Introduction Flashcards
Why do we need to have stem cells?
To regenerate tissues and systems
Who propose the origin of the stem cell?
What did he show?
Ernst Haeckel in 1868
Showed:
- There was a commonality of the origin of the species and how species branch out through evolution
- Proposed that in the same way species have diverged, cells and tissues during development have diverged –> MUST have common branches and stemmed from a common tree
What is a Stammbaum?
Who proposed this model?
The tree of life:
- With many different branches
- Have 2 common points where the cells have the capacity to go one way or the other
- Stem cells can give rise to all the different branches/cells/tissues
Proposed by Ernst Hackel
What did Boveri propose in 1892?
That stem cells are not the only initial cells but also those of between the fertilised egg and the committed germ cell
What did Hacker do in 1892?
Applied stem cells to the cyclops embryo undergoing asymmetric division
What did Pappenheim do in 1905?
- Used stem cells to understand the development of the red and white blood cell lineages
- Understand Hematopoiesis
What does the word ‘stem cell’ describe?
A wider and wider range of cell types, all with similar underlying concepts (that the cells produce different lineages and progenies)
What is a stem cell?
A cell that has the potential to generate different specialised cell types/tissues (DIFFERENTIATION)
As well as copies of themselves (SELF-REPLICATION)
What are the 3 ways of classifying stem cells?
1) Age of development
2) Tissue of origin
3) Potential to produce different cell types (functional capacity)
4) Therapeutic potential
How are stem cells classified by the age of development?
1) Embryonic
2) Adult
Where are embryonic stem cells taken from?
The very early stage embryo (blastocyst stage)
Where are adult stem cells taken from?
The SOMATIC and FOETAL tissues
How are stem cells classified by their tissue of origin?
Where taken from, eg:
- Neural stem cells (from neural tube)
- Hematopoietic (from the blood)
- Umbilical cord
How are stem cells classified by their functional capactiy?
Capacity to produce other lineages:
1) TOTIPOTENT
2) PLURIPOTENT
3) MULTIPOTENT
4) UNIPOTENT
What are TOTIPOTENT stem cells?
Give an example of these cells
Cells that can give rise to ALL of the cells of the human body, including the trophoblast (extra-embryonic tissues)
Eg. Cells of the fertilised zygote
What are PLURIPOTENT stem cells?
Give an example of these cells
Cells that can produce the derivatives from all 3 of the germ layers: ectoderm, endoderm and mesoderm
Eg. ES cells (embryonic stem cells)
What are MULTIPOTENT stem cells?
Give an example of these cells
TISSUE SPECIFIC stem cells (give rise to different cell types from a specific tissue or organ)
Can produce different lineages but of a reduced number (normally related to that proliferative organ/tissue)
Eg. neural stem cells - give rise to neurons, astrocytes, Schwann cells
What are UNIPOTENT stem cells?
Give an example of these cells
Cells that produce a single cell type
Eg. Muscle satellite cells
What is the trophoblast?
Gives rise to the placenta
How do stem cells usually behave in a tissue?
They normally replicate (self-renew) slowly
How are cells kept in their slow, self-renewing stage in the tissue?
By the niche:
Cells in the niche secrete factors that contribute along with the extracellular matrix to keep the cells quiescent
What happens to the stem cells when they are needed to divide?
They are triggered to divide RAPIDLY:
- Cells become progenitors (transit amplifying cells)
- Create a gradient of cells with DIFFERENT MARKERS depending on the tissue
- Then after cells have divided and acquired a more restricted type of lineage - cells will differentiate and produce post mitotic, terminally differentiated lineages
What are the 3 different therapeutic potentials for stem cells?
1) ALLOGENIC treatment
2) AUTOLOGOUS treatment
3) RECRUITMENT
What is ALLOGENIC treatment with stem cells?
Examples?
Stem cells are derived from a DONOR, expanded in a dish and used to treat a larger population of patients (outside of the initial person)
Eg. ES cells, cord blood cells
What must be done before allogenic treatment with stem cells?
Need to look for an immunogenic comparison - need to look for compatibility of the cells
What is AUTOLOGOUS treatment with stem cells?
Examples?
Cells taken from the initial patient, expanded outside of the body and put back into the SAME patient
Eg. Auto-transplant from the bone marrow or producing induced pluripotent cells (iPSCs)
What can occur to the cells when they are expanded outside of the body?
They can be:
- Transformed
- Reprogrammed (to become pluripotent)
- Directly reprogrammed into another tissue
How are iPS cells created?
1) Take cells from the patient
2) Apply a number of factors
What are the factors applied to the cell to make them iPS cells?
SOX2
OCT4
MYC
KLF4
What are the characteristics of iPS cells created from skin cells similar to?
Embryonic stem cells
Describe the treatment that involves the recruitment of stem cells?
Recruitment of the endogenous stem cells from the same tissue:
- ATTRACT the cells from the same patient that are dormant in the particular organ with drugs –> ACTIVATES the cells to repair cells to repair the tissues
(Awakens the stem cells using medicines in the damaged tissues)
As well as the direct potential application of stem cells for therapies, what can they also provide?
1) Models to screen drugs (eg. toxicity)
2) Models to study genetic conditions
3) Models combining drug screens and models to study genetic conditions
4) Insight into the fundamental biological problems
What are the problems with using stem cells for drug screens?
Ethical considerations
How can stem cells be used to study genetic conditions?
Using iPS:
- Take cells from a patient with a genetic mutation and create a pluripotent stem cell –> model of that particular tissue
- Compare this to normal cells
- To try and understand the biology and and impact of the mutation in the tissue
How can stem cells be used to study the new drugs and genetic conditions?
Trying to understand if we can use drugs to treat a genetic condition:
- Drugs may compensate or ameliorate the PHENOTYPE the genetic mutation produces
Why need to use iPS cells to study the effect of drugs and genetics?
As different mutations may produce a slightly different problem - need to be done in a patient specific way
What should the strategies for manipulating stem cell differentiation be based on?
Why?
The knowledge of the mechanisms by which lineage decisions are made during early embryogensis
Why?
- Need to recapitulate the DEVELOPMENT of the cells and each signal they encounter
- As every single decision point the cells will try and resemble a certain tissue
What are the signals that stem cells encounter during development?
Either:
- POSITIVE REINFORCERS
- INHIBITORS
What must be taken into account when trying to recapitulate the development of the tissues from stem cells?
1) WHEN to apply the signal
2) The LEVEL/CONCENTRATION of the signal
What is lots of knowledge on/not so much knowledge on in regards to regenerative medicine?
Lots of background of how to transplant and repair tissues (done most at the organ level) - due to transplants/grafts in the war
In the last 20 years - concentrating on more isolated cell populations
What experiments and trials should be performed before stem cells can be routinely used for therapies?
- Efficacy
- Safety
- Purity and controlled manufacturing to develop the cells
What questions need to be asked before stem cells can be routinely used for therapies?
- How to IDENTIFY the stem cells and maintain/culture large numbers in a dish
- How to DIFFERENTIATE them appropriately in the lineages we went in culture
- Any IMMUNOLOGICAL/rejection problems?
- How to assess FUNCTIONALITY?
- How to determine the RISKS?
What is the problem with cancer?
Fast expanding tissue that OVERTAKES one particular organ and COMPETES for resources and nutrients
How are cancer cells produced?
By few initial stem cells that have had an ALTERATION in the metabolism or the genome
What was the focus of previous cancer cell treatment?
Focussed on:
1) Stopping the cells from PROLIFERATING
2) SHRINKING the size of the tumour
Why have previous cancer cel treatments failed?
Failed to understand:
- That tumours are established/generated by stem cells
- That stem cells are initially SLOWLY DIVIDING
Many of the treatments were controlling the mass of the tumour but preserving the stem cell –> tumours came back
What is the focus of new cancer treatments?
Trying to target and kill the INITIAL cancer stem cell
