In the field of ecology, the term "homing" refers to a species' ability to return to a given place, often over great distances. The primary navigational clues used during homing seem to be the same as those used in migration, but homing may occur in any compass direction and during any season. How pigeons do this has fascinated people for centuries.
In stem cell science, the word "homing" describes stem cells' ability to find their destination, or "niche." Identification of specific cues that steer stem cells to their niche and increase the efficiency of the homing process is an area of intense investigation. The effort has several parts: making the destination more attractive; making the navigation cues more obvious to the cells; and making the stem cells more responsive to the cues.
Finding their niche
Understanding how blood stem cells home has many implications for bone marrow transplants, a life saving treatment that was first performed more than 30 years ago. In this procedure, donated marrow, which carries blood stem cells that will provide a new blood-producing system, is transplanted into the patient. The more blood stem cells that find their way to their niche in the patient's bone marrow, the more likely the transplant will be successful. Thus, by increasing the efficiency of stem cell homing, it's possible to increase the efficiency of bone marrow transplants.
Recent studies by HSCI co-Director David Scadden, MD, and colleagues have identified a cellular mechanism that directs blood stem cells to their destination. This finding holds the promise of greatly increasing the efficiency of the bone marrow transplants and also has implications for future therapies utilizing other types of stem cells.
"Figuring out the mechanism that tells stem cells how to get to where they need to go is a major problem when we're thinking about stem cell therapies," said Scadden.
In their study, the team treated blood stem cells with pharmacological agents that were known to stimulate a pathway believed to be involved in stem cell homing. When injected, the cells that were treated with the drugs homed to the bone marrow much more efficiently than untreated stem cells.
In another seminal study in understanding the mechanism of blood stem cell homing to the bone marrow, Scadden's group, in collaboration with Charles Lin, PhD, a colleague at MGH's Wellman Center for Photomedicine, developed a technique that provides a real-time view of a single stem cell making its way to its niche inside a bone marrow cavity of a living mouse.
"Now," said Scadden, "we can actually watch the cells divide and can see the process by which cells engraft and regenerate the bone marrow."
Arriving at the scene of the crime Mesenchymal stem cells
(MSCs) are another population of cells with therapeutic potential. MSCs are generally defined as multipotent cells that are capable of self-renewal and can also give rise to a number of unique, differentiated cell types that result in connective tissue, bone, and cartilage. Scientists have shown that these cells exist in many parts of the body and are capable of contributing to the repair of a variety of damaged tissues and organs. Although local transplantation or injection may prove therapeutically useful, the ability to target these cells to specific tissues with high efficiency will be crucial in developing new treatments.
Damaged or inflamed tissues call for repair by sending out signals, some of which act as cues for MSCs and attract them to the injured tissue, and many of these signals have been identified, including stromal derived factor 1 (SDF-1). Though SDF-1 can be effective in attracting MSCs, under normal conditions it is kept in an inactive state by enzymes in the body.
In order to increase the number of stem cells that home to a damaged tissue, HSCI faculty member Richard Lee, MD, created a version of SDF- 1 that could not be inactivated. He found that by directly injecting this version of the SDF-1 into the injured heart of a rat, more stem cells were recruited to the damaged heart and were observed to improve heart function.
"This is a very promising field for stem cell therapy and there is a lot to do, but also a lot of unknowns," said Lee.
A recent study in Germany has produced a similar finding, in which drugs were used to keep SDF-1 active in combination with factors that help mobilize stem cells, resulting in improved heart function in laboratory mice.
Signal sensitivity
In addition to making the desired destination more attractive, scientists are also working on ways to make the stem cell surface more responsive to homing factors by using genetic engineering or chemical modification.
Robert Sackstein, MD, PhD, an associate professor of medicine at Harvard Medical School, has shown that attaching a sugar molecule, which acts as a binding site for bone marrow homing cues, to MSCs helps the cells home to the bone marrow more efficiently. Similar studies led by HSCI faculty member Jeffrey Karp, PhD, have shown other chemical modifications of MSCs help them find their way to the bone marrow more easily.
For stem cell therapy and tissue regeneration to be successful, it is important to increase the efficiency of stem cell homing, and that is not a simple task. For stem cells to navigate back to their niche or be recruited by injured tissues, a sequence of coordinated interactions between the cells and their environment provide the signals and sign posts that guide the cells along their journey. Meeting the challenge of unraveling these complex mechanisms will be rewarded with therapeutic potential across the field of stem cell biology.