During the next few months of human development, a process
of increasing specialization takes place. Every step in
the formation of each organ requires a precise orchestration
of a number of processes to form the tissue, grow the tissue
and differentiate the many different kinds of cells within the
tissue,says Deborah Gumucio, Ph.D., associate professor
of cell and developmental biology and co-director of the U-M
Center for Organogenesis.
Adult stem cells and tissue renewal
Photo: D.C. Goings
U-M stem cell researcher Sean Morrison,
Ph.D., who was a graduate student in Weissmans laboratory
during the mid-1990s, refined the techniques scientists use
to find mouse hematopoietic stem cells in different types of
tissue and at different periods of development. Morrison is
now an assistant professor of internal medicine and of cell
and developmental biology in the U-M Medical School, and a Howard
Hughes Medical Institute assistant investigator.
Since he joined the U-M faculty in 1999, Morrison has found stem cells in the peripheral nervous system of rats. Other scientists have identified adult stem cells in several areas of the brain and spinal cord, skeletal muscle, bone marrow, liver and skin of rats, mice and humans.
Scientists have known for 50 years that hematopoietic stem cells found in bone marrow, liver and the spleen can reconstitute every cell in the blood and immune systems. Cancer patients often receive transplants of these cells following intense radiation or chemo-therapy. Injected into the bloodstream, they somehow home directly to bone marrow and begin differentiating, replacing the red and white blood cells killed during treatment. Even though hematopoietic stem cells grow rapidly inside the body, scientists have yet to find a way to grow them outside the body in cultures where they can be studied.
Identified more recently than blood-forming stem cells, neural stem cells currently are under intense study, because some scientists believe they could replace dead or damaged neurons after spinal cord injuries or in Parkinsons and Alzheimers disease. Scientists have shown that neural stem cells produce three different kinds of specialized cells in the central nervous systems of mice, rats and humans. Neural crest stem cells, which develop into the peripheral nervous system, also have been isolated in rats.
The discovery that stem cells exist in many types of tissue has led to new research on stem cell plasticity the ability of adult stem cells or precursor cells to shift gears, change their differentiation pathway and become a completely different type of cell. Under certain conditions, scientists can force a developmental shift by treating cultured stem cells with specific proteins called growth factors or by inserting genes into their DNA.
Photo: D.C. Goings
Growth factors can trigger a series of changes inside
the cell that cause differentiation, says Michael
Long, Ph.D., professor of pediatrics and another of the
Medical Schools stem cell scientists. But ultimately,
genetics is everything. If you dont have the right genes
turned on or turned off, all the external factors in the world
wont make any difference.
Scientists are interested in plasticitys potential for regenerative medicine growing new organs or tissues from stem cells to replace those dam-aged by accident or disease. When I was in school, I learned that bone marrow, gut, blood and skin were the only tissues capable of regeneration, Long says. But recent experiments in mice show that bone marrow stem cells can regenerate the liver. Liver cells can develop into pancreas cells. Muscle cells can give rise to many types of tissue. Someday, we may be able to transplant bone marrow cells and treat diseases in ways we never thought possible before.
Many obstacles remain before scientists can tap the full potential of adult stem cells, however. For one thing, most of the successful plasticity studies so far have involved stem cells from mice and rats. Scientists are all too familiar with the fact that just because something works in mice doesnt mean it will work in people.
There is limited evidence that adult stem cells may have broader potential than previously thought, Morrison cautions, but much of that evidence is still controversial and inconclusive.
cells in the ectoderm or outer layer become
Skin Neurons in Brain & Spinal Cord Peripheral Nervous System Pituitary & Part of Adrenal Glands Eyes & Ears
Stem cells in the mesoderm or middle layer become
Bone Marrow & Blood Cartilage & Fat Cardiac, Skeletal & Smooth Muscle Heart & Blood Vessels Connective Tissue Kidneys Lymphatic System Reproductive Organs
Stem cells in the endoderm or inner layer become
Thyroid Gland Lungs & Respiratory System Bladder & Urethra Liver & Pancreas Stomach & Intestinal Lining
Even in the earliest stages of an embryos development,
death is part of life. Some cells must die to make it possible
for organs to grow into the proper size and shape. Scientists
are intrigued by the role stem cells play in programmed cell
death a process they call apoptosis because the
ability of stem cells to regulate the balance between cell proliferation
and cell death is directly relevant to cancer.
Tissues like skin, blood and intestine have stem cells that proliferate constantly, explains Deborah Gumucio. For example, the entire lining of the gut is renewed every three to four days. A process of programmed cell death must accompany this proliferation to prevent the accumulation of too many cells. Cancer in these tissues is, in many cases, simply a mismanagement of this balance too much proliferation, too little cell death, or both.
U-M stem cell scientist Michael Clarke has been intrigued by the relationship between stem cells and cancer since during his medical residency at the Indiana University Medical School he had to watch helplessly as one of his patients, the girlfriend of basketball legend Larry Bird, died from leukemia. I realized then that if we understood stem cells, wed have a better chance at a cure, Clarke says.
Now he studies self-renewal of adult hematopoietic stem cells and recently discovered an important gene involved in the process. Self-renewal is a tightly regulated process under strict genetic control, Clarke explains. Only an absolute or fixed number of hematopoietic stem cells are allowed to exist in bone marrow. Otherwise every stem cell would be like a cancer.
In a nationally televised address last August, President George
W. Bush announced new regulations for scientists conducting
federally funded research with human embryonic stem cells. The
new rules restricted research to stem cell lines already in
existence that were derived from leftover or excess
human embryos created at fertility clinics. Since then, the
National Institutes of Health have listed 72 cell lines worldwide
that meet the approved criteria.
Intense media attention and public interest followed the Presidents announcement much of it focused on important ethical and religious questions about the morality of using human embryos for research. Most scientists appreciate that, for many, this is a controversial issue. But somewhere in the process, they say between national opinion polls, opposing newspaper editorials, dueling expert television coverage and Congressional politics facts about the science of stem cells are being lost, misrepresented or ignored.
Following the Bush decision on human embryonic stem cell research, scientists were flooded with calls from reporters wanting to know when the public could expect cures for diabetes, Parkinsons disease or cancer. U-M researchers stress that we are a long way from knowing whether stem cell research will lead to cures or even more effective treatments for these and other diseases.
Photo: D.C. Goings
The fundamentals of stem cell biology have been skipped
in the excitement these cells generate, says Marie
Csete, M.D., Ph.D., assistant professor of cell and developmental
biology, associate professor of anesthesiology, and one of several
stem cell biologists in the U-M Medical School who emphasize
the need for more basic research. We are all likely to
be sorry about skipping these ABCs down the road.
Then theres the fact that stem cell research often is portrayed as leading to cloning or creating a genetically identical copy of an organism, especially a human being. Stem cell research and cloning are two different things, Morrison says. The public needs much more education about the different types of stem cells and different types of cloning.
Photo: D.C. Goings
Theres a big difference between reproductive cloning
the technology used to create Dolly the sheep
and therapeutic cloning, says U-M stem cell scientist
Sue OShea, associate professor
of cell and developmental biology. No reputable scientist
is interested in reproductive cloning of human beings and, clearly,
it should be banned. But therapeutic cloning has great potential
to help people who need to replace damaged or diseased tissue
In therapeutic cloning, physicians take a small sample of your tissue and transplant the nucleus from some of these cells into a line of human embryonic stem cells, OShea explains. Under the right culture conditions, scientists could grow neurons with your specific antigens. Because they are genetically identical to you, there should be no immune transplant reaction.
Photo: D.C. Goings
While OShea, Clarke, Csete, Long, Morrison and Richard
Mortensen, M.D., Ph.D., the newest stem cell scientist to
join the Medical School, have chosen to focus their research
on these cells, there are many U-M scientists using stem cells
in other scientific or clinical research initiatives. For example:
In a series of recent animal studies, U-M neurologist Jack M. Parent, M.D., has shown that neural progenitor cells in the brain respond to acute brain injury by moving to damaged areas and producing new neurons. Understanding this self-repair mechanism could help physicians limit brain damage from strokes or neurodegenerative diseases.
U-M pediatricians John E. Levine, M.D., and Gregory A. Yanik, M.D., recently performed the U-Ms first cord blood stem cell transplant for sickle cell anemia using stem cells from the umbilical cord of the patients infant sister.
James Ferrara, M.D., professor of pediatrics and internal medicine, hopes to learn how to prevent an immune reaction called graft-versus-host disease in cancer patients following bone marrow stem cell transplants. In recent studies with laboratory mice, Ferrara discovered that giving mice additional interleukin-18 during the procedure helped prevent this serious complication.
We can see stem cells potential for developing new cell therapies for diabetes, cancer and neurodegenerative diseases, says Mortensen, associate professor of internal medicine and physiology. We have the expertise and the commitment. Working together, we hope to begin to tap that potential.
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