An international team of researchers funded in part by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health, has discovered distinct roles for two types of vessels within the bone marrow, an understanding that could help improve stem cell transplants and create better interventions for diseases like leukemia. One type of vessel preserves a pool of stem cells, while the other type promotes stem cell differentiation into new blood cells and the migration of the new blood cells out of the bone marrow. The results are reported in the April 21, 2016 issue of Nature.1
“This work makes an important distinction in the dual roles of the bone marrow,” said Behrouz Shabestari, Ph.D., Director of the NIBIB program in Optical Imaging and Spectroscopy. “Knowing the specific locations for each activity gives researchers a better idea of where to look for stem cells and where to transplant them.”
Bone marrow contains two main types of blood vessels: arteries and sinusoids. Arteries carry blood into the bone marrow and branch into smaller arterioles that connect with sinusoids. Sinusoids then send the blood into the central sinus and back out of the bone marrow. Between these two vessel types, bone marrow accomplishes two main tasks: regulating the movement of new blood cells in and out of the marrow and maintaining a supply of stem cells. But it remained unknown where each of these tasks take place and whether there is a division of labor between the two vessel types.
“The bone marrow is like a large corporation with a well-defined organizational chart, but we do not have a seating chart,” said Charles Lin, Ph.D., a professor at Harvard Medical School and one of the senior authors on the paper. Lin compared the stem cell to the company’s CEO; it’s problematic that we don’t yet know where to find or how to get access to the CEO.
To discern which functions are performed in which locations, the group characterized endothelial cells, which form a thin lining within both types of vessels. The researchers used a cell staining technique that highlighted a cellular marker only present on arteriole cells, thereby distinguishing them from sinusoid vessels. It also revealed different shapes of the cells’ nuclei and diameters of the vessels. Stem cells in the sinusoids had high levels of reactive oxygen species—molecules that promote cell differentiation—while stem cells in the arterioles had low levels of reactive oxygen species and higher levels of inactive stem cells. Cell differentiation is required for such stem cells to take on specific roles within the blood, such as red and white blood cells, and platelets.
Imaging in live animals allowed the researchers to see that sinusoids were also more leaky, or permeable, meaning cells could more easily move in and out of the vessel compared to arterioles. Indeed, both mature and immature blood cells migrated in and out of the sinusoid exclusively; no such movement took place in the arteriole. Finally, when the endothelial cells were manipulated to be more permeable, more stem cells differentiated and migrated out of the vessel.
The findings reveal the two vessel types serve two different functions: arteriole vessels maintain the stem cell supply, while sinusoids allow for stem cell differentiation and transport out of the bone marrow. This better understanding of the location of certain vessel functions could help improve stem cell transplant procedures and create ways to encourage successful transplantation, such as increasing or decreasing the permeability of different endothelial cells.
NIBIB funding supported Lin’s contribution to the collaboration, which included imaging the flow rates and permeability of vessels in live mice. “This information is needed if we want to manipulate the bone marrow for therapeutic purposes,” Lin said. He noted the harvesting of stem cells for transplantation to treat leukemia. “Since we know so little about the spatial organization within the bone marrow, focusing our imaging studies on the vasculature is a good place to start,” he said.
Funding for the research included support from NIBIB (EB017274) and the National Heart, Lung, and Blood Institute (HL100402).
1. Distinct bone marrow blood vessels differentially regulate haematopoiesis [http://www.nature.com/nature/journal/v532/n7599/full/nature17624.html]. Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, Ledergor G, Jung Y, Milo I, Poulos MG, Kalinkovich A, Ludin A, Kollet O, Shakhar G, Butler JM, Rafii S, Adams RH, Scadden DT, Lin CP, Lapidot T. Nature. 2016 Apr 21.
—Teal Burrell, special to NIBIB