cats

Dogs

Pigs

PrimatesContusions model Transection model

CellCellss Source Sourcess

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 TransplantationSite of Transplantation

Donor cells are transplanted in

the spinal cord cerebro-spinal fluidintravenously intramuscularly

Surgical practiceSurgical practice in spinal cord injuryin 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.

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) hastransplanted 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-marrowderived stem cells

Olfactory TissueOlfactory Tissue and and Cell TransplantationCell Transplantation

Dr. Carlos Lima (Lisbon) implant whole olfactory tissue fromthe patient back into the injury site Dr. Hongyun Huang (Beijing)transplants OECs isolated fromfetal olfactory bulbs Dr. Alan MacKay-Sim (Australia)has implanted autologous OECsback into the patient’s injured cord Dr. Tiansheng Sun (Beijing)have transplanted OECs intopatients with SCI 

OTHER CELL TRANSPLANTATIONOTHER 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!Thank you!