Stem cells and aging

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Stem cells and aging

• AS300-002 Jim Lund

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Whats 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.

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The 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.
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Additional 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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Adult 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.

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Stem 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.

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• 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.

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Werners 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).

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Differences 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!

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Pros 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
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Multipotency of Some Somatic Stem Cells
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An 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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CELL 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
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Stem 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.

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Current 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.

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Bone marrow transplant
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Bone marrow transplant improves survival
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CR 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.

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• 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).

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• 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.

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• 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

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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
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ultrastem (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
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Hematopoietic stem cells can contribute to muscle
myoblasts (Mb), myotube (Mt), myofiber (Mf)
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• 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)

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Motor 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
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Stem 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
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Stem cell grafts into the brain
GFP-expressing cells grafted into the
caudate-putamen region in the recipient rat
brain. FERNÁNDEZ et al., 2004
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Stem 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