Researchers atAlbert Einstein College of MedicineofYeshiva Universityand the Icahn School of MedicineatMount Sinaihave found that macrophages, white blood cells that play a key role in the immune response, also help to both produce and eliminate the body’s red blood cells (RBCs).

The new findings may lead to the development of new therapies for diseases or conditions in which the red blood cell (RBC) production is thrown out of balance. The results of the study, conducted in mice, is published on March 17, 2013 in the online edition of the journalNature Medicine.

“Our findings offer intriguing new insights into how the body maintains a healthy balance of red blood cells,” said study leaderPaul Frenette, M.D.,professor ofmedicineand ofcell biologyand director of theRuth L. and David S. Gottesman Institute for StemCell and Regenerative Medicine Researchat Einstein. “We’ve shown that macrophages in the bone marrow and the spleen nurture the production of new red blood cells at the same time that they clear aging red blood cells from the circulation. This understanding may ultimately help us to devise new therapies for conditions that lead to abnormal RBC counts, such as hemolytic anemia, polycythemia vera, and acute blood loss, plus aid recovery from chemotherapy and bone marrow transplantation.”

Further use:licensingoptions
Einstein has filed a joint patent application withMount Sinairelated to this research, which is currently available for licensing and further commercialization.

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Nurse cells for Erythroblasts
Previous studies, all done in the laboratory, had suggested that macrophages in the bone marrow act as nurse cells for erythroblasts, which are RBC precursors. But just how these “erythroblastic islands” (macrophages surrounded by erythroblasts) function in living animals was unclear.

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A few years ago,Andrew Chow, a Mount Sinai M.D./Ph.D. student in the laboratories of Frenette, andMiriam Merad, M.D., Ph.D., professor of oncological sciences and immunology atMount Sinaifound that bone marrow macrophages express a cell surface (or cell adhesion) molecule called sialoadhesin, or CD169 ? a target that could be used for selectively eliminating macrophages from bone marrow. Doing so would help pinpoint the role of macrophages in erythroblastic islandsin vivo.

Anemia
That’s what Frenette and Merad did in the current study involving mice. They found that selectively eliminating CD169-positive macrophages in mice reduces the number of bone marrow erythroblasts. This evidence suggest that these macrophages are indeed vital for the survival of erythroblasts, which develop into RBCs.

“What was surprising is that we couldn’t see any significant anemia afterward,” Frenette noted. The researchers then analyzed the lifespan of the red blood cells and found that they were circulating for a longer time than usual.

“After we depleted the macrophages in the bone marrow, we discovered that we had also depleted CD169-positive macrophages present in the spleen and liver. It turns out that the macrophages in these two organs are quite important in removing old red blood cells from the peripheral circulation. Taken together, the findings show that these macrophages have a dual role, both producing and clearing red blood cells,” he said.

Polycythemia vera
Researchers also examined the role of macrophages in polycythemia vera, a genetic disease in which the bone marrow produces too many RBCs, typically leading to breathing difficulties, dizziness, excessive blood clotting and other symptoms. Using a mouse model of polycythemia vera, they found that depleting CD169-positive macrophages in bone marrow normalizes the RBC count. “This points to a new way to control polycythemia vera,” Frenette said. “Right now, the standard of care is phlebotomy [the periodic removal of blood], which is cumbersome.”

Macrophage depletion also normalized the erythroid compartment in a JAK2 V617F-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments.These results indicate that CD169-positivemacrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.

The study was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL097700, R01HL069438, and R01HL116340); the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056638); and the National Cancer Institute (R01CA112100), all part of the National Institutes of Health.

For more information
– Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y, Pinho S, Leboed M, Noizat C, van Rooijen N, Tanaka M, Zhao ZJ, Bergnan A, Merad M, Frenette PS. CD169+macrophages provide aniche promoting erythropoiesis under homeostasis andstress.Nat Med. 2013 Mar 17. doi: 10.1038/nm.3057. [Epub ahead of print][Abstract]
– Jiang K.Red blood cell production relies on white blood cell help, Nature Medicine |Spoonful of Medicine (Blog) ; March17, 2013.
– McLornan D, Percy M, McMullin MF. JAK2 V617F: A Single Mutation in the Myeloproliferative Group of Disorders.Ulster Med J 2006; 75 (2) 112-119

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