WHY stem cell research? Potential medical applications

Stem cells produce new cells –Adult: replace damaged/lost cells –Embryonic: build the organism Can this power be harnessed to produce new cells artificially?

Potential medical applications Manipulate stem cells: replace lost/damaged cells –Injury Burns, spinal cord damage (paralysis) –Degenerative diseases Heart disease, juvenile diabetes, Parkinson’s –“Non-degenerative” diseases Cancer?

General Procedure Isolate highly potent stem cells Coax SC to differentiate into the needed specialized cell Introduce differentiated cells to the site of damage Cells formerly known as stem cells replace the lost cells

DAMAGED TISSUE One way: ‘Niche’-directed differentiation HEALTHY TISSUE Cultured stem cells in the lab DELIVER (inject/transplant) the cultured SC Cells ‘home in’ on the site of injury Peer pressure: Neighbors cause SC to differentiate appropriately

Leukemia treatment “Bone marrow transplants” Cancer of the blood cell progenitors Rapid production of blood cells –Acute: high # of immature blood cells crowd bone marrow –Chronic: high output of abnormal blood cells Lack of normal blood cells: –Platelets…clotting disorders –White blood cells…propensity for infection –Red blood cells…anemia

Production of blood cells occurs in the bone marrow

(One form of…) Stem Cell Treatment Kill patient’s bone marrow –Radiation/chemotherapy –Destroys cancerous (and healthy) stem cells Patient needs RBC, platelets from donors Highly susceptible to infection –Now it’s a ‘degenerative disease’ Refurbish the bone marrow –‘Healthy’ stem cells Patient’s own bone marrow, treated to enrich for healthy cells Healthy donor –Stem cells ‘move in’ to the bone marrow, start making new blood cells

Problems… Susceptibility to infection before new stem cells kick in Stem cells may not ‘take’ Graft-vs-Host disease –New immune system attacks the recipient Skin, liver, intestinal tract

DAMAGED TISSUE Another way: Factor-directed differentiation HEALTHY TISSUE Culture stem cells in the lab Add a chemical factor to induce differentiation Allow cells to differentiate appropriately DELIVER (inject/transplant) the differentiated cells Cells heal the damage

Factor-directed differentiation Retinoic acid + insulin: fat cells Retinoic acid: nervous system Retinoic acid + DMSO: muscle cells Interleukin-3: neurons, white blood cells

Niche-directed differentiation –Advantages Don’t need to know a whole lot about the cells (Let the ‘niche’ do the dirty work) –Disadvantages Will all the cells differentiate appropriately? (Remember the teratoma)

Factor-directed differentiation –Advantages More control over the identity of the delivered cells –Disadvantages More research needed to determine the correct factors (may be impossible in some cases) Too differentiated? Lose proliferation?

Niche- vs. factor-directed differentiation –Ultimate answer: hybrid between the two?

Paralysis (spinal cord injuries) Juvenile diabetes Parkinson’s

Spinal cord injuries Hwang Mi-Soon: South Korea Paralyzed 19 years Multipotent adult stem cells injected into her spinal cord Currently: debilitating pain Published in 2005 (Cytotherapy) Success of stem cell therapy?

Dr. Hans Keirstead Use of human embryonic stem cells to ‘cure’ paralyzed rats Partially differentiate in culture (factor- directed) Inject into the spinal cord

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Trials in humans ‘soon’…one to two years? –Need to convince FDA that it’s safe enough…and ethically responsible

Juvenile (Type I) Diabetes Insulin: hormone that regulates the amount of sugar in the blood Lots of sugar: insulin released by the pancreas (islet cells) –Tells cells (mainly muscle & fat cells) to take up sugar from the blood stream

Diabetes mellitus “Sweet urine” –High blood sugar Cells don’t take up sugar appropriately Type I: pancreas doesn’t make insulin –Inject insulin Type II: cells don’t respond to insulin –“Non-insulin dependent”

Type I Diabetes “Auto-immune disorder” –Your immune system attacks your own body –Pancreatic islet cells damaged Body can’t make insulin Blood sugar remains high Damage to blood vessels, other tissues Stem cells to the rescue? –Replace insulin-producing cells

Treatments Insulin injection –pain, inconvenience, expense –Lack of ‘natural’ regulation of insulin levels Islet cell transplantation –From cadavers’ pancreases –Works well (~300 trials) –Shortage of pancreases

Embryonic stem cells? ES cells: good at proliferation –Overcome the shortage problem But can they be induced to specialize properly?

Dr. Ron McKay, NIH Induced mouse ES cells to form islet cells –At least cells that look like islet cells Seem to behave like islet cells when injected into mice

What about humans? Can human ES cells be differentiated appropriately? –Right ‘cocktail’ of factors Lab at University of Florida (Bryon Petersen) –Made insulin-producing cells –Cured diabetic mice for ~ three weeks –Teratoma formation

Parkinson’s disease Motor disorder –Tremor –Slow movement, Rigidity –Poor balance

Degeneration of brain cells Cells in the substantia nigra Loss of the chemical dopamine No clear reason why

Treatments Several drugs –Mimic dopamine OR enhance the effect of what little dopamine is left –L-dopa Transplantation –No positive results yet

Stem cells to the rescue? Harvard study: –Rats with “Parkinson’s disease” –Injected healthy ES cells –Cells began producing dopamine –Motor function improvement –20% formed brain teratomas

Stem Cell Targets Degenerative diseases (or pseudo-degenerative: see leukemia) Chronic diseases Discrete/defined tissues AIDS?