Lecture 20 - Myogenesis: from stem cells to to muscles Flashcards
True or False
muscle can regenerate itself
true
POst-natal myogenesis follows a similar path to that of embryonic myogenesis, the main difference being the starting cell is a _____
satellite cell
muscl regeneration/repair is mediated by a population of resident adult stem cells termed satellite cells
Describe satellite cells, how the are activated, what they express, where they reside.
Quiescent cell population capable of synthesizing mulscle
activated in response to damage
Distinct from myonuclei -reside between the plasma membrane and the basal lamina (referred to as the satellite cell niche)
heterogeneous population
lineage negative, not expressing markers specific to any type of cell (MyoD-, CD45-, Sca1-)
Express Pax7, Pax3, CD34 = muscle precursor cells (same things expressed)
describe the muscle stem cell niche.
defined anatomical location between the muscle fibre and the basal lamina
localised close to BVs
allows systemic regulation of satellite cell activity
What are the two theories of how satellite cells self renew?
Theory A - asymmetric cell division
Satellite cell divides to form one new quiescent satellite cell whihc populates the niche, and one activated satellite cell which enters the cell cycle and proliferates
Theory B - return to quiescence
Satellite cell becomes activated and proliferates after which one cell will return to quiescence and repopulate the niche
True or false
in adults we don’t usually see the formation of new muscle fibres
truw
True or False
In the adult, Pax3 expression is maintain in all satellte cells and proliferating myoblasts, and decreased rapidly prior to differentiation
False
this is Pax7
Pax 3 is co-expressed in satellite cells only in the diaphragm and body wall muscles
True or false
If you don’t have Pax7 you don’t have satellite cells
true
Damaged muscle fibres release ___ ____ ______ which is known to activate satellite cells
hepatocyte growth factor
What is atrophy related to old age?
sarcopenia
dystrophy = genetic disease
Why do satellite cells fail to continue regeneration?
Limited ability to regenerate after a certain age?
Changes in local/systemic environment no longer favour regeneration?
What is the evidence for and against the statement that “Satellite cells wear out’’?
Old muscles don’t regenerate as well as young muscles
satellite cell number may/may not decrease with age and after repeated cycles of degeneration/regeneration (such as in muscle disease)
Old muscles can regenerate weill if placed in a ýoung’environment - indicates that loss of regenerative capacity (at least in aging) is not due to the loss of satellite cells but due to changes in the EC environments (i.e hormones, growth factors etc)
You will wear out long before your satellite cells do!
Young muscles transplanted into old mice ___ regenerative ability
lose
old muscles transplanted into young mice ___ regenerative ability
gain
it must be systemic changes (circulating factors) in the rat itself that make it lose the ability to regenerate
True or False
satellite cells are capable of forming new muscle fibers as well as replicating to replace themselves in the satellite cell pool
True
stem cell-like property
True or False
ANY injury to msucle cells will result in repair by satellite cells
true
myopathies
trauma
exercise
but other types of cells can participate in muscle regeneration
What cells are also capable of generating new muscle?
Mesangioblasts
Pericytes
(both in the vessels)
bone marrow stem cells
AC133+ cell
muscle-derived stem cells
'’side population’’ cells
Describe the features of mesoangioblasts
BV (large)assoicated stem cells from embryonic stage msucle
Able to differentiate into several types of mesodermal tissues such as smooth, cardiac, and skeletal muscle, bone and fat
Not thought to contribute greatly to normal muscle regeneration
possess great potential as therapeutic cell type
Describe the features of Pericytes
BV (small) associated stem cells from post-natal stage muscle
located beneath the basal lamina of the small BVs
suitable for intravascular delivery
Describe the features of AC133+
Blood-derived and skeletal muscle-derived populations that express the glycosylated epitope of human CD133 antigen
Make up 1% of the total mononucleated cells in human skeletal muscle regardless of age
Both blood and muscle derived populations can form myogenic cells
Describe the features of bone marrow derived stem cells
circulating myogenic precursor cells have been described in the bone marrow
minimal contribution to muscle generation
Describe the features of Muscle-derived stem cells (MDSC)
population of stem cells located in the muscle interstitial space and characterised as being positive for CD34 and SCA1
Demonstrated to regenerate skeletal muscle in a dystrophic mouse when delivered into the muscle or the vasculature
identified by a pre-plating technique from muscle biopsy samples
May represent a predecessor of the satellite cell
good myogoenic potential in vivo
Describe the features ofSide population (SP) cells
population of stem cells identified by their unique ability to efflux the DNA-binding dye, hoechst
Located in both skeletal msucle and bone marrow
express Sca1 and do not express satellite cell markers (Pax7, Desmin)
Anatomically located outside of muscle fibers and are associated with the vasculature
haematopoietic potential in vitro
Myogenic potential when injected into regenerating muscle
True or False
Other sources of stem cells may have a therapeutic benefit for treatment of disease
true
What are the characteristics of the ideal stem cell to treat muscle wasting?
8 points.
- Be expandable in vitro without losing stem cell properties
- Be immuno-privileged (make sure they’re not recognised as foreign)
- be systematically-deliverable
- survive, proliferate and migrate upon arrival within host muscle
- differentiate into muscle fibers either to repair damaged fibers or replace lost fibers
- Reconstitute the satellite cell pool with functional stem cells
- Be capable of expressing required muscle genes once contributed to muscle
- Lead to improvement in muscle strength in order to improve patient quality of life
Myoblast transplantation is the initial choice for cell therapy in skeletal muscle due to ..
ease of isolations
demonstrated good potential for therapy in mdx mouse
moved to clinical trials for DMD patients
- up to 10% dystrophin positive fibers in immunosupressed patients with multiple injections; hower
poor survival in vivo
limited migration from injection sites
unable to participate in long term regeneration
Multiple studeis have demonstrated that satellite cell transplant result in muscle fiber formation and contribution to the satellite cell compartment
however, what are the issues with this?
satellite cells must be delivered directly to the muscle (cannot migrate)
poor contribution in the absence of a regenerating environment
exhibit poor survival in vivo (need to inject large numbers)
Multiple injections would be required for a therapeutic benefit
What is a potential way of improving satellite cell transplantation?
Transplantation of myofibers and associated stem cells into injured muscle protects against age-related muscle degeneration in mice
What are the advantages and disadvantages mesoangioblast transplants?
Advantages:
- demonstrated to ameliorate dystrophy in the dog model of DMD
- Can be delivered systemically
Disadvantages:
- Difficult to purify and relatively poorly defined cell population
True or False
To date, no one cell type qualifies the criteria for a perfect therapeutic cell
true
many cell types are currently under investigation for use in muscle cell therapy
Post-natal myogenesis follows a similar path to that of embryonic myogenesis, the main difference being the starting cell is a _____
satellite cell
muscle regeneration/repair is mediated by a population of resident adult stem cells termed satellite cells
True or False
To date, no one cell type qualifies the criteria for a perfect therapeutic cell
true
many cell types are currently under investigation for use in muscle cell therapy
