Week 7 Flashcards
What are stem cells
Stem cells are the only type of cell that can generate itself and differentiate into a different cell type
Asymmetrical division: two cells one identical copy of parent cell required to maintain a pool of stem cells in every tissue, one slightly differentiated progenitor cell which will then differentiate into the cell type the tissue requires
Symmetrical division: produces 2 stem cells identical to parent cell, increases stem cell numbers they will later differentiate into progenitor cells known as self renewal
Stem cell production
Stem cells are capable of mass cell production via a transit amplifying cell population
Understanding potency
Totipotent: all cells of both the embryo and extra-embryonic tissues (cells of the developing embryo up to the 8 cell stage)
Pluripotent: all cell types of the embryo proper (embryonic stem cells)
Multipotent: two or more cell types usually restricted to a single tissue (haematopoietic stem cells)
Monopotent: a single cell type (skeletal muscle stem cells)
Stem cell niche
Stem cell very sensitive to its environment
Its the extracellular matrix that governs the concentration gradient of extracellular signals that the stem cell is sensitive to in the external environment
Extracellular signals: GF, cytokines, pH, chemical composition of the plasma and the serum
The stem cells orientation to the ECM also has an impact on how that cell divides
Haematopoietic stem cells
Stem cells
-extensive self renewal
Progenitor cells
-limited self renewal, extensive proliferation
Mature cells
-no self renewal except for some specialised exceptions (memory lymphoid cells, tissue macrophage)
Haematopoietic stem cells lead the way in therapeutic treatments
Routine therapy for the treatment of various leukaemias
1950s: observations in mouse model that healthy bone marrow infused into myelosuppresed bone marrow recovered function
First successful transplant between monozygotic twins in 1957 to treat leukaemia
First allogeneic BM performed in minesotta in 1968 to treat a paediatric patient with severe combined immunodeficiency disease
Only 5-6% of transplants performed are to treat non malignant disease
Adult stem cell challenges
Stem cells are rare
The cells within adult tissue are heterogenous
Stem cell numbers limit applications
Not all tissue stem cells are characterised well enough to isolate pure populations
Some adult tissues are inaccessible for isolation eg the brain
Removal from the niche can change the properties of the stem cell
These challenge can make adult stem cells difficult to effectively use
What are the limitations to allogeneic bone marrow stem cell treatment
Every 14 minutes someone is diagnosed with blood cancer
More than 2000 people in UK need a bone marrow transplant every year
70% UK patients wont find match through family
72% white/caucasian patients find a match
37% ethnic minority patients find a match
Sickle cell disease
Homozygous single point mutation in beta-globin gene HBB resulting in a valine to glutamic acid substitution
main symptoms are anaemia, episodes of severe pain
SCD can cause pulmonary hypertension, stroke, retinopathy, renal failure
Approx 300 babies born with SCD in the UK every year
Current treatment includes pain management, hydroxyurea and blood transfusions
The only cure is a stem cell transplant
What about using autologous HSC and correcting the mutation prior to transplant?
Gene editing methods in clinical trials for SCD
Using a guide RNA the Cas9 enzyme can target and repair the faulty B-globin gene
B-globin gene repaired and normal red blood cells produced
Cas9 promotes the production of fetal haemoglobin by breaking a gene that encodes a repressor such as BCL11A
Fetal haemoglobin production no longer blocked and sickling of red blood cells prevented
The future of HSC therapy
More than 2100 clinical studies using HSC but long term culture remains a challenge
Researching methods to culture HSC long term since removal from niche causes differentiation
Pluripotent stem cell differentiation towards haematopoietic stem/progenitor cells
how could ES cells transform medicine in futrue
Source differentiated cell types for regenerative medicine (heart failure, diabetes, stroke, haematological disorders, neurodegeneration, blindness, spinal cord injury)
Source of differentiated cell types for the study of disease mechanisms when derived from patients with genetic disorders
Source of differentiated cell types for therapeutic and toxicity screens
Ethical consideration
Embryo destruction
Teratoma formation
Are iPS cells the solution
IPS cell derived oocytes produce viable offspring
IPS cell therapy for diabetes
IVG
In vitro gametogenesis IVG from a single parent pluripotent cell
Generate egg and sperm from one parent and produce offspring
Remove Y chromosome from PSC, reversine, differentiate, co culture with fetal ovary cells
Challenges in iPS cell therapeutics
Reprogramming methods can cause viral integration that can potentially lead to disease
Use of MYC as a reprogramming factor- known as oncogene leading to neoplastic risk
Risk of transplantation undifferentiated iPS cells into recipient leading to teratoma formation
Genetic instability of long term iPS cell cultures for large scale cell production
Cost
