This document discusses stem cell types and their potential applications for treating neurological diseases. It describes embryonic stem cells as pluripotent and able to differentiate into almost any cell type. Adult stem cells are multipotent and can only produce a limited range of cell types. Neural stem cells are discussed as a promising source for cell replacement therapies for conditions like Parkinson's disease. Challenges and limitations of stem cell therapies are also outlined.

1. Dr. Parag Moon
Senior resident
Dept. of Neurology

2.  Stem Cell- cell which can make exact
copies of itself indefinitely, can
differentiate, and produce specialized
cells for various tissues of body
 Self-renewal and multipotentiality

3.  Totipotent- can become any kind of cell
Early Embryonic SC
 Pluripotent- almost any kind of cell
Blastocyst Embryonic SC
 Multipotent- limited range of cell types
Adult SC: nerve cells, blood cells, muscle
cells, bone and skin cells.

4. 1. EMBRYONIC STEM CELL
- from embryos that develop eggs that
have been fertilized in vitro.
- not derived from eggs fertilized in a
woman’s body.
2. ADULT STEM CELL
- undifferentiated cell types in a tissue or
organ.
- multipotent (limited range of cell type)

6. (a) capacity to proliferate in culture and large
numbers of cells can be derived from a
limited source;
(b) potential to be harvested from the patients
themselves;
(c) ability to migrate and disseminate following
implantation within the adult CNS;

7. (d) possible tropism for areas of pathology;
(e) ease of manipulation using viral and non-viral
gene transfer methods;
(f) ability to better integrate into normal brain
cytoarchitecture with the potential for
physiologically regulated release of
substances.

8.  Derived from the inner cell mass of the
embryonic blastula
 Pluripotent with great proliferative potential
 Risk of teratomas.
 Majority of research done on mouse derived
embryonic stem cell
 Showed promising results in animal studies.

9.  Human embryonic stem cells been isolated,
grown in culture with enrichment for neuronal
lineages with help of growth factors and
mitogens.
 When placed in the developing rat brain, can
migrate widely and differentiate in a site specific
fashion without the formation of teratomas.
 The safety of these cells needs further
investigation
 Issue of therapeutic cloning is a major concern.

10.  Derived from the neuroepithelium of the
developing embryo.
 Respond in vitro to mitogens such as
epidermal growth factor (EGF) and fibroblast
growth factor (FGF2)

11.  Primarily found in the subependymal layer of
the ventricular zone and the dentate gyrus of
the hippocampus and other sites
 Potential for autologous grafts is possible,
assuming that the NPCs are not themselves
involved in the disease process
 Tried in one pt. with parkinsonism

12.  It is theoretically possible that stem cells
derived from non-neural system through a
transdifferentiation process can be used for
nerve cell therapy.
 Haematopoietic stem cell transplanted into
irradiated recipients can differentiate into
microglia, astrocytes, and possibly neurons

13.  Some functional benefit in a rodent model of
Parkinson’s disease when transfected with the
dopamine synthetic enzyme tyrosine
hydroxylase
 Limitation-robustness and efficiency of this
system to produce neural cells is still poor.

14.  Reversal of the terminally differentiated cells
to totipotent or pluripotent cells
 Achieved using nuclear transplantation, or
nuclear transfer (NT), procedures (often called
"cloning").
 Error-prone procedure with a very low
success rate
 Used to produce patient-specific ES cells
carrying a genome identical to that of the
patient

15.  The capacity to differentiate into cell types
outside their lineage restrictions.
 HS cells may be converted into neurons as
well as germ cells
 May provide a means to use tissue stem cells
derived directly from a patient for therapeutic
purposes

16.  Proliferation of ENPs in culture is not
indefinite.
 “Hayflick limit”-equivalent to approximately
50 population doublings after which non-transformed
cells enter replicative senescence
and stop dividing.
 Seems to be species dependent,and although
greater for human than rodent ENPs

18.  Capable of clonal propagation in vitro to ensure
homogeneity
 Genetic stability at high passage
 Integration within the host brain following
transplantation
 Connectivity within host circuits
 Migration and engraftment at sites of damage
 Correct differentiation into appropriate neural
cell types
 Functional benefits
 Lack of side effects

19.  Investigations confirmed the
immunomodulatory properties of NPCs in EAE
in mice.
 NPCs promote apoptosis of type 1 T-helper
cells, shifting the inflammatory process in the
brain toward a more favorable climate of
dominant type 2 T-helper cells
 Significant suppression of proinflammatory
cytokines

20.  The primary goal of NSC therapy is to replace
missing cells and tissue.
 Best targets for stem cell–based therapies->
those that would be improved by the
transplant or induced replacement of a
limited number of cell types.

21.  Aim to replace the lost motor neurons with
those that express normal levels of SMN1.
 Neural progenitors are not particularly
migratory and would not be expected to
spread much from the injection site
 Multiple injection needed

22.  ALS- or SMA-specific ESC lines can be
generated either
1. engineering
2. therapeutic cloning

23.  Dopaminergic fetal cells delivered to brains of
Parkinson’s patients.
 Transfer of fetal midbrain progenitors to the
striatum
 Two recent double-blind placebo-controlled
clinical trials -limited efficacy for the
procedure
 Limitations- availability limited, the
transplanted cells are heterogeneous

24.  Embryonic stem-derived dopaminergic neural
progenitors
 Can be produced in great abundance
 Can be engineered to express additional
proteins that might assist with survival,
differentiation, or pathfinding of the new
neural cells

25.  Limitation-In vitro, NPCs derived from the
developing ventral mesencephalon lose the
ability to spontaneously differentiate into
dopaminergic cells after only a few divisions
 Solution-employ ex vivo genetic techniques
to modify cells prior to implantation to
express tyrosine hydroxylase

26.  Transplanting neural stem cells to an injury
site leads to increased behavioral
improvement in rats
 Side effects seen due to the addition of
inappropriate circuitry
 Difficulty of preventing scar tissue from
forming at the site of the transplant which
hinders growth of neural projection.

27.  Blindness-stem cells of a particular stage
when placed into the subretinal space can
incorporate into the adult retina and form
functional circuits.
 Hearing-stem cells with the ability to
differentiate into new hair cells exist in the
adult inner ear.

28.  Oligodendrocytes can develop from adult or
fetal neural stem cells and from ESCs
 Oligodendrocyte precursors delivered to the
nervous system migrate readily and myelinate
neuronal projections in several disease
models.
 Useful in demyelinating disorders.
 Transplanting the cells intrathecally and
intraventricularly is a promising approach for
cell delivery

29.  Studies using NSCs limited but some evidence
of appropriate neuronal differentiation with
human NSCs.
 Functional efficacy and connectivity of these
cells in repairing the brain has not been
demonstrated.

30.  Transplantation of the MHP36 line (ReNeuron
holdings) has been reported to ameliorate
cognitive deficits in rodent models of
ischaemia.
 hNT neurons derived from a human
teratocarcinoma cell line
 No evidence for tumorigenesis or other
adverse effects in the 12 patients in the
phase I study

31.  The associated neurodegeneration is too
widespread and diffuse.
 Therefore unlikely to be ameliorated by
adding more cells to the system.
 Disease-specific ESC lines could be used to
study the degeneration of neurons in vitro.

32.  Role as efficient and flexible vectors for the
sustained, local delivery of neuroactive
compounds to the brain
1. Neurotrophic factors for neuroprotection
2. To replace proteins lost because of single
gene defects

33.  Inherited neurological conditions attributed
to the loss of function of a single gene that
encodes for a metabolically or
developmentally critical enzyme
 Tried in mucopolysaccharidosis type VII (MPS
VII, Morquio).

34.  NSC’s delivery strategy is attractive compared
to a viral vector based delivery system
because
1. Host brain is not genetically manipulated,
preventing insertional mutagenesis
2. Preserving the function of neurons in the
host.
 Can be incorporated with “suicide cassette”,
allowing elimination of cells

35.  Certain ENPs may show a tropism for areas of
pathology and can be used for chemotherapy
 C17.2 NSC line which is highly migratory in
the adult brain when retrovirally transfected
to express the anti-mitotic compound
cytosine Deaminase.
 Appeared to migrate preferentially towards
the tumours, which decreased in size

36.  Stem cells are an attractive option in drug
discovery process.

38.  Stem cells and neurological disease:R A
Barker, M Jain, R J E Armstrong et al; J Neurol
Neurosurg Psychiatry 2003 74: 553-557
 The Changing Face of Neural Stem Cell
Therapy in Neurologic Diseases:Ofira
Einstein,Tamir Ben-Hur:Arch Neurol.
2008;65(4):452-456
 Cell replacement therapy in neurological
disease:Philos Trans R Soc Lond B Biol Sci.
2006, 361(1473):1463-1475.
 Harrisons principle of internal medicine.