The National Heart, Lung, and Blood Institute (NHLBI) believes that human pluripotent stem cell research can develop exceptional new tools to address many important public health problems. The broadest potential application of stem cell research is the generation of cells and tissues that could be used as therapies. If scientists can learn how to control stem cell conversion into new, functionally mature cells, then physicians might be able to cure many cardiovascular diseases for which therapy is currently inadequate. For example, stem cells could potentially be used to repair the failing heart when it can no longer pump, to generate growth of heart chambers when infants are born with malformed hearts, and to repair vascular damage resulting from high blood pressure and atherosclerosis. Preliminary work in mice and other animals has demonstrated that healthy heart muscle cells transplanted into the heart successfully repopulate the heart tissue and work together with the host cells. These experiments show that stem cell transplantation is feasible. Stem cell research could also have ramifications for lung disorders and could lead to methods to correct defects in lung development or promote tissue repair following injury to the lung.
Diabetes and Digestive and Kidney Diseases Research
Human pluripotent stem cells offer the potential for treating a number of major diseases of concern to all of our NIDDK programs. Because of their special plasticity, these cells offer the possibility to differentiate into highly important tissue specific cells. For example, there is an intense effort underway to understand the genetic rules by which an undifferentiated cell becomes a beta cell of the islet of the pancreas, which is capable of secreting insulin. For this to happen, it is important to understand the genes that are expressed temporally that are not only related to the growth of this type of cell, but also related to its important differentiated function of recognizing glucose concentrations and responding by secreting insulin. Isolated cells of this type are used for transplantation studies and, to a limited extent, in human therapeutic approaches to treat type 1 diabetes. The human pluripotent stem cell could offer an unlimited supply of these cells once the rules of differentiation are known.
Other examples include attempts at cellular therapy to replace diseased liver tissue. In this case a cell would need to differentiate along the lines of a functional liver cell. Again, a similar set of rules are necessary for this to happen, but again the plasticity of the human pluripotent stem cell would form an excellent base for this to occur. Other examples could include various forms of kidney cells or potentially bladder cells. At the present time, there are a number of studies underway in an attempt to grow bladder cells that could be used to reconstruct a human bladder.
There are numerous other examples in addition to diabetes, liver failure, kidney failure, and urologic diseases in which human pluripotent stem cells may have a major therapeutic role. It would also be important to try and understand the genetic rules of development so that these important cells may be applied to important therapeutic uses.
In no area of medicine is the potential of stem cell research greater than in diseases of the nervous system. The most obvious reason is that so many diseases result from the loss of nerve cells, and mature nerve cells cannot divide to replace those that are lost. In Parkinson's disease, nerve cells that make the chemical dopamine die. In Alzheimer's disease, cells that make acetylcholine die. In amyotrophic lateral sclerosis the motor nerve cells that activate muscles die. In stroke, brain trauma, and spinal cord injury many types of cells are lost. There are many more disorders that affect both adults and young children in which nerve cells die.
It might seem hopelessly optimistic to think that supplying new cells to a structure as intricate as the brain would do any good. Can new cells become well enough integrated to restore function? The encouraging preliminary results from fetal tissue transplantation trials for Parkinson's disease argue that they can. Here, the difficulty of obtaining enough cells of the right type杢hat is, dopamine producing nerve cells--limits success. This year, in animal experiments scientists developed methods to isolate neural stem cells and coax them to proliferate for several generations in cell culture, and then, on cue, to specialize into mature dopamine nerve cells. A large supply of "dopamine competent" stem cells will remove the barrier of limited amounts of tissue. When these cells were implanted into the brains of rodents with experimental Parkinson's disease, the animals showed remarkable improvements in their movement control. In other experiments, scientists inserted the gene for a crucial enzyme into stem cells, then transplanted these cells into animals with experimental Tay-Sachs disease, again with very encouraging results. Experimental cell replacement therapies are underway for other chronic diseases and for acute disorders like spinal cord injury and stroke. Transplant therapies for intractable epilepsy are also not out of the question. The potential for cell transplant therapies using cells derived from stem cells is enormous.
Because stem cell therapies have been proposed for so many neurological disorders, it is important to note that stem cells might be used to do very different things to treat different disorders. For example, in some diseases stem cells might specialize and replace a particular type of nerve cell--a different kind of nerve cell for Parkinson's than for Alzheimer's than for amyotrophic lateral sclerosis and so on. For other disorders, like multiple sclerosis, it is not nerve cells, but supporting cells, the glial cells that wrap electrical insulation around nerve fibers, that stem cells might help replace. In other problems, for example brain trauma or stroke, we could speculate about using stem cells to regenerate regions of brain tissue, with many integrated types of brain cells. In the many devastating disorders in children where a single enzyme is missing, the ability of stem cells to migrate widely in the brain and supply the needed enzyme might be the key. There are several other strategies that might rely upon stem cells, such as using stem cells to supply neurotrophic factors, the natural growth and survival signals of the nervous system.
Stem cells have important uses beyond cell transplant therapy. Other possibilities include drug development and drug screening methods. One enticing possibility follows from some surprising results that were reported just last year. Contrary to a longstanding belief that nerve cells in the adult human brain cannot be replenished, scientists found neural stem cells in one part of the brains of adult, even 60 year old, humans. If we can identify the natural signals that control the proliferation and specialization of stem cells, and understand how best to encourage these restorative reactions, we may be able to help the brain repair itself in certain vulnerable regions.
