Stem Cells: Opportunity for Understanding and Treating Childhood Diseases

Bruce Appel, PhD, Visiting Associate Professor and Director,
Program of Pediatric Stem Cell Biology, University  of Colorado Denver

The ability to identify and propagate stem cells has opened exciting new avenues that could lead to a better understanding of childhood diseases and more effective treatments. To capitalize on the tremendous potential
of stem cells, The Children’s Hospital has launched the Pediatric Stem Cell Biology Program. This program will function as part of a larger stem cell initiative known as the Charles C. Gates Regenerative Medicine and Stem Cell Biology Program at the University of Colorado Anschutz Medical Campus. These programs, which were made possible by generous funding from the Gates Frontiers Fund, aim to catalyze both basic research in stem cell biology and application of stem cell-based medicine. This article will summarize some of our current knowledge of stem cell biology and highlight potential areas of basic and clinical research that could benefit sick children.

Embryonic Stem Cells

Our current concepts and understanding of stem cells derive largely from studies of embryonic development because developmental biologists and stem cell researchers face the same fundamental question, “How can cells divide repeatedly to produce all the different kinds of tissues and organs in the body?” Developmental biologists have worked for decades to understand cellular differentiation, the process by which cells acquire their terminal, specialized characteristics, and to identify the genes that control differentiation. This work led to the realization that each of the cells of very young embryos are competent to produce all kinds of differentiated cells and that, under the proper conditions, embryonic cells could maintain that competency even when removed from the embryo and placed into a culture dish.

What are the special features of stem cells? In developing embryos, cells that divide do so using one of three basic patterns.

First, a cell can divide to produce two progeny cells that also divide. This pattern is called replicative, or proliferative, because it expands the cell population.

Second, a cell can give rise to two progeny cells that do not themselves divide but turn into skin, hair, kidney, neurons or any of the numerous kinds of cells that contribute to tissues and organs. This pattern is called differentiative because the progeny cells become different from their precursor cells.

Finally, a cell can divide to produce one cell that also divides and one cell that differentiates. This pattern is called asymmetric, self-renewing because it produces two different cells, one of which maintains the capacity for further division. The defining characteristic of stem cells is that they can undergo repeated, asymmetric, self-renewing divisions, producing distinct kinds of cells over time.

The ultimate stem cell is a newly fertilized egg, or zygote, because it can divide and give rise to all the different kinds of cells that make an embryo as well as extraembryonic tissues that are necessary to support fetal development. In humans, fertilization occurs while the egg travels along the oviduct. After fertilization the zygote and its progeny cells divide several times to make a tightly compacted ball of cells called a morula. All of the cells of the morula have equal potential to give rise to all embryonic and extraembryonic tissues. We therefore refer to them as totipotent. At about the time that the morula enters the uterus, the cells rearrange to form a sphere surrounding a small mound of cells called the inner cell mass. At this point, which is called the blastocyst stage, the cells are no longer totipotent. The cells of the sphere only contribute to formation of the placenta whereas the inner cell mass cells give rise to the embryo but do not contribute to extraembryonic tissues. The ability to make all embryonic but not extraembryonic cells is called pluripotency.  

Fertilization and development of human embryos through the blastocyst stage can occur in a dish. In fact, this is the strategy used by in vitro fertilization clinics for treatment of infertility. Blastocysts can be dissociated into individual cells, which, in culture, divide and maintain their pluripotent characteristics. Cells produced in this manner are known as embryonic stem cells (ESCs).

Adult Stem Cells

Although the notion of adult stem cells seems fairly recent, adult stem cells have been used therapeutically for many years. In effect, reconstitution of the blood system following bone marrow transplant results from hematopoietic stem cells that occupy bone marrow. It is now evident that most, if not all, adult tissues and organs have small numbers of slowly dividing cells that maintain stem cell characteristics. In healthy individuals, these stem cells probably help replace at least a portion of cells lost through normal wear and tear. Notably, it seems that in some instances adult stem cells can divide more rapidly to replace cells damaged by disease and injury. Like ESCs, adults stem cells can divide and differentiate in culture. However, most scientists currently think that, in general, adult stem cells are more limited than ESCs in their ability to grow and produce many different kinds of cells, which might restrict their therapeutic potential.

Induced Pluripotent Stem Cells

One long-held notion in developmental biology was that once a cell differentiated it lost the ability to function as a stem cell. This has now been overturned by two important advancements. First, researchers learned that if the nucleus, containing the genetic material, of a differentiated cell is transplanted to an egg, a procedure called somatic cell nuclear transplant (SCNT), the host cell could be induced to divide and give rise to ESCs. This showed that the process of differentiation does not irreversibly change DNA. Second, just within the past two years, skin cells from both mice and humans have been “reprogrammed” to a stem cell-like state by forcing them to express a combination of just two to four genes. These cells are called induced Pluripotent Stem Cells (iPSCs). This strategy bypasses the need for eggs and potentially provides an easier, more direct path toward making patient-specific stem cell lines.

The Need for Basic Research

Despite exciting progress, there is much that needs to be learned about stem cells before they have broad therapeutic application. For example, we do not completely understand how embryonic stem cells, adult stem cells and induced pluripotent stem cells are similar and different. This information is vital for designing treatments that have the best chance of success. Lifting current limitations on federal funding for stem cell research will result in rapid progress toward filling this gap in our knowledge. Another critical key to translating research to treatment is tighter control over how stem cells divide and differentiate. Resolution of this challenge will enable production of the specific kinds of cells that need to be replaced in a patient and prevent uncontrolled stem cell division.

In addition to their potential use in cell-replacement therapies, stem cell research will help us understand more about disease, which will enable better strategies for prevention and treatment. Generally, clinical diagnosis occurs at a late stage in the progression of a disease, which might come too late for the most effective therapies. Furthermore, many diseases that have a similar clinical diagnosis might, in fact, result from different genetic defects. The ability to produce patient-specific stem cells and study them in culture will likely have a profound
effect on the way we understand and treat disease.

The way forward

There are two fundamental ways in which stem cells can be used to treat disease and injury. First, stem cells or their directly differentiated progeny cells could be transplanted into patients. Second, a patient’s native stem cells could be stimulated to divide and produce new cells using drug therapy. Which strategy is chosen will depend largely on the nature of the disease or injury. For instance, some genetic diseases eliminate or impair stem cell populations or cause differentiated cells to die. These diseases might be best treated with cell transplants. In principle, cells produced from well-characterized stem cells maintained in stem cell repositories could be used. Perhaps even better, a patient’s own cells could be used to produce induced Pluripotent Stem Cells, followed by correction of the genetic defect and transplantation. In other circumstances, such as particular instances of cerebral palsy or traumatic injury, stimulation of repair by resident stem cells might prove effective without the need for invasive surgery.

The ability to study and use stem cells opens up powerful new opportunities for understanding and treatment of childhood disease. The Children’s Hospital, through its partnership with the University of Colorado Denver , is committed to discovering the full potential of stem cells for making sick kids better.

For more information

For more information about stem cell research, contact the Charles C. Gates Regenerative Medicine and Stem Cell Biology Program at (303) 724-3050 or access the program’s website.