Cracking open the secrets of bone stem cells

Dr. Carl Gregory, an assistant professor in the Institute for Regenerative Medicine at the Texas A&M Health Science Center College of Medicine, discussed adult stem cells and their applications for medical treatment Mini Medical School public lecture on the TAMHSC Bryan campus on January 24. The public talk, and the Q&A that followed it, can be viewed via the Mini Medical School Lecture Archive, where you can also download a copy of his presentation.

We sat down with Dr. Gregory to find out what adult stem cells do and how the stem cells hidden in human bones could eventually help doctors treat not only bone injuries, but a surprising range of autoimmune diseases.

TAMHSC-COM: How long have you been interested in stem cell research?

Dr. Carl Gregory: I’ve been interested in the regeneration of damaged tissue since my Ph.D. days back in 1995. I really started to work on mesenchymal stem cells in 2001 when I came to Tulane University Medical School from the United Kingdom. The principle behind regenerative medicine is to enhance the body’s natural process of regeneration, which means studying and working with stem cells.

COM: We’d better start with a refresher on what exactly “stem cells” are.

Gregory: Sure. Classical physiological principles dictate that organs like the heart and lung have a finite number of cells and when they’re gone, they’re gone. But we now know that as adults, we have cells that reside in our tissues that can change (or differentiate) into specialized cells to replace lost or damaged ones. They reside in the tissue – the brain, the heart, and so on – for the lifetime of the host. These are the cells we’re talking about when we talk about “adult” stem cells. Embryonic stem cells, or ES cells, are another story.

COM: Why was the initial scientific interest in stem cells focused on embryonic stem cells?

Gregory: Early on, ES cells showed great promise. To understand why, you need to understand how adult stem cells work.

So we know that the brain and heart can regenerate, to a limited degree, thanks to our “adult” stem cells. But when the stem cells are extracted and expanded in culture, they age and die after a few cell divisions. We can still use them for some applications, but there is a limited supply. The impacts on research are obvious.

Then we throw in another limitation to adult stem cells, which is that a given adult stem cell will only differentiate into a limited range of cell types, depending on the tissue it comes from. For example, hematopoietic stem cells will only differentiate into the cells of the blood. This is impressive in itself because there are at least 10 major types of blood cell in the body, but that’s nothing compared to the ES cell, which has the capacity to differentiate into virtually all cell types in the human body – at least 300 different types of cells.

And unlike adult stem cells, ES cells divide indefinitely in culture, making the generation of limitless numbers of cells possible. They could also generate tissues from virtually every part of the human body, suggesting that one stem cell could satisfy all of our needs.

COM: But there seems to have been a shift away from them. Why?

Gregory: ES cells have fallen out of favor in many countries for three major reasons. First, ES cells have to be prepared from very early human embryos. Many argue that the embryos have not developed very far, but nevertheless, the ethical concerns are quite clear. This is a hotly debated area and funding into ES research has been sporadic.

Secondly, ES cells can do some strange things. When a mouse ES cell is implanted into a mouse embryo, it engrafts, divides, and contributes to all of the tissues of the resultant adult mouse. When ES cells are injected into adult mice, the ES cells seem to lose control and form a unique class of tumor called a teratoma. Teratomas are usually benign, but they are destructive and contain cells from just about every tissue in the developed body. Some teratomas even have teeth and hair growing out of them. In short, ES cells only function properly in a developing embryo. We can differentiate the ES cells in the dish and inject them into adult recipients, but it’s risky because no differentiation method is 100% effective and you only need a single cell to initiate a tumor.

Third, even if we could solve the teratoma problem, we now have a good workaround. Shinya Yamanaka’s group has devised a way to make ES-like cells from adult tissues. These cells, known as induced pluripotent stem cells (iPS cells) can be made from a simple skin biopsy. They divide without limit, and differentiate into virtually every cell in the body. Yamanaka won the Nobel Prize for Medicine this year.

Overall, although the field of regenerative medicine is still in its fledgling years, we understand more about adult stem cell preparations. Even with their limitations, adult stem cells are safer and more predictable than ES or iPS cells.

COM: What appear to be the most promising areas of application of stem cells in medicine today?

Gregory: The earliest stem cell therapy was performed on a class of cell called the hematopoietic stem cell – the single stem cell that is able to generate all of the blood cells in our body. This work grew rapidly in the seventies and eighties, and now physicians routinely perform stem cell infusions in the clinic for the treatment of blood cell malignancies, anemias and immune deficiencies, and acute radiation poisoning.

I think the most exciting areas of stem cell biology come from mesenchymal stem cells (MSC), which come from bone marrow, adipose tissue, skin, and deciduous teeth (a baby’s temporary teeth) and form a number of connective tissue types.

Of course, I’m biased – MSC cells are my research area. But here are the facts: MSC cells can be expanded in the millions in culture from about two teaspoons of adult bone marrow. They can differentiate into osteoblasts, the cells that repair bones, and can therefore be used to regenerate bone tissue. However, a rapidly expanding field of MSC research has capitalized on the fact that the cells also differentiate into a tissue called stroma. This tissue is found all over the body and is responsible for secreting growth factors that support tissue survival and repair. It also modulates the immune system. This means that MSCs could help control autoimmune diseases where the host recognizes some tissues as foreign and kills them – diseases like Type 1 diabetes, Crohn’s disease, graft-versus-host disease, issues in tissue transplantation, arthritis, asthma… the list goes on!

In experiments and in some clinical trials, MSCs have been shown migrate to the site of autoimmune damage, support survival of the cells at risk, and inhibit the inflammatory and autoimmune effects. MSCs may even be used to target tumors and deliver cell-killing drugs or support the re-growth of cardiac muscle after a heart attack. Given that nearly all chronic diseases have an inflammatory component, MSCs might be a widely used clinical tool of the future.

In my talk tonight, we’ll look at one specific application of MSCs: repairing human bones.

COM: Tell us more about your work with the Institute for Regenerative Medicine. How does the institute link basic science and clinical translation in a way that lab research can’t do on its own?

Gregory: We are a state-of-the-art institute attracting stem cell biologists from around the world. Currently, we have about 50 members working in many areas of regenerative medicine. Our key foci are diabetes, cancer, transplant rejection, heart disease, traumatic brain injury, Crohn’s-like diseases and bone regeneration. I believe we are able to do a lot more regarding translation of technology to the clinic because we have a diverse range of expertise (PhDs, MDs, and DVMs) and we have close ties with surrounding hospitals and veterinary clinics. For example, we have a strong collaboration with Scott and White Hospital in Temple and the Texas A&M College of Veterinary Medicine and Biomedical Sciences. We also have facilities to generate cells that meet the stringent requirements of the FDA.

COM: Tell me a bit more about the general direction of your research and what you hope it can contribute to. What could the end results of this type of research be?

Gregory: Our research group is one of many at the IRM, but we specialize in two main areas – bone regeneration and malignant bone disease. Currently, repair of severe bone trauma and vertebral fusion procedures can have a poor success rate because our synthetic bone fillers cannot mimic bone tissue with sufficient complexity. In our lab, we are generating a living bone-like tissue using MSCs manipulated to become very primitive bone repair cells – it is not rejected by the immune system and can be frozen alive until needed. We have shown that this material has unprecedented healing properties in experimental models and are now looking into veterinary applications. If these approaches succeed, we will go into human trials. We also use MSCs to examine how some cancers spread to bone and destroy bone tissue. Using MSCs as a model for bone development, we have identified a molecule from the shells of shellfish that inhibits division of tumor cells while simultaneously accelerating the host’s own bone repair mechanisms.