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CEDB30004 > lecture 17: neural stem cells and their niches > Flashcards

lecture 17: neural stem cells and their niches Flashcards

1
Q

What is the functional definition of stem cells?

A
  • properties of a stem cell:
    • self-renew
    • generate all the cell types of the tissue (multipotent)
  • allows for normal tissue homeostasis
  • the decision between self-renewal and differentiation must be tightly controlled
  • self-renew - if uncontrolled could lead to tumours
  • differentiation - too much could lead to loss of stem cells
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2
Q

What are neural stem cells?

A
  • can self renew and differentiate to three major cell types:
    • neurons
    • glia
    • oligodendrocytes
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3
Q

What are glial cells of the nervous system?

A
  • oligodendrocytes: insulate CNS neurons
  • astrocytes: provide trophic support to CNS neurons and involved in inflammation
  • schwann cells: insulate PNS neurons, derived from neural crest
  • all have different origins in the developing nervous system
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4
Q

What are cell types within the NS?

A
  • neurons (both central and peripheral nervous system)
  • oligodendrocytes (myelinating cells of the CNS)
  • schwann cells (myelinating cells and glia of the PNS)
  • astrocytes (glia of the CNS)
  • neural crest (stem cells that form PNS and other non-neural types)
  • radial glia (adult neural stem cells)
  • ependymal cells (line central canal)
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5
Q

What are neurospheres?

A
  • aggregates of neural stem cells cultured in suspension
  • neurosphere + laminin substrate neural media GF (-)
    • neurons
      • βIII-Tubulin
      • NCAM
      • NESTIN
      • MAP2AB
  • neurosphere + fibronectin substrate, neural media GF (+) (EGF/bGFG/PDGF-AA [20ng/ml]), neural media GF (+) (T3 [30nM])
    • astrocytes
      • GFAP
    • oligodendrocytes
      • O4
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6
Q

Of what do neurospheres consist?

A
  • a heterogeneous population of neural stem cells and progenitor sub types
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7
Q

What are sources of neural stem cells?

A
  • pluripotent stem cells (embryonic and iPS)
  • foetal tissue: neuroepithelial cells of the neural tube
  • adult brain: subventricular zone of ventricles, hippocampus
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8
Q

What can be done with pluripotent stem cells?

A
  • in vitro differentiation of stem cells into cell type of interest
  • embryonic stem cell colony
    • endoderm: hepatocytes, islet cells
    • mesoderm: cardiomyocytes, muscle, kidney cells
    • ectoderm: neural tissue (neuroectoderm), skin
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9
Q

What is the maintenance and expansion of neural stem cells?

A
  • monolayer
  • mechanical dissociation
    • pieces are cultured in suspension in Neural Basal Media with growth factors, bFGF and EGF, required for maintenance of neural stem cells
  • cluster of neural stem and progenitor cells in neurosphere
  • rosette structures: similar to neuroepithelial cells of the embryonic neural tube
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10
Q

What are some of the signals involved in directing formation of neural progenitors from ES cells?

A
  • ES cell → BMP → extraembryonic endoderm
  • noggin ⊣ BMP
  • next is neural progenitor
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11
Q

What are neural inducing factors for embryonic stem cells?

A
  • noggin
  • dickkopf
  • FGF2
  • retinoic acid
  • HESC colony → noggin 14 days → neural induction
  • genes expressed in neural stem cells: Pax6, Sox1, Sox2, Sox3, Nestin, CD133
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12
Q

To what does neural induction default?

A
  • forebrain progenitors
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13
Q

What proteins are expressed in different regions of the brain?

A
  • FOXG1
    • Tel of forebrain
  • SIX3
    • Ros Di, Tel of forebrain
  • PAX6
    • all of forebrain (tel, ros di, cau di)
  • OTX1
    • part of Mes (midbrain)
    • all of forebrain
  • OTX2
    • all of mid brain and forebrain
  • IRX3
    • from cau di to met (hind brain)
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14
Q

In the presence of noggin, how will human ES cells progress (roughly)?

A
  1. human ES cells
  2. neurospheres
  3. dorsal anterior cell types
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15
Q

What happens with addition of exogenous factors (e.g. Shh, Wnt, RA, FGF8) during neural induction?

A
  • ventral posterior cell types
  • e.g. sonic hedgehog → ventral GAD67+ neurons
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16
Q

Summary of induction of pluripotent stem cells

A
  • induction of pluripotent stem cells to neural requires inhibition of BMP and Nodal (or downstream SMAD) signalling
  • expression of Sox2 and Pax6 are expressed in neural stem cells
  • differentiation of hPSC-derived neural stem cells defaults to forebrain cortical neurons
  • derivation of specific neuronal cell populations of other lineages in culture may require supplementation of factors involved in neurogenesis patterning and cell fate
17
Q

What are iPSCs?

A
18
Q

What is the structure of neural tube along the dorsal-ventral axis?

A
19
Q

What is the ventricular zone of the neural tube?

A
  • consists of dividing neuroepithelial cells (foetal neural stem cells)
  • one cell layer thick
  • nuclei move within cell as they divide
  • mitosis occurs closest to lumen of neural tube
  • not present in the adult nervous system (becomes the ependymal layer)
20
Q

What are symmetric versus asymmetric cell divisions of neuroepithelial cells?

A
  • symmetric cell division (horizontal)
    • divide to give rise to self i.e. mitotic neuroepithelial cell
    • forms the ventricular zone
  • asymmetric cell division (vertical)
    • divide to give rise to post-mitotic progenitor cell
    • forms the intermediate/mantle zone
21
Q

How is the spinal cord organised?

A
  • ventricular zone: dividing germinal neuroepithelial cells (adult - ependymal layer)
  • intermediate/mantle zone: grey matter (cell bodies of neurons and glia)
  • marginal zone: white matter (axonal connections)
22
Q

summary of foetal neuroepithelial cells

A
  • foetal neuroepthelial cells can be isolated from developing neural tube and cultured in vitro to form neurospheres
  • fate of neural stem cells tends to be restricted to region of neural tube where isolated from, especially along the anterior-posterior axis
  • foetal neural stem cells have been used in clinical trials for cell replacement (e.g. Parkinson’s disease)
  • highly ethical because obtain tissue from aborted foetuses
  • often used in research to study properties of neural stem cells
23
Q

What is identification and assessing properties of adult stem cells?

A
  • a lack of definitive markers has hampered unequivocally identifying stem cells in many adult tissues
  • in most cases, adult stem cells turnover slowly
  • gold standard: testing self-renewal and multipotency in vitro and in vivo
  • strategy 1:
    • in vitro/transplantation combination
    • stem cells are identified on the basis of a molecular marker and followed by in vitro culture or in vivo transplantation in recipient animal
  • strategy 2:
    • genetic marking in situ
    • marker introduced into stem cell, allows visualisation of the modified SC and its clonal offspring over time
  • can’t do step 2 without step 1
24
Q

How do neuroblasts migrate?

A
  • radially, along the radial glial processes, to the outer cortical plate zone
25
Q

What is corticogenesis?

A
  • neuroepithelial cells within ventricular zone become:
    • radial glial cells: extend processes into cortical plate
    • neuroblast (short neuronal precursor cell): migrates to cortical plate
    • intermediate progenitor cell: proliferate in subventricular zone and also give rise to migrating neuroblasts
26
Q

What is the adult subventricular zone (SVZ) niche?

A
  • niche:
    • stem cell in contact with progenitor and niche cells as well as basal lamina
    • influenced by axons and blood vessels
  • SVZ astrocyte /stem cell → self-renewal → transit amplifying cell → neuroblast
  • ciliated cells line walls of ventricles
  • blood bessels
  • basal lamina
27
Q

What do neuroblasts from the SVZ do?

A
  • neuroblasts from the SVZ of the brain ventricles migrate along the rostral migratory stream to the olfacto bulb where they differentiate into neurons
  • SVZ astrocytes (B cells) in this region are stem cells which generate migrating neuroblasts (A cells) via a rapidly dividing transit-amplifying cell (C cells)
  • chains of neuroblasts travel along the rostral migratory stream to the olfactory bulbs and differentiate to neurons
  • signals released from axons (pink) regulate proliferation and survival in this region
  • a specialised basal lamina (BL) extends from perivascular cells and contacts all cell types
  • endothelial cells, blood vessels (BV) and the BL are all likely key components of the niche
28
Q

What is the adult SubGranular Zone (SGZ) niche?

A
  • SGZ astrocytes divide to generate intermediate precursor cells (type D) which progressively generate more differentiated cells D1 D2 D3, which mature into granule neurons
  • niche: stem cells in direct contact with progenitor and differentiated cells, blood vessel, basal lamina and influenced by neurons
29
Q

What is known of adult stem cells undergoing cell division?

A
  • can undergo symmetric or unidirectional cell division when required for tissue regeneration or repair
  • some progenitor cells retain the ability to return to stem cells or act as stem cells when required
30
Q

How do different daughter cells arise?

A
  • anchored to niche cells e.g. to basal lamina between stem cells and stroma or between stem cells and blood vessels
  • unequal distribution of determinants
31
Q

What is the definition of a stem cell niche?

A
  • describes the microenvironment in which stem cells are found and which interacts with stem cells to regulate stem cell fate
  • ‘niche’ can be in vivo or in vitro stem cell microenvironments
  • stem-cell populations are established in ‘niches’ - specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair
  • the niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation
  • it constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms
  • yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets
  • the interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics
  • the simple location of stem cells is not sufficient to define a niche
  • the niche must have both anatomic and functional dimensions
32
Q

What are possible signalling factors and interactions regulating a stem cell niche?

A
  • possible interactions:
    • cell-cell interactions between stem cells
    • cell-ECM interactions
    • cell-BL interactions
    • cell-BV or nerve cell interactions
    • via
    • adhesion molecules, gap junctions, receptor-signalling molecules, hemi-channels (allow communication between cell and the interstitial fluid environment)
  • diffusible factors:
    • growth factors , cytokines, ECM proteoglycans (can sequester molecules and inhibit signalling or release when needed)
    • physiochemical nature of the environment: - pH, metabolite or ion concentration, e.g. ATP or oxygen tension
  • note: the stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood
33
Q

What happens to adult stem cells during ageing?

A
  • in an organ or tissue, generally adult stem cells remain in an undifferentiated state throughout adult life
  • when cultured in vitro they appear to undergo an ‘ageing’ process i.e. their morphology and prolifertive capacity are altered
  • as the adult ages, the niche atrophies and stem cells deteriorate over time and exhibit a decline in proliferation rate - why?
  • a clue came from studying stem cells in Drosophila
  • a key-self-renewal factor expressed by neighbouring niche cells decreases over time
  • by genetically activating signals, stem cells can retain activity in ageing fly and mouse
  • see Method to Delay Aging of Stem Cells Developed
  • see: Toledano H et al., the let-7-lmp axis regulates ageing of the drosophila testis stem-cell niche
34
Q

What are challenges of stem cells?

A
  • differentiation of neural stem cells to a specific cell lineage
  • isolation and purification of cells
  • integration, migration and function of cells in vivo
35
Q

What are issues with transplantation using stem cells and/or their derivatives?

A
  • do they survive?
  • do they integrate?
    • embryonic microenvironment
    • adult microenvironment
    • diseased microenvironment
  • are they tumourgenic?
  • do they function?
  • the microenvironment influences the fate of stem cells

CEDB30004 (29 decks)

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