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 cellsin the lab

DELIVER (inject/transplant)the cultured SC

Cells ‘home in’on the site of injury

Peer pressure:Neighbors cause SC todifferentiate 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 cellsin the labAdd a chemical factorto induce differentiationAllow cells to differentiateappropriately

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

• http://www.hopkinsmedicine.org/Press_releases/2006/images/video1.wmv

• http://www.hopkinsmedicine.org/Press_releases/2006/images/video2.wmv

• http://www.uci.edu/experts/video.php?src=keirstead&format=mov&res=high

• 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?