Stem Cells: the Potential and Promise of Brain Repair

1. Role of Stem Cells in
Neurosurgery
Dr Amit Agrawal

2. Stem Cells: the Potential and Promise of Brain Repair
∗ Brain disorders represent a vast unmet
medical need and all are virtually
incurable
∗ This creates a need of new methods in
'Brain Repair' with the potential to
limit or even reverse the neurological
damage
Introduction

3. Nervous System Illnesses
∗ Parkinson’s disease
∗ Alzheimer’s disease
∗ Multiple sclerosis
∗ Stroke
∗ Epilepsy
∗ Spinal cord injury
• Brain tumors
• Chronic pain
• Many neurodegenerative
diseases
• Batten disease (a
pediatric lysosomal
storage disease that
leads to neuronal loss)

4. Stem Cells: the Potential and Promise of Brain Repair
• Neural stem cells (NSCs) are defined as undifferentiated
cells that have the ability of self-renewal, proliferate and
potentiality to differentiate into neurons, astrocytes, and
oligodendrocytes in the CNS
• Ultimately able to repair injured tissue
• Loeffler M, Potten CS: Stem cells and cellular pedigrees-a conceptual
introduction. In: Potten CS, ed, Stem Cells, London, Academic Press,
1997; 1–28
Neural Stem Cells

5. Endogenous Stem Cells in the Adult
•The walls of the
ventricular zone of
the CNS
•The dentate gyrus
of the hippocampus

6. •Replacement of damaged cells
•Restoration of function

7. Stem Cells: the Potential and Promise of Brain Repair
∗ Preclinical and clinical trials have shown promising
results in neurodegenerative disorders
Stem cells in neurosurgery

8. Brüstle O et al. Embryonic stem cell-derived glial precursors: a source
of myelinating transplants. Science. 1999 ;285(5428):754-6.
•Fetal tissue
•Immortalized
neural cell lines
•Hematopoietic/en
dothelial
progenitors
•Bone marrow
•Umbilical cord
blood
•Peripheral blood
•Adipose tissue
Sources
Self-renewing, totipotent embryonic stem
(ES) cells may provide a virtually unlimited
donor source for transplantation.

9. Stem Cells: the Potential and Promise of Brain Repair
Mechanism Mode of action
Tissue damage Inflammation-induced
stimulation of host plastic
responses
Interference with host neural
activity
Correction of biochemical deficit Release of missing transmitter
(‘minipump’)
Growth factor secretion Stimulation of plastic responses
and improved survival and
function of host neurons
Local reinnervation Restoration of synaptic
transmitter release
Reconstruction of neural
circuitries
Re-establishment of functional
afferent and efferent
connections
Possible mechanisms

10. Stem Cells: the Potential and Promise of Brain Repair
∗ Neural transplantation can restore striatal
dopaminergic neurotransmission in animal models
∗ Neural transplantation of fetal ventral mesencephalic
(VM) dopaminergic neurons has been introduced in
the clinic as an alternative treatment for PD
Stem cell therapeutics in Parkinson’s
Disease

11. Stem Cells: the Potential and Promise of Brain Repair
• Neural stem cells (NSCs) possess robust tropism for infiltrating
tumor cells
• Can be used to deliver therapeutic agents directly to tumor
satellites, with significant therapeutic benefit
• Vehicles for tumor-toxic molecules can be disseminated in
tumor pockets and can inhibit glioma cell proliferation,
migration, and angiogenesis
• Ehtesham M et al. Stem cell therapies for malignant glioma. Neurosurg Focus. 2005 ;
19(3):E5.
• Flax JD et al. Engraftable human neural stem cells respond to developmental cues,
replace neurons, and express foreign genes. Nat Biotechnol. 1998;16(11):1033-9.
• Ourednik V et al. Neural stem cells -- a versatile tool for cell replacement and gene
therapy in the central nervous system. Clin Genet. 1999;56(4):267-78.
• Heese O et al. Neural stem cell migration toward gliomas in vitro. Neuro Oncol.
2005;7(4):476-84.
Role in Brain Tumors

12. Stem Cells: the Potential and Promise of Brain Repair
• Embryonic stem cell (ESC)–derived astrocytes expressing a
doxycyclineinducible transgene has been used as a vector
for gene therapy
• Fully differentiated ESC-derived astrocytes have been
stereotactically transplanted in the mouse brain
• Uzzaman M et al. Embryonic stem cell-derived astrocytes: a
novel gene therapy vector for brain tumors. Neurosurg
Focus. 2005 ;19(3):E6.
Malignant gliomas

13. Stem Cells: the Potential and Promise of Brain Repair
∗ No treatment currently exists to restore lost
neurological function after stroke.
∗ There potential of stem cell transplantation as a novel
therapeutic approach for stroke.
∗ Immortalized NT2 human teratocarcinoma (hNT
neurons) have been investigated in phase I and II
clinical transplant trials of basal ganglia stroke
Cell Transplantation Therapy for
Stroke

14. Stem Cells: the Potential and Promise of Brain Repair
• Neural transplantation- Experimentally and clinically
to develop new treatment options for intractable
epilepsy
• Significant, although transient, anticonvulsant
effects has been observed after transplantation
• Nolte MW et al. Benefits and risks of intranigral transplantation of
GABA-producing cells subsequent to the establishment of kindling-
induced seizures. Neurobiol Dis. 2008;31(3):342-54.
• There is no conclusive evidence in support of using
stem cells for treating TLE hitherto
Intractable Epilepsy

15. Stem Cells: the Potential and Promise of Brain Repair
• Schwann cell precursors
• For myelin repair in the Central Nervous System
• Demyelinating disorders i.e. Multiple sclerosis
• Woodhoo A et al. Schwann cell precursors: a favourable cell for myelin
repair in the Central Nervous System. Brain. 2007 ;130(Pt 8):2175-85.
Myelin repair

16. Stem Cells: the Potential and Promise of Brain Repair
∗ Neurogenesis and Alterations of Neural Stem Cells in
Mouse Models of Cerebral Amyloidosis
∗ Ermini FV et al. Neurogenesis and alterations of neural stem cells in
mouse models of cerebral amyloidosis. Am J Pathol.
2008;172(6):1520-8.
Cerebral Amyloidosis

17. Stem Cells: the Potential and Promise of Brain Repair
∗ Lindvall O et al. Stem cell therapy for human neurodegenerative disorders-
how to make it work. Nat Med. 2004;10 Suppl:S42-50.
Human neurodegenerative disorders
Cholinergic neurons in the fetal
brain or autologous vagal
ganglion
Alzheimer's disease
Striatal GABAergic neurons Huntington's chorea
Fetal spinal cords Amyotrophic lateral sclerosis
Spinal cord injury
Stem cells or progenitor cells Demyelinating brain to supply
myelin
Fetal locus ceruleus In Epilepsy, has been
experimentally grafted into the
hippocampus

18. Stem Cells: the Potential and Promise of Brain Repair
• Human GPCs has been used as transplantable agents
both for mediating enzymatic restoration to the
enzyme-deficient brain
• And for therapeutic myelination in the disorders of
congenital hypomyelination
• Goldman SA et al.Stem cell-based strategies for treating
pediatric disorders of myelin. Hum Mol Genet. 2008 ;
17(R1):R76-83.
Glial progenitor cells (GPCs)

19. Stem Cells: the Potential and Promise of Brain Repair
∗ To have them act as a cellular bridge providing
chemical and mechanical cues for axons to traverse
the bridge into the spinal cord below the injury site
∗ To provide a source of new neurons which may repair
damaged circuits in the spinal cord
∗ To secrete neurotropic substances which promote
repair
Neural stem cells for spinal cord
repair

20. Stem Cells: the Potential and Promise of Brain Repair
• To repair or regenerate the degenerated intervertebral
disc
• Mesenchymal stem cells (MSCs)
– Possess the capacity to differentiate into nucleus pulposus–
like cells capable of synthesizing a physiological,
proteoglycan-rich extracellular matrix characteristic of
healthy intervertebral disc
• Acosta FL Jr et al. The potential role of mesenchymal stem cell
therapy for intervertebral disc degeneration: a critical overview.
Neurosurg Focus. 2005 ;19(3):E4.
Low-back pain

21. Stem Cells: the Potential and Promise of Brain Repair
• The therapeutic potential of stem cell
therapy for injured peripheral nerves is
largely unknown.
• These data suggest that transplanted
neurally induced ES cells differentiate into
myelin-forming cells and provide a
potential therapy for severely injured
peripheral nerves.
• Cui L et al. Transplantation of embryonic stem cells improves nerve repair and
Peripheral Nerves

22. Stem Cells: the Potential and Promise of Brain Repair
• Optimum donor source
• The manner of storage
• Duration of storage or culture in medium
• The minimally required number of cells for transplantation
• Viability of transplanted cells
• Conditions of the host- age of patient and severity of
disease
• Detection of the most appropriate site for transplant
Difficulties

23. Stem Cells: the Potential and Promise of Brain Repair
• Technological advances are needed to make precise
genetic modifications of stem cells or their progeny to
enhance their capacity for migration, integration and
pathway reconstruction
• Need to develop animal models that closely mimic the
human disease
• Collaboration between neuroscientists, neurosurgeons,
and neurologists is required to translate cell
transplantation therapy to the clinic
Future

24. Stem Cells: the Potential and Promise of Brain Repair
“I don’t want to become immortal through
my great works, I want to become
immortal by living forever”
...Woody Allan