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Stem Cells 101

The what, why, where, when and how of today’s biggest scientific debate

Stem Cells 101

They’ve got politicians ranting, picketers marching, moralists moralizing and water cooler talk heating up. From the White House to the dinner table, everyone is talking about stem cells!

Feel like you missed that biology lecture? Find out what has everyone in an uproar.

Stem cell transplants could treat a variety of diseases and ailments that result from cell and organ damage, such as cancer, diabetes, stroke, arthritis, heart damage and paralysis, to name a few. Could Christopher Reeve’s quadriplegia have been cured by stem cells? What about Michael J. Fox’s Parkinson’s Disease? Research is advancing at such a rapid rate that this “pie in the sky” is now a reality.

Stem cell magical mystery tour

Cells are the basic building blocks of life. You started out from a romantic encounter between an egg and a sperm. Fertilization of the egg triggered division, and from this process you are here today—a mass of billions of walking, talking, thinking, breathing, cells. How did the fertilized egg know to divide to make, say, your heart? Over the course of development, some stem cells stopped dividing and decided to become heart cells.

Stem cells are a little like those “choose your own adventure” novels. The story turns out in several ways depending upon what you choose to happen next. Internal and external signals guide a stem cell to choose its adventure, or fate—to become a specific cell type from many possible choices of cell types. This process is known as differentiation.

At some point in development, stem cells specialize to become part of a tissue. The unique properties of specialized cells define the function of a particular organ. For example, brain cells have cellular tools and properties that help them function to do brain-specific tasks. Pulmonary cells are specialized to perform lung duties and skin cells perform specific functions to be, well, skin.

Stem cells have three qualities. They:

  • divide and renew themselves for a long time
  • remain unspecialized (undifferentiated)
  • can become specialized.

“No other cell in the body has that combination of self-renewal, extensive proliferation and differentiation capacity,” states Paul Simmons, Ph.D., director of Stem Cell Research at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at The University of Texas Health Science Center at Houston (IMM). “Understanding how to control the differentiation of stem cells is still a major endeavor that is underway in many labs around the world.”

The stem cells with the most therapeutic promise are the ones at the center of the uproar: embryonic stem cells. These cells have the potential to become any of the 200 or so different cell types that comprise the human body— they are pluripotent. As an embryo develops however, stem cells have a more limited choice about which cell type they can become. These multipotent stem cells play a central role in the formation of tissues and organs and continue to participate in regeneration and repair in the adult.

The step-by-step process of stem cell differentiation is the lineage of that cell, and the endpoint is known as its fate. One main area of research focus is learning to control the fate of embryonic stem cells. “We have to learn how to train these cells to go down particular lineages that we want,” Simmons says. These cells can be used to replace damaged or diseased cells in a particular organ.

“In addition to their use in cellular therapy, pharmaceutical companies can use stem cells as the basis for discovering and testing drugs,” says Simmons, who also is president of the International Society for Stem Cell Research. “You can screen for a drug that has a specific effect on the liver, for example, and has no effect on bone, skin, or heart cells. This would eliminate some of the drugs that have major side effects in other tissues.”

‘You got potential

Stem cells come in two basic varieties—embryonic and adult. Human embryonic stem cells (hESCs) were first isolated in 1998— more than a decade after the technique was mastered in the mouse. “Human embryonic stem cells have amazing therapeutic potential,” Simmons says.

These cells are harvested from a human egg that has been fertilized in a Petri dish. The source, called a blastocyst, is a hollow ball of cells about five days old that has grown from the fertilized egg. Fertilized eggs, the most common source of hESCs, are donated by patients from in vitro fertilization clinics.

Embryonic stem cells that grow and divide in a dish for a long time while remaining unspecialized are referred to as a stem cell line. Removing some of these cells and allowing them to grow and divide in a new dish is called a passage. Passaging—the process of seeding and dividing the stem cells—can potentially continue indefinitely in the case of embryonic stem cells.

The ‘new stem cell line’ debate

The federal government allows federal funding for hESC research only on cell lines established before August 9, 2001. President George W. Bush used his first veto to block an amendment to that rule which would allow federal funding of research on cell lines created after this date. So why do scientists want new hESC lines?

“The problem with federally approved human embryonic stem cell lines is that they contain contaminants from mouse cells such as viruses and mouse proteins,” explains Dr. Eva Zsigmond, assistant professor of molecular medicine and associate director of the Laboratory for Developmental Biology at the IMM.

“A challenge faced by all those engaged in stem cell research is the importance of balancing the hype and hope.”

The hESCs were grown on a feeder layer of mouse cells. “Mouse contaminants make the federally approved hESCs unsuitable for human use,” Zsigmond explains. New hESC lines do not contain mouse contaminants. In addition, a high number of passages increases the likelihood of genetic mutations in the stem cell line.

“The current approved stem cell lines are all too old for clinical use,” echoed Dr. Rick Wetsel, professor at the Research Center for Immunology and Autoimmune Diseases and director of the Laboratory for Developmental Biology at the IMM. The older the cell line, the more passages it has undergone, and the higher chance of genetic mutation that then is passed on to the next generation of cells. “You want pure, clean and healthy cells,” Wetsel says.

You have your very own

Even as an adult, you have stem cells living in your body. They hang out in your brain, blood, muscle, skin and liver. Adult stem cells are undifferentiated, but the choices of cell types an adult stem cell can become are more limited than embryonic stem cells.

“Adult stem cells are restricted in their capacity for differentiation to the cell types that make up the organ in which they live,” states Simmons. Within adult tissues, stem cells are located in a specific microenvironment which is referred to as a stem cell niche.

Adult stem cells reside in specific tissues and differentiate within that tissue. “A lot of effort is currently being devoted to examining the range of adult tissues in which stem cells exist,” Simmons says.

In contrast to embryonic stem cells, which can be grown in abundance, stem cells in adult tissues are generally rare and therefore difficult to isolate in large numbers. “Consequently, it may be difficult to isolate sufficient stem cells to provide a therapeutically effective dose,” explains Simmons, “We therefore have to learn how to propagate adult stem cells in order to expand their numbers.”

One of the main problems in adult stem cell research is how to carry out this propagation. “We don’t yet know how to grow many types of adult stem cells well in a culture medium. The cells spontaneously differentiate and lose a lot of their key stem cell properties,” Simmons says.

Stem cell transplants, older than you think

Stem cell transplants have been around for almost 40 years. You already knew that. (You just didn’t know you knew it.)

“Adult stem cells are already the basis of a number of cellular therapies for different diseases,” Simmons says. Bone marrow transplants, the first successful adult stem cell transplant, have been around since 1968. These transplants have been used to treat people with disorders such as leukemia and lymphoma.

Hematopoietic stem cells from hip bone marrow of a donor are transplanted into the blood of the recipient. These stem cells travel through the bloodstream to the bone marrow where they lodge and differentiate into all types of blood cells to help prevent infection and repair the body.

Another familiar stem cell therapy is skin grafting. “There are already therapies based on stem cell therapy for skin transplantation for serious burns,” Simmons explains.

In addition to transplants, adult stem cells can be used to develop disease models. Through a process known as nuclear transfer, a cell nucleus from an individual suffering from a particular disease is transplanted into the cytoplasm of an egg. This process reprograms the adult nucleus to a pluripotent (embryonic) state.

“This allows us to create disease models that are derived from patients with diseases we don’t fully understand. We can explore the molecular basis of that disease and use those cells to develop drugs and appropriate treatments,” says Simmons.

The trouble with different tissues

“Stem cell transplant varies from tissue to tissue, and disease to disease,” says Wetsel. Thus, a new set of rules must be created for each type of stem cell transplant, according to what is being treated, and where.

Manipulation of stem cell fate is a hot area of research. “You cannot put non-differentiated stem cells into people,” states Zsigmond, “They have to be differentiated. Otherwise the stem cells will differentiate into cell types inappropriate to the target tissue, forming teratomas [tumors composed of many different cell types].”

“Neurons and cardiomyocites [heart cells] are easier to differentiate,” Wetsel adds. This explains why advances have been made in these areas of transplant, while progress lags in the transplant of other types of differentiated embryonic stem cells.

Everyone hates rejection

“There are three major hurdles to stem cell transplant,” Zsigmond explains, “cell line purity, differentiation, and immune rejection.”

The low rate of donor-to-recipient bone marrow matches reflects the main problem with stem cell transplants: rejection. Most potential bone marrow donors are not a good match for the recipient. The cells would be rejected by the recipient’s immune system. The body sees foreign cells as an invasion by the enemy. It mounts an offensive, as it does with an invading virus or bacterium. Rejection is an immune system reaction that can result in death.

Stem cells have proteins on their surfaces which tell the immune system if that cell is a product of the host. The immune system makes sure that any cell that expresses the foreign proteins is destroyed. Surface proteins on stem cells may trigger rejection following transplantation.

“We need to learn how to control the immune response,” Simmons says.

Another barrier to successful transplantation may be the condition of the diseased or injured tissue. “Some tissues may respond to transplantation, while others may not work so well,” says Wetsel. “Tissues respond best to therapy immediately after cell damage. Older areas of damage may not respond well to cell transplant.”

We’ve only just begun

Given the relatively new field of human stem cell therapy, the future is bright for these tiny celebrities. The progress made in less than a decade of human stem cell research promises hope for millions of disease sufferers worldwide.

“A challenge faced by all those engaged in stem cell research is the importance of balancing the hype and hope,” cautions Simmons. “One way to deliver on the considerable expectations of the stem cell field is to conduct clinical trials that demonstrate what the cells can do.”

For more information visit http://stemcells.nih.gov/ or http://www.isscr.org.