This document discusses stem cells in the central nervous system. It defines different types of stem cells including totipotent, pluripotent, multipotent, and unipotent stem cells. It describes the two main sites of neural stem cell activity - the subventricular zone and dentate gyrus of the hippocampus. It also discusses the regulation of neurogenesis, astrocytes as stem cells, gliogenesis, the response to injury, evidence for adult human neurogenesis, and potential stem cell-based therapies.

1. STEM CELLS BIOLOGY IN
CNS
DR LOMESH WANKHEDE
SENIOR RESIDENT
DEPT OF NEUROSURGERY
PGIMER

2. STEM CELLS
“Nonspecialized cells that have the capacity to self renew and
differentiate into specialized cells”

3. STEM CELL
TYPE
DESCRIPTION EXAMPLE
UNIPOTENT
STEM CELLS CAN FORM ONLY ONE
TYPE OF SPECIALIZED CELL TYPE
MUSCLE STEM
CELLS
TOTIPOTENT
STEM CELLS CAN DIFFERENTIATE
INTO EMBRYONIC AND
EXTRAEMBRYONIC CELL TYPES (EG.
PLACENTA). SUCH CELLS CAN
CONSTRUCT A COMPLETE, VIABLE
ORGANISM
CELLS FROM EARLY
(1-3 DAYS OF
EMBRYO)
PLURIPOTENT
STEM CELLS CAN FORM ANY ADULT
CELL TYPE. HOWEVER, THEY ALONE
CANNOT DEVELOP INTO ADULT
ANIMAL BECAUSE THEY LACK THE
POTENTIAL TO CONTRIBUTE TO
EXTRAEMBRYONIC TISSUE (SUCH AS
THE PLACENTA)
BLASTOCYST ( 4 TO 5
DAY OLD EMBRYO)
MULTIPOTENT
STEM CELLS CAN FORM MULTIPLE
TYPES OF CELLS AND TISSUE TYPES
FETAL TISSUE, ADULT
STEM CELLS

4. Stem cell
Progenitors
(represent an intermediate cell type along the
differentiation spectrum: lineage-committed cell)
Transit-amplifying cell
Fully differentiated cell
(Injury or disease: cytokines, cell-to-
cell contact, and certain molecules in
their particular niches)

5. Neural stem cell
• Two most important sites of NSC activity :
1. Sub-ventricular zone,
2. Dentate gyrus of Hippocampus.

7. Sub-Ventricular Zone:
• lateral aspect of lateral ventricle.
• Expresses GFAP, polysialylated neural cell adhesion molecule (PSA-
NCN).
• These astrocytes extend their apical process that directly contact the
ventricles.
• These astrocytes can differentiate into astrocytes, OPC and
myelinating oligodendrocytes in response to demyelinating lesion.
• This multi-potential nature of SVZ astrocytes lead to their
classification as Neural Stem Cell.
• Ependymal cells of SVZ helps in neurogenesis by producing Noggin
and, an antagonist of bone morphogenic protein, which is inhibitor
of neurogenesis and induce astro-gliogenesis.

9. Rostral Migratory Stream
• Astrocytes from SVZ differentiate into immature neuron called
neuroblast migratory pathway to olfactory bulb – differentiate
to NEURONS.
• precursor astrocytes are called as “Type-B” cells.
• This gives rise to Transit amplifying cells called as “Type-C“ cells –
antigenetically distinct from type-B cells.
• Type-C gives rise to migrating neuroblasts (“Type – A” cells) - they
travel via RMS to olfactory bulb to form neurons.

10. SUB-GRANULAR ZONE
• Second principal site of neurogenesis, which lies between dentate
gyrus and hilum of hippocampus.
• Like SVZ there are B-cells(astrocytes) immature D- cells, which are
smaller, divides less frequently and more differentiated from C- cells
of SVZ.
• D- Cell excitatory granule neurons that migrates to granule cell
layer of hippocampus – they integrate in circuit tree – implicated in
learning and memory process.

12. REGULATION OF NEUROGENESIS
• Several factors - like environmental cues, learning related stimuli
and neuronal activity.
• Example : Post-natal unilateral olfactory deprivation result in
significant reduction in bulb volume and can be reversed with
sufficient restoration of stimulation.
• Stress and raised cortisol level result in decline in neurogenesis
and memory.
• Additionally number of growth factors and extracellular matrix
component influence birth and maturation of neurons.

13. ASTROCYTE – AS STEM CELLS
• In some way astrocytes is suited to fulfil the role of primary
progenitor – as they have numerous processes that contact many cell
type and basal lamina of blood vessels and inter-astrocyte
connections.
• These structural features poise astrocytes to integrate signals from
variety of sources to effectively regulate stem cell niche.
• Parenchymal astrocyte in the region other than SVZ and SGZ do not
appear to be neurogenic in vivo.
• But can give rise to neurosphere in vitro.

14. GLIOGENESIS
• Cells capable of differentiating into astrocytes, oligodendrocytes are
called as glial progenitors.
• Only select region of adult brain are neurogenic, much of the brain
and spinal cord are gliogenic.
• Transcription factor Olig-2 : Important molecular marker of
gliogenesis.
• Other markers:
1. Chondroitin sulphate proteoglycan Neuron glial 2 (NG2),
2. Platelet derived growth factor receptor alpha(PDGFR),
3. Cell surface gangliocyte A2B5.

15. • Although glial progenitors are multi-potent, they appear to lack self-
renewal characteristic of adult NSC and thus have limited capacity to
divide.
• OPC generally remain in quiescent phase unless triggered by injury,
ageing and inflammation.
• Astrocyte progenitors are less well characterized than OPCs.
• Astrocyte – restricted precursors : Negative for GFAP expression
and A2B5 Positive.
• FGF for survival.
• CD44 – astrocyte precursor cell marker : detected in human fetal
tissue.
• Early oligodendrocytes – negative for CD44.

16. NEURAL STEM CELLS IN THE SPINAL CORD
• Near central canal and in white matter parenchyma
• glial-restricted(i.e., they do not give rise to neurons).
• able to generate neurons in vitro and when transplanted into the
neurogenic dentate gyrus, indicating that in addition to intrinsic
factors, the niche in which NSCs are located is a critical determinant
of cell fate.
• Essential elements of neurogenic microenvironment are :
1. Molecular (cytokines, growth factors)
2. Cellular, including astrocytes and endothelial cells.

17. STEM CELL AND PROGENITOR RESPONSE TO INJURY
Brain injury(traumatic, ischemic or
chemical)
Neurogenic regions(SVZ & hippocampus) -
By increasing proliferation & number of
new neurons – which survive & integrate
Following an ischemic lesion to striatum,
these neurons acquire phenotype of
striatal neurons .

18. Proliferative response to CNS injury
occurs predominantly in Glial
precursors in parenchyma.
Number of growth factors are
upregulated after injury of which
PDGF, FGF are mitogenic for OPCs.
OPCs proliferate, migrate to the
lesion site, myelinate in response to
trauma, ischemia & demyelination

19. EVIDENCE FOR ADULT HUMAN
NEUROGENESIS
• NSCs resides in adult human hippocampus, SVZ, cortex, subcortical
white matter and can generate neuronal and glial progeny in vitro.
• Adult human NSCs repond to CNS insults by proliferating and
differentiating.
• When transplanted into demyelinated rodent spinal cord, ahNSCs
contribute to remyelination.

20. STEM CELL-BASED THERAPIES
• Stem cells constitute a potential resource for treatments of wide
variety of conditions.
• Putative therapies
1. Treatments that modulate behaviour of endogenous stem cells
2. Transplantation of exogenous cells.
diagram

21. STIMULATION OF ENDOGENOUS MECHANISMS OF
REPAIR
• Some spontaneous neurogenesis does occur after brain injury, it is
insufficient to generate functional recovery.
• To augment -steps targeted includes – survival, proliferation, migration
and differentiation.
1. Basic FGF,
2. Epidermal growth factor,
3. Bone-derived neurotrophic factor,
4. Noggin,
4. Erythropoietin,
5. Vascular endothelial growth factor(VEGF), etc.
• Investigators have used Transforming growth factor alpha to induce NSCs
to proliferate, migrate and differentiate into neurons in animal model in
parkinsons disease.
• Consideration - safety - tumerogenesis

22. TRANSPLANTATION OF STEM CELLS
• Replacement of cells lost to injury or disease.
• Transplanted either in their
1. Undifferentiated state - if multiple cell types are required to
repopulate the damaged tissue,
2. Differentiated in vitro - if specific cell type is selectively lost like
Parkinson’s disease or ALS

23. CONCLUSION
• Versatility of NSC allows for wide range of applications in
understanding of biology and disease as well as potential treatments
• Many of treatment will involve neurosurgeons

24. Thank you