For most of the tissues in the human body, the anatomy of cell differentiation is known. This is not true, however, for bone marrow. One of the reasons lies in the complexities that surround the differentiation of myeloid progenitor cells into the diverse population of innate immune cells, or myelopoiesis. Now, a team has developed approaches for imaging myelopoiesis in mice. In turn, they used a combination of cell-by-cell analysis techniques to build the first “atlas” of bone marrow tissue showing the differentiation of granulocytes, monocytes, and dendritic cells. The findings advance scientific understanding of how tiny blood vessels organize the bone marrow and regulate how blood gets produced.

This research is published in Nature, in the article, “In situ mapping identifies distinct vascular niches for myelopoiesis.

“We finally have the tools to directly observe bone marrow cell differentiation. These results show that the bone marrow is a highly organized tissue and that this organization is provided by specific subsets of vessels,” said Daniel Lucas, PhD, assistant professor at Cincinnati Children’s Medical Center. “This is telling us that the organization of the vasculature dictates blood production. If we determine how the vessels function we will be one step closer to controlling the production of specific blood cells at will.”

Researchers at Cincinnati Children’s and other major centers have been producing a growing library of “maps” that describe human tissue development in unprecedented detail. This effort is known as the Pediatric Cell Atlas project. Making this bone marrow atlas required the development of novel confocal imaging methods for unprecedented resolution of blood cells in the marrow.

Until now, tracing the lineage of cell types during stages of development required destroying the tissue. In this project, the team developed ways to image and trace for the first-time unique progenitors within the larger mass of bone marrow cells—without destroying the tissue structure.

“Tracking these special cell clusters revealed new information about the structure of bone marrow,” Lucas said, “including the insight that the bone marrow has a surprising degree of organization and that specific blood vessels support the production of unique blood cell types.”

More specifically, the team found that the generation of granulocytes and dendritic cells–monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures.

They wrote that “acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated.”

The data, they said, indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.

Translational applications 

It typically takes several years of further research to translate basic science discoveries into practical applications. One potential direction for this line of study could be to support future development of highly customized blood cell factories that would mimic bone marrow function in laboratory settings.

Such blood organoids could be used to produce populations of blood cells with specific genetic variations, which scientists could analyze to develop improved treatments for disease. For example, a controlled method of blood cell production would be useful to scientists studying the immune system and how bodies defend themselves against infection, Lucas said.

Eventually, blood organoids might become a form of treatment themselves by allowing clinicians to replace a patient’s diseased cells with gene-edited healthy cells that face no risk of rejection. Having a new understanding of how blood cells are produced in the bone marrow will help this effort.

“This certainly has implications for generating blood organoids,” Lucas said. “The groups working on blood organoids have been trying to produce organoids that can maintain or expand stem cell production. Our data indicate that additional structures are needed to produce mature blood cells in a balanced manner.”

More study is needed to identify the molecular signals produced by the different blood vessels that regulate production of each type of blood cell. Knowing those signals will be a crucial step in regulating blood cell production.

Meanwhile, the research team plans to continue its work developing tools to image blood cell production, especially to expand imaging to earlier-stage progenitors.

“We want to be able to visualize every step in the production of the different types of blood cells,” Lucas said.