All blood and immune cells are formed from blood stem cells, which can develop into many different cell types. During fetal development, this ability is particularly important because the body needs to rapidly build a functioning blood and immune system. In practice, this may mean that the cells’ DNA is organized differently, allowing greater flexibility between different lineages and enabling the cells to adapt more easily to the body’s needs.
“It has long been known that blood formation differs between fetal life and adulthood, but we know less about what controls these differences at the cellular level,” says Sara Palo, doctoral student at the Stem Cell Center, Lund University.
To investigate this, the research group analyzed hematopoietic stem and progenitor cells –blood-forming cells on their way to becoming specialized – from an early developmental stage. They also mapped how the genome was organized in the cells and compared the results with corresponding cells from adults.
“We looked at how DNA is organized in the cells – what is known as chromatin. When DNA is more loosely packed, it becomes easier for the cell to activate different genes,” Sara Palo continues.
What is new about the study is that the researchers have been able to study blood formation very early in development, during the first trimester, when the blood and immune systems are still being established. Moreover, they have studied blood-forming cells at an immature stage, before they become more specialized. The study, which is part of Sara Palo’s doctoral research, shows that blood-forming cells during early development differ substantially from those in adults. Some immature immune cells do not appear to be as clearly committed to the B cell lineage as corresponding cells in adults. Instead, they retain greater flexibility and may still develop along other paths.
“You may think of it as a kind of hybrid programme. The cells are not yet locked into a single cell fate and this flexibility appears to be important as the immune system is formed,” says Charlotta Böiers, research group leader at Lund University.
But this flexibility may also involve vulnerability. The researchers link this to the gene PAX5, which is central to B-cell development. The fact that PAX5 is regulated differently during early development may help explain why certain genetic changes behind acute lymphoblastic leukemia can arise before birth. If a leukemia-driving mutation occurs during fetal life, it may have different consequences than if it affects a more restricted adult cell.
“The study provides a detailed picture of how blood stem cells change from an early developmental phase to adulthood. By understanding how the cells’ genetic programmes are regulated during development, we hope to gain new insights into both normal blood formation and diseases that originate early in life,” Charlotta Böiers concludes.
Publication in Blood Advances: Chromatin Accessibility Shapes Developmental-Specific Lineage Plasticity in Hematopoiesis
Sara Palo will defend her doctoral thesis on 5 November: The fetal hematopoietic progenitor compartment and the initiation of childhood leukemia.