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Blood, Immune Cell Formation in Fetal Bone Marrow Detailed in Cell Atlas Effort

NEW YORK — Researchers have mapped out how the blood and immune systems develop within prenatal bone marrow using single-cell omic approaches.

As part of the Human Cell Atlas, an international consortium started in 2016 with the goal of creating reference maps for all cell types, scientists previously examined how hematopoiesis first occurs in the yolk sac and liver. Now, researchers have examined how its development continues in prenatal bone marrow, which then produces blood and immune cells for the rest of individuals' lives.

But disturbances to the establishment of hematopoiesis can lead to an increased risk of immune disorders and leukemia, something that is more common among individuals with Down syndrome.

To map the development of blood and immune systems, researchers from the Wellcome Sanger Institute and elsewhere profiled cells found within fetal bone marrow from more than a dozen fetuses, including four with Down syndrome. As they reported this week in Nature, the researchers found that blood and immune cells quickly diversify within the bone marrow, within six to seven weeks in the second trimester of pregnancy, and the balance of cells produced differs from that seen in fetal liver.

"However much we may have thought that we understood the immune system, it is actually far more complex than we had realized," co-senior author Muzlifah Haniffa from the Sanger Institute and Newcastle University said in a statement. "Data like this provides the resolution needed to properly understand what is happening at a molecular level during development."

To develop their atlas, the researchers analyzed single bone marrow cells collected from nine fetuses between 12 and 19 weeks of age post-conception and four samples from fetuses with Down syndrome.

In all, they generated data on nearly 116,000 different cells, including mRNA and epitope data, which they compared to single-cell reference data from cord blood, yolk sac, and fetal liver samples.

The researchers found that the portion of blood and immune cells, in relation to stromal cells, increases quickly between 12 and 19 weeks post-conception. Before then, the ratio of blood and immune cells to stromal cells is 5:1 but increases to 18:1. The number of B lymphoid cells in particular increased in comparison to age-matched fetal liver samples. These cells, the researchers noted, are needed to both respond to infections and mount a vaccine response.

Additionally, myeloid cells were more expanded among fetal bone marrow than in yolk sac or fetal liver, and granulocyte and monocyte precursor cells in fetal bone marrow expressed higher levels of CEBPA, a neutrophil specification, as compared to SPI1, a monocyte specification, than in fetal liver.

The researchers noted the emergence of plasmacytoid cells and natural killer cells within fetal bone marrow in addition to the development of B cells.

At the same time, the researchers uncovered differences between Down syndrome and disomic bone marrow samples. For instance, as compared to age-matched samples, Down syndrome bone marrow samples had lower levels of megakaryocytes and B cell lineages and an enrichment of erythroid cells. Down syndrome bone marrow samples additionally overexpressed chromosome 21 transcription factors with roles in hematopoiesis.

"We know that children with Down syndrome have a higher risk of developing leukemia but we don't know why," co-senior author Irene Roberts from the University of Oxford said in a statement. "This study characterizes some of the differences in gene expression in their bone marrow, which will allow us to start figuring out whether these differences are significant and in what way. We hope this will ultimately help researchers develop better ways of treating, or even preventing, leukemia in these children."