Lecture neurodegenerative disorders 7: stem cells Flashcards
What are the three most important properties of stem cells?
A stem cell is able to:
- divide
- self-renewal
- differentiate
Explain the meaning of a stam cell that is termed as:
- Totipotent
- Pluripotent
- Multipotent
- Totipotent → stem cell can differentiate in any cell type
- Pluripotent → stem cell can differentiate into any cell types that belongs to one of the three germ layers
- Multipotent → stem cell can only differentiate in the cell types that are present in specific issue
What sources are there for stem cells (i.e. how/where can we get stem cells for e.g. research)?
- Embryonic stem cells are pluripotent (we can isolate and use them)
- Embryonic germ cells
- Tissue stem cell
- Nuclear reprogramming of somatic cells into embryonic stem cell (ESC)-like cells.
How are induced pluripotent stem cells (iPSCs) generated?
Somatic cells, like fibroblasts can be converted into iPSCs with the use of Yamanaka factors. By introducing 4 Yamanaka factors with the help of retroviruses, specialized cells can be reprogrammed into EPSCs.
What are Yamanaka factors, also name examples?
Factors/genes that are expressed or have an important role in ES cells. 24 candidate genes have been identified; Oct3/4, Sox2, KIf4 and c-Myc are examples of these Yamanaka factors.
Name examples of iPSC technology
- Disease modeling
- Drug development
- Cell replacement therapy (personalized medicine)
How can iPSCs be used in in vitro disease modeling?
Skin cells from a control and a patient are taken and induced as pluripotent stem cells. These cells can then be differentiated in certain cell types that are important for disease modeling. You can then use these differentiated cells to e.g. compare the control with the differentiated cells from the patient by e.g. DNA-microarray analysis.
iPSC technology can be used to study genetic complex disorders like schizophrenia, autism and depression. Current knowledge of these diseases is based on research in postmorterm tissue and animal models. What are disadvantages of these types of research?
- Postmortem tissue → you only have an idea of the end-stage of the disease
- Animal models → not human-specific and drug testing is slow and no prediction of efficacy (due to that the drug is tested on an animal and not on a human).
What kind of information does iPSC technology gives us?
- Background of human cells and genetics
- More information about the different developmental stages
- Specific cell types
- Cellular mechanisms / pathways
Think of what can be researched when iPSCs are used from Alzheimer Diseased patients.
Since one of the pathological features of AD is the accumulation of Aβ and formation of aggregates in the brain. Besides this, it’s known that oligomers (not plaques) drive neurodegeneration and cognitive decline in AD patients. What is not known about oligomers are two thing:
- The mechanism of oligomer toxicity in AD pathology
- Can this mechanism be targeted by drugs
Fill in:
- β- and γ-secretases cleave amyloid precursor protein (APP) into β-amyloid peptides, the 40 and 42 amino acid forms (Aβ40 and Aβ42). Accumulation of Aβ… (1) in the brain is thought to underlie AD pathogenesis.
- Causative genes for autosomal-dominant familial Alzheimer’s disease are … (2) and … (3), encoding components of γ-secretase.
- Mutations … (4) in PS1 and … (5) in PS2 are reported to induce elevation of Aβ42 in human plasma.
- β- and γ-secretases cleave amyloid precursor protein (APP) into β-amyloid peptides, the 40 and 42 amino acid forms (Aβ40 and Aβ42). Accumulation of Aβ42 (1) in the brain is thought to underlie AD pathogenesis.
- Causative genes for autosomal-dominant familial Alzheimer’s disease are Presenilin 1 (PS1) (2) and Presenilin 2 (PS2) (3), encoding components of γ-secretase.
- Mutations A246E (4) in PS1 and N141L (5) in PS2 are reported to induce elevation of Aβ42 in human plasma.
How was it researched that A246E and N141I mutations showed increased Aβ42?
By deriving iPSC neurons from patients with these mutations and studying them in vitro.
After inducing iPSC neurons from patients with mutations A246E in PS1 and N141I in PS2 and studying them in vitro, what else was researched here?
By treating these iPSC-derived neurons with different γ-secretase inhibitors/modulators. They saw that compound W decreased the amyloid β42/β40 ratio. This supports the fact that iPSCs can be used for identification and validation of potential candidate drugs.
What is a disadvantage of using iPSC-derived neurons from AD patients?
Not all patient iPSC-derived cells respond the same
Not all AD patient iPSC-derived cells respond the same. What did they see when analyzing iPSC-derived neural cells from familial and sporadic AD?
- They saw that intracellular Aβ oligomers accumulated only in some patient lines.
- They saw that Aβ oligomer accumulation is associated with cellular stress.
These iPSC-derived neural cells from familial and sporadic AD patients where then treated with docosahexaenoic acid (DHA) (failed in clinical trial). What was the outcome?
That in the case of cellular stress (i.e. ER and oxidative stress), it improved the cell’s viability. But this was only the case for patients that had intracellular Aβ oligomer that caused cellular stress. So DHA was only effective in a portion of AD patients.
