Lecture 8 Flashcards
(9 cards)
Describe the importance of stem cells
Stem cells give rise to key cell lineages and also participate in tissue homeostasis and repair. They divide to self renew and produce cells that differentiate.
The differentiation requires cell remodeling, which is achieved by autophagy. Overall, autophagy helps to preserve SC function by simultaneously regulating cell remodeling and metabolism.
Stem cells have high levels of autophagy
Very few mitochondria, in naïve state v juvenile cristae
Low level of reactive oxygen species – relates to low levels of mitochodnria
Switch from oxidative phosphorylation to relying more on glycolysis
Metabolise lactate
Limits their proliferation
When they divide lead to progenitor cell and another HSC – self renewal
Describe how Autophagy is Essential for iPSC Generation
iPSCs are not formed in cells without the autophagy protein Atg5
Autophagy is induced early in iPSC formation and then decreases
Direct evidence for involvement of autophagy
•Sox2 initiates autophagy by repressing mTOR expression early in reprogramming
- Subsequently, restoration of mTOR expression is required to complete reprogramming
- Sox2 binds to a repressor region in the mTOR promoter and recruits the NuRD complex
Express yamanaka factors, sox2 binds to that region, reduces levels of mTOR – induce autophagy, allows reprogramming
iPSC formation v inefficient
Make it more efficient – facilitate regenerative medicine
What is the metabolic state hypothesis?
Low mitochondrial numbers, under-developed mitochondria and low ROS is a common feature of ‘stemness’
Cells change metabolism from oxidative phosphorylation to glycolytic pathway (produces less ROS generation)
In normal cells you have active mTOR and mitochondrial respiration
Stem cells - Less ROS and ATP
Involved in iPSC reprogramming
From ES cells to differentiated cells you shift away from naïve mitochondria, increased numbers of mitochondria - more dependence on oxidative phosphorylation
Proposed that autophagy and thus mitophagy can modulate mitochondria and ROS and help shift cells to a glycolytic metabolism similar to that seen in ESCs.
When you take a somatic cell, reprogram it and add in Yamanaka factors, majority of cells will go to these senescent cells – dependent on OP
Only very small proportion become iPSCs
Creating iPSCs rejuvenate tissue, reverse effects of aging
Why and how does autophagy augment (make) reprogramming?
Mitophagy results in the loss of mitochondrial function and in the accelerated onset of the glycolytic metabolism that is required to fuel reprogramming.
Conclusion: Modulators of autophagy increase the efficiency of iPSC formation
What is the relationship between stem cells and autophagy?
Stem cell properties: self renewal, multipotency, differentiation and quiescence in adult tissues.
SCs must control rates of protein and organelle turnover and ATP production
Autophagy is required for SC quality and for maintaining the cellular homeostasis of SCs
If autophagy goes wrong causes problems for stem cell
How does autophagy play a paradoxical role in cancer?
Autophagy, particularly in stem cells, is pivotal since it functions as a ‘guardian’ by promoting adaptation under changing conditions and/or stress, maintains protein/organelle quality control and metabolism, prevents accumulation of p62, regulates removal of damaged mitochondria (that would otherwise produce ROS and damage DNA), and therefore promotes genetic stability i.e. prevents cancer formation
However
Evidence suggests autophagy acts as a survival mechanism within cancer cells
Explain the link between cancer stem cells and autophagy
Cancer stem cells in solid tumours will see hypoxia, low nutrients, increased acidity i.e. stress. CSC may therefore rely more on autophagy than other cells
Autophagy will protect against apoptosis, ROS and promotes self-renewal
High levels of autophagy linked to differentiation and metastasis
The role of autophagy in cancer is not clear, it very much depends upon the cancer
Explain how Inhibition of Autophagy in HSC promotes Acute Myeloid Leukaemia (AML)
Autophagy is required for HSCs to differentiate into multiple lineages
Inhibition of autophagy leads to cellular damage and a pre-leukaemic state and subsequently stabilization of oncoproteins
Cancer therapy can induce cytoprotective autophagy where the cell tries to combat the toxic effects of the drug
Inhibition of autophagy is being used alongside chemotherapy
Explain how Inhibition of Autophagy reduces Chronic Myeloid Leukemia (CML) progenitor cells
The core autophagy protein ATG4B (and ATG4A, ATG5 and Beclin-1) is over expressed in CML stem/progenitor cells and may be useful in predicting treatment response.
ATG4B knockdown reduces autophagy, impairs the survival of CML stem/progenitor cells, and sensitizes them to chemotherapy (Imatinib mesylate) treatment.
