10 May 2019

Researchers have completed the first detailed assessment of the mouse bone marrow microenvironment, defining the roles for influential sets of bone marrow cells, it has been announced.

The microenvironment, which makes up less than 1% of the marrow mass in most mammals, is believed to influence the maturation of early haematopoietic stem cells into different types of blood cells.

Scientists at NYU School of Medicine, New York, USA, have used an imaging-mapping tool to painstakingly track the gene expression of 17,374 mouse bone marrow cells, one by one. After excluding all blood cell types and mature fat cells, they focused on the remaining cell types in the marrow microenvironment.

They identified nine types of cells and even more subtypes, most of which were identified as vascular endothelial cells or mesenchymal cells.

Because the function of other rare cells types remained unknown, the team treated the mice with chemotherapy to try to mimic the stress faced by such tissues after injury or with disease. The result was that one set of stem cells which typically develop into osteoblasts or muscle cells only turned into adipocytes. Researchers say this genetic reprogramming possibly explains why the phenomenon of excess marrow fat is seen in leukaemia patients receiving chemotherapy.

They also found that levels of vascular Notch ligand delta-like 4 (Dll4) dropped significantly after chemotherapy, causing a shift in a tiny subset of blood stem cells sensitive to these signals. This suggests that these vascular cells were responsible under normal circumstances for triggering most of the production of T cells and B cells in bone marrow.

The researchers, whose study is published in the journal Nature, believe this is an important advance in the anatomical understanding of essential elements in haematopoiesis.

Senior investigator Professor Iannis Aifantis, of the Department of Pathology at NYU Langone Health and its Perlmutter Cancer Center, said: “Our study represents the first detailed assessment of the bone marrow microenvironment, revealing the critical role of subsets of cells involved in cancer chemotherapy and immune cell production.

“Until now, scientists have often had to rely on observing only the effects of blood cell group actions. These technical advances allow us to get at the underlying processes that cause those effects to happen in real time.”

Co-lead investigator Anastasia Tikhonova, of NYU Langone said: “Our results show how single-cell tracking and analysis can expose the roles of each cell and cell type, not just in orchestrating blood cell production, but also in triggering and propelling other blood-related disease processes in the body, such as leukaemia.”


Source: Tikhonova, A.N., Dolgalev, I., Hu, H., Sivaraj, K.K., Hoxha, E., Cuesta-Domínguez, Á., Pinho, S., Akhmetzyanova, I., Gao, J., Witkowski, M., Guillamot, M., Gutkin, M.C., Zhang, Y., Marier, C., Diefenbach, C., Kousteni, S., Heguy, A., Zhong, H., Fooksman, D.R., Butler, J.M., Economides, A., Frenette, P.S., Adams, R.H., Satija, R., Tsirigos, A., Aifantis, I. (2019) “The bone marrow microenvironment at single-cell resolution”, Nature, available from doi: 10.1038/s41586-019-1104-8


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