One step closer to coaxing blood stem cells to multiply
Blood stem cells renew themselves indefinitely in the body, but can scientists accomplish that in vitro?
BY LOU BERGERON
Somewhere in our bone marrow, hematopoietic stem cells are deciding whether to create more blood cells or more of themselves, but they're not sharing their reasoning with us. It's a shame they keep their motivations so private.
If these crucial stem cells were better understood, they could conceivably be cultivated outside the body and transplanted into patients to replenish bone marrow after chemotherapy and combat virtually every known blood disease.
Growing them in a lab has so far been impossible, but recent work by Camilla Forsberg, PhD, postdoctoral scholar in pathology, and Susan Prohaska, PhD, research associate in pathology, has revealed new characteristics of these hematopoietic, or blood-forming, stem cells in mice that will likely point the way to a far greater understanding of what drives them. The two researchers are the co-first authors of a paper detailing these findings in the September issue of the journal Public Library of Science-Genetics.
The key to understanding and controlling these stem cells lies in proteins perched on the outside of the cells. Proteins dot the outside of almost every cell in the human body, regulating the cell's response to changes in its environment and also serving as useful markers for identifying the cell.
By searching for these markers on blood-forming stem cells with an unprecedented thoroughness, Forsberg and Prohaska estimate they have discovered on the order of a 100 new markers, each a possible clue to the stem cells' behavior.
Forsberg and Prohaska unearthed the new markers by means of a detailed process of sorting, testing and statistical analysis. They looked at long-term hematopoietic stem cells, which can self-renew indefinitely, plus the next two cells in the overall sequence that future blood cells follow as they mature. The second-stage cells can self-renew only a few times, third-stage cells not at all.
Since each of the three cell types has slightly different abilities, the researchers reasoned that each should also have at least a few protein markers the other cells don't have, some likely corresponding to their differing abilities.
Being able to replicate themselves indefinitely makes long-term hematopoietic stem cells unique and also tremendously powerful in treating any disease that affects bone marrow or blood, since they can repopulate and sustain the entire blood system.
But for all their vast power to self-renew in the body, Forsberg said that in the lab they decline to replicate, choosing instead to churn out later-stage blood cells with abandon. "It's just unbelievable how many cells you can get from one long-term cell," she said, noting that a lone long-term stem cell can produce millions of more mature cells in a couple of weeks in the lab.
But though later-stage cells are closer to becoming mature blood cells, they're of only fleeting use to a patient whose entire blood system is damaged. Since they only self-renew a few times, they eventually die off, leaving a patient who receives them no better off than before.
Knowing which protein markers are unique to each cell type doesn't reveal which ones influence the cell's decision making. Prohaska said that protein markers have been compared to spots on a dog. "They help you identify it, but they don't necessarily tell you anything about what the dog's going to do," she said.
But there's still a lot of value in knowing which proteins are perched on the stem cells. "They're the tools for future discovery and future experiments," said Prohaska, since the proteins do suggest what environmental signals might stimulate the cells. She and Forsberg hope that by learning those signals, they can someday persuade long-term hematopoietic stem cells to multiply outside the body, so they can be given to the bodies that need them.
Forsber and Prohaska did their research in the lab of Irving Weissman, MD, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, who is senior author on the paper. Also participating in the research and listed as co-authors were Garrett C. Heffner, a graduate student in immunology; Sol Katzman, graduate student in biomolecular engineering at UC-Santa Cruz, and Josh M. Stuart, PhD, assistant professor of biomolecular engineering at UC-Santa Cruz.
This study was funded by grants from the National Institutes of Health, the Cancer Research Institute and an anonymous donor to the Institute for Stem Cell Biology and Regenerative Medicine.