Panel Highlights Medical Promise of Stem Cells

The potential for stem cell research to lead to ways to replenish lost cells — and restore crucial functions in those with diseases ranging from heart disease and neurological disorders to diabetes — emerged clearly from a panel discussion presented by the UCSF Foundation on Thursday in Palo Alto. The panel discussion, “Stem Cell Research: Transforming Medicine,” was moderated by KQED Radio’s Michael Krasny, PhD. It featured four UCSF faculty members: Arnold Kriegstein, MD, PhD, director of the Institute for Regeneration Medicine at UCSF; Matthias Hebrok, PhD, interim director of the UCSF Diabetes Center; Yerem Yeghiazarians, MD, director of the Translational Cardiac Stem Cell Program; and Thea Tlsty, PhD, a program leader at the UCSF Helen Diller Family Comprehensive Cancer Center. Kriegstein and Tlsty also had been featured on Krasny’s Forum radio program earlier in the day. What Is a Stem Cell? Kriegstein described how stem cells are able to keep dividing, renewing themselves for a very long time. They are not specialized, but they do have the potential to spin off more specialized types of progeny cells. There is more than one type of stem cell. Kriegstein explained how, within a few days, a fertilized human egg — a single cell — becomes a structure with an outer layer and an inner cell mass. The inner cells are the source of embryonic stem cells. These cells have the potential to become any type of cell in the body. Researchers are seeking to grow stem cells and to shape the functional fate of specialized stem cell progeny. The goal is to create ample amounts of specialized cells for the development of new treatments based on the regeneration of tissue lost to disease. Embryonic stem cells are not the only stem cells, Kriegstein explained. There also are adult stem cells. These reside in adult tissues and organs, although they are rare, compared with completely specialized cells in these same tissues. Adult stem cells are more limited in their potential. They usually only give rise to cell types normally found in their organ of origin. Adult stem cells have actually served for decades as the basis of an important treatment: Bone marrow transplants allow individuals to regenerate an immune system, thanks to adult stem cells in the blood. In 2006, Shinya Yamanaka, MD, PhD, a stem cell researcher who is now with the UCSF-affiliated Gladstone Institute of Cardiovascular Disease, greatly advanced the field of stem cell research by developing a way to turn back the development program in adult skin cells, making them more similar to embryonic stem cells in their potential to give rise to the myriad types of cells that populate tissues throughout the body. Yamanaka accomplished this — first with mouse cells and later with human cells — by using just four of the dozens of previously identified molecules discovered to have the capability of controlling key genes in embryonic stem cells. These cells, called induced pluripotent stem cells, hold great promise for research. Unlike embryonic stem cells, they can be developed using cells from adults who already have a disease. A stable supply of these cells could be used in the lab to learn more about the development of human diseases, using human cells rather than animal cells and animal disease models. In the development of cell therapies to regenerate tissue, induced pluripotent stem cells can be derived from the patient’s own tissue, which should eliminate the risk of transplant rejection. However, the capability of producing induced pluripotent stem cells does not diminish the importance of embryonic stem cell research, according to Kriegstein. Krasny asked Kriegstein about the importance of eliminating a ban on federal funding for embryonic stem cell research. Kriegsten noted, “It’s only by studying embryonic stem cells that one could even have achieved a way of inducing pluripotent stem cells. Embryonic stem cells are the gold standard that you compare these other cell lines to.” UCSF researchers have used all three types of stem cells in their investigations. Diabetes and Stem Cell Research Diabetes is sometimes viewed as the most promising area of regenerative medicine. The disease is associated with the death of the beta cells within the pancreas. These are cells that make and secrete insulin. The capability of restoring these cells would provide a long-lived source of insulin to the recipient. Unlike with current treatments, these transplanted cells ought to restore the body’s normally fine-tuned control over insulin secretion and blood sugar. Hebrok is using stem cells to develop beta cells that make and secrete insulin. “I do believe we actually have a real shot of generating a functional beta cell in a relatively short period of time,” he said. Hebrok compared his research efforts to move stem cells along a developmental path leading to the desired specialized cell to a cross-country journey from San Francisco to New York. After decades of work to identify molecules that guide a cell’s journey from embryonic stem cell to pancreatic beta cell, Hebrok says researchers have come close to inducing stem cells to do the same thing in the lab — the travelers are close to New York. The beta cells must be able to sense glucose levels in the blood and to secrete insulin appropriately in response. To do to do this, Hebrok believes, beta cells do not need to reside where they normally do, deep within the pancreas in structures called the islets of Langerhans. “We don’t have to go back into the pancreas, which actually would be quite difficult,” he said. Stem Cells to Treat Parkinson’s Disease and Epilepsy Kriegstein and colleagues are aiming to use cell therapy to treat Parkinson’s disease. In Parkinson’s, cells die off in a specific brain region called the substantia nigra. The loss of these cells, which make the neurotransmitter dopamine, impairs nerve signaling and results in movement disorders and other symptoms. Kriegstein proposes to place transplantable cells into an easier-to-target brain region that normally receives these signals. Kriegstein was asked about other research teams’ earlier, unsuccessful efforts to use cell therapy to treat Parkinson’s, and noted that the cells being developed for transplantation today are much more promising. “In just the last six months,” Kriegstein said, researchers have developed “a much better way of making exactly the kind of dopamine-producing cells that would target this part of the brain.” Kriegstein explained that the loss of nerve cells in Parkinson’s disease results in an increase in signaling among certain other nerve cells, which act to inhibit and slow down behaviors. Kriegstein is pursuing a strategy of inhibiting these inhibitors to balance out the nerve signaling equation. Kriegstein presented slides showing the success of this approach in restoring normal gait in mice with a Parkinson’s-like movement disorder. Kriegstein and colleagues are working on a similar approach to tackle epilepsy. Stem Cells to Treat Heart Attacks and Heart Failure Yeghiazarians is a stem cell researcher, but also a clinician who works to unblock arteries of heart attack victims and restore blood flow to the heart muscle. “Time is muscle,” he likes to say. Unfortunately, as a result of heart attacks and impaired blood flow, heart muscle can die, and it does not grow back. After muscle cell death caused by a heart attack, the heart may no longer pump blood efficiently. This condition is called heart failure. Compared with the past, more patients are surviving heart attacks. But many are surviving with heart failure, which has reached epidemic proportions in the United States. Yeghiazarians is working on stem cell strategies to replace muscle cells that have died within the walls of the heart’s pumping chambers. Working with animal models, his lab group is delivering cells directly into the heart through catheters. In small animals, he said, “We can indeed improve heart function, and we’re trying to figure out how exactly this happens.” Cancer, the Dark Side of Stem Cells While many researchers are mining the regenerative potential of stem cells, others are exploring the ways in which abnormally acting stem cells may play a role in cancer. Tlsty has made strides in this realm, especially in investigating the role of stem cells in breast cancer. “Tumor cells actually have many stem cell properties,” she said. “They look like stem cells. They have several behavioral characteristics that look like stem cells, and tumor cells seem to arise in areas where stem cells are known to reside.” In addition, Tlsty explained, stem cells and cancer cells both resist signals that cause most other cells to die. Furthermore, only certain cancer cells among the entire population of cells within a tumor appear to be able to regenerate tumors on their own. Cancer cells that are able to spread to distant sites in the body and regrow — a process called metastasis — are the ultimate cause of death in most cases of cancer. It may be that conventional cancer treatments are missing the cancer stem cells that may be the source of continued growth and spread. “If we can target these cells and actually overcome their resistance to death signals, we’ll be much, much more effective in terms of therapeutics for cancer,” Tlsty said.