Title: Stem cells and aging
1Stem cells and aging
2Whats special about stem cells?
- Capable of dividing many, many times, dont
undergo the replicative senescence typical of
somatic cells. - Active telomerase.
- Capable of regenerating/reproducing into over 200
types of tissues that our body has- RBCs,
Platelets, B Cell, T Cell, Basophils - Delivery of stem cells has the potential to cure
many serious ailments, including diseases of
aging, and perhaps aspects of aging.
3The stem cell fountain of youth or antithesis
of aging,
redundant elements that function as backups in
the event of failure
Adult stem cells continuously restore vigor to
tissues and organs by replacing effete cells
while, at the same time, renewing the adult
stem-cell population.
Reserve stem cells respond to stress by
regenerating damaged tissue and renewing their
population.
4Additional Empirical Observation
Many age changes can be explained by cumulative
effects of cell loss over time
- Atherosclerotic inflammation - exhaustion of
progenitor cells responsible for arterial repair
(Goldschmidt-Clermont, 2003 Libby, 2003
Rauscher et al., 2003). - Decline in cardiac function - failure of cardiac
stem cells to replace dying myocytes (Capogrossi,
2004). - Incontinence - loss of striated muscle cells in
rhabdosphincter (Strasser et al., 2000).
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6Adult Stem Cells
- Many adult tissues have stem cells.
- The most well studied are the blood stem cell
(hematopoietic stem cell or HSC used in bone
marrow transplants) and the neural stem cell. - Recently, it was discovered that an adult stem
cell from one tissue may act as a stem cell for
another tissue, i.e. blood to neural.
7Stem cell depletion in old age
- Stem cells may not be able to divide
indefinitely - Serial bone marrow transplants done in mice work
for several serial transfers, then fail. - In AIDS patients, CD4 T-cells are destoyed, and
have a huge turnover and declines after several
years. - In the gut, 4-16 stem cells sit at the base of
each villus in the crypt of Lieberkuhn. - Crypt cells undergo apoptosis when damaged, and
have a higher rate of apoptosis in older
individuals. - Stem cells live in special cellular environments,
and depend on signals from neighboring celle to
maintain their stem cell type. - Aging of niche cells may cause stem cells to
differentiate or undergo apoptosis.
8- Harmful effects of telomere shortening
current status - In mice none at all, unless engineered to have
telomeres at birth much shorter than they
normally are at death - In humans dyskeratosis congenita (DC) -- age of
onset 7-8 years on average (big variance).
Symptoms as you might guess (bone marrow
failure, skin disorders, malignancy. Mostly
caused by mutations in TERC or dyskerin (a key
telomere-maintenance protein) - Stem cell therapy (bone marrow transplantation)
has long been used against DC.
9Werners syndrome cellular features
- Normal human fibroblasts achieve approximately 60
population doublings in culture. - Werner syndrome cells usually achieve only about
20 population doublings. - (lower Hayflick limit).
10Differences between Werners syndrome,
Hutchison-Gilford syndrome, and normal aging
- Affected individuals dont suffer
- Degenerative brain disease (Alzheimers,
Parkinsons, etc.). - Muscle wasting (sarcopenia)
- Primarilay post-mitotic tissues are the least
affected!
11Pros and cons of stem cell sources
Type Advantage Problem ES grow
well non-self pluripotent directed
differentiation ES contamination in
product ES-self grow well directed
differentiation (therapeutic cloning) pluripotent
labor intensive, inefficient, self oocyte
supply ES contamination in
product Neonatal (eg cord blood) availability,
could be growth, numbers, cell
types self Adult stem cells unexpected
plasticity grow poorly, accessibility could
be self numbers, interconversions may be
very rare
12Multipotency of Some Somatic Stem Cells
13An example mast cells from stem cells
- Cause allergic disease
- Grown from stem cells in the bone marrow after
enormous complexification - We have grown mast cells from mouse embryonic
stem cells and from adult hematopoietic stem cells
Virginia Commonwealth University
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15CELL THERAPY is administration of cell
suspensions containing stem cells thatRemain
to live there Allocate in tissues and
organs Produce generations of new cells
Restore functional activity of tissues and
organs.
Stem Cell Therapy
16Stem cell therapy today
- Treatment of diseases of aging
- Alzheimers disease
- Parkinsons disease
- Heat disease (replace cell lost to heart attack)
- Immune cancers
- Acute Myelogenous Leukemia
- Irradiation followed by bone marrow transplant.
17Current Clinical Uses of Adult Stem Cells
- CancersLymphomas, multiple myeloma, leukemias,
breast cancer, neuroblastoma, renal cell
carcinoma, ovarian cancer - Autoimmune diseasesmultiple sclerosis, systemic
lupus, rheumatoid, arthritis, scleroderma,
scleromyxedema, Crohns disease - Anemias (incl. sickle cell anemia)
- Immunodeficienciesincluding human gene therapy
- Bone/cartilage deformitieschildren with
osteogenesis imperfecta - Corneal scarring-generation of new corneas to
restore sight - Strokeneural cell implants in clinical trials
- Repairing cardiac tissue after heart attackbone
marrow or muscle stem cells from patient - Parkinsonsretinal stem cells, patients own
neural stem cells, injected growth factors - Growth of new blood vesselse.g., preventing
gangrene - Gastrointestinal epitheliaregenerate damaged
ulcerous tissue - Skingrafts grown from hair follicle stem cells,
after plucking a few hairs from patient - Wound healingbone marrow stem cells stimulated
skin healing - Spinal cord injuryclinical trials currently in
Portugal, Italy, S. Korea.
18Bone marrow transplant
19Bone marrow transplant improves survival
20CR and wound healing
- Wound healing is impaired in old mice.
- CR alone does not improve this, but
- CR abundant food intake -gt healing as rapid as
in young mice. - Ad libitum feeding 4 weeks prior to wounding.
21- Transplants of stem cells to replace declining
renewing cell populations - Potential to reverse decline in cells and cell
turnover in somatic tissues with rapidly cells
turnover. - Problem addition of lots of cells with active
telomerase could cause cancer (pro-neoplastic).
22- Can stem cells without telomerase restore
cellular pools? - Literature consensus
- In humans, bone marrow and epidermal stem cells
divide only every few months. - Gut stem cells divide once a week.
- Thus, other tissues might survive a decade
without telomerase but surely the gut would not.
23- Why dont gut stem cells exhaust before other
stem cells? - A possible explanation stem cell population
dynamics - Option 1 all stem cells divide all the time (but
slowly) - Option 2 clonal selection one stem cell does
all the work until it fails, then another takes
over. Much data contradicts this - Option 3 most stem cells divide all the time,
but a few ultra-stems divide only when the
stemness of their neighbors falls (e.g. a stem
neighbor dies), and then usually produce an
ultra-stem and a normal stem cell
24stem (50) progenitor (50)
stem
slow
few
stem (rarely) progenitor (rarely) committed
(usually)
cell div. rate
cell abun- dance
progenitor
committed
fast
differentiated (all)
many
nil
differentiated
25ultrastem (50) stem (50)
very very few slow
ultrastem
stem (50) progenitor (50)
stem
slow
few
stem (rarely) progenitor (rarely) committed
(usually)
cell div. rate
cell abun- dance
progenitor
committed
fast
differentiated (all)
many
nil
differentiated
26Hematopoietic stem cells can contribute to muscle
myoblasts (Mb), myotube (Mt), myofiber (Mf)
27- Promoting stem cell longevity current status
- Key idea
- Inhibited stem cell differentiation
- Increased stem cell number
- Slower necessary stem cell division rate
- Extended time before stem cell telomeres run out
- Key regulatory genes are being discovered
- Blood MIP-1a (Graham GJ, others)
- Skin 14-3-3s (Dellambra et al., J Cell Biol
1491117)
28Motor function declines with age
- Aging is associated with impaired motor function
- Decreases in movement speed, balance, spontaneous
activity levels, and coordination. -
- In part due to reduced dopaminergic transmission
in the basal ganglia. - Region important for coordinating movement.
- In the basal ganglia, the striatumconsisting of
the caudate and putamenreceives dopaminergic
innervation from the substantia nigra compacta.
FERNÁNDEZ et al., 2004
29Stem cell grafts into the brain
- Bone Marrow Stem Cells
- Have shown the potential to differentiate into
different tissue type cells, including neural
cells. - Grafted to Striatum and Hippocampus of Impaired
Aged Rats. - Examined motor and cognitive function, observed
improvement of function
FERNÁNDEZ et al., 2004
30Stem cell grafts into the brain
GFP-expressing cells grafted into the
caudate-putamen region in the recipient rat
brain. FERNÁNDEZ et al., 2004
31Stem cell grafts into the brain
Performance of aged rats before and after
grafting treatment at hippocampus or striatum
during cognitive and motor tests. Morris Water
Maze (MWM) --a memory test. Transverse Bridges
test --a coordination test. FERNÁNDEZ et al., 2004