Stem cell therapy

Question 1

Stem cell overview

Answer 1

• SCs have the ability to self renew and differentiate
• Totipotent-> pluripotent-> multipotent
• 2 major types: embryonic (ESCs) and adult (ASCs)
• ESCs are pluripotent and ASCs are multipotent
• While ESCs can be turned into any type of cell, ASCs can only be used to replace the type of cell that is the ASCs’ tissue of origin
• ASCs cannot be grown indefinitely (where as ESCs can), but ASCs can be reprogrammed to behave like ESCs

Question 2

ESCs

Answer 2

• All ESCs are derived from the inner cell mass (ICM)
• ESCs have unlimited self-renewal capacity
• They are pluripotent and thus can generate all cell types
• Induced pluripotent stem cells (IPS) are ASCs that are reprogrammed to enter an ESC-like state by forcing the expression of 4 TFs: Oct4, Sox2, Klf4, c-Myc

Question 3

Neural stem cells (NSCs)

Answer 3

• A type of ASC that can produce all 3 major CNS cell types: neurons, astrocytes, oligodendrocytes
• NSCs are mainly found in the sub ventricular zone of the LV and the dentate gyrus of the hippocampus
• NSCs can be derived from ESCs and IPS cells
• Fibroblasts can be converted to NSCs by expression of certain TFs

Question 4

Therapeutic uses of NSCs

Answer 4

• Replacement of missing or damaged cells
• Therapeutic delivery of macromolecules, neuroprotection, drug therapy, stimulating repair
• Drug discovery via stem cell based disease models

Question 5

Parkinson’s disease (PD)

Answer 5

• Due to degeneration of dopaminergic neurons in the substantia nigra
• Possible to graft in dopaminergic neurons (NSCs) to the SN to improve PD symptoms
• These cells reinnervate the denervated striatum and restore dopamine release
• Results can be monitored by PET
• Problems encountered: lack of sufficient amounts of tissue, variability in outcome, troublesome dyskinesia after Tx

Question 6

Spinal cord injury

Answer 6

• Delivery NSCs to spinal cord after injury can allow for cell replacement, trophic support of surviving cells, and axon regeneration
• Grafted cells secrete trophic factors that support growth of surviving cells and axon regeneration

Question 7

Challenges facing NSC Rx

Answer 7

• Generating pure populations of NSCs that function like their in vivo counterparts
• Heterogenous differentiation of ESCs/IPS, no way to determine if these are functionally equivalent to in vivo counterparts
• Need to define a developmental stage of NSCs
• Improve survival and delivery of NSCs, also the connectivity/functionality of them
• Overcoming scar formation and utilizing endogenous signals that impact proliferation, migration, and differentiation of NSCs