Scientists at the University of Wisconsin School of Medicine and Public Health have used human stem cells to make blood-forming cells and demonstrated that they can function as lymphoid precursors, or the earliest cells from which various immune cells arise.
These findings may be helpful for treating a variety of blood cancers, according to Igor Slukvin, MD, PhD, professor of pathology and laboratory medicine, and lead scientist of the research studies.
“Among the vast potential of human pluripotent stem-cell research is a possibility of using them for manufacturing off-the-shelf blood products for treating cancer and genetic diseases,” he said. “To achieve this goal, it is critical to identify how nature makes blood cells and apply this knowledge as a tool to make blood cells in a culture dish.”
Slukvin and his colleagues’ work was recently published in the journal Nature Communications.
During embryonic development, blood cells emerge from vessels at several sites inside and outside the embryo, like the embryonic aorta and yolk sac, respectively, by budding from a unique population of hemogenic endothelial cells.
Although blood production through hemogenic endothelium occurs in different types of vasculature such as arteries, veins and capillaries, cells with the ability to become lymphoid and hematopoietic stem cells arise only from hemogenic endothelium, the special cells lining the arteries.
To explore whether arterial programming can produce the arterial type of hemogenic endothelium with lymphoid potential from human pluripotent stem cells, Slukvin’s team focused attention on a NOTCH signaling that cells use to communicate genetic information that lead to establishing arterial programming in endothelial cells.
Using a chemically defined differentiation system combined with the use of the protein DLL1-Fc and small molecule DAPT to manipulate the NOTCH pathway in chemically defined conditions, the researchers produced an arterial type of hemogenic endothelium that could be manipulated to create lymphoid cells and adult-type blood cells.
These studies also revealed an important link between program regulating arterial and lymphoid development from pluripotent stem cells, according to Slukvin.
Hemogenic endothelium is a unique population of endothelial cells, which is distinct from non-hemogenic endothelium, he said.
However, it was not clear whether hemogenic endothelial cells similar to non-hemogenic endothelium undergo specification to arterial fate and whether this atrial specification is important to establish a lymphoid program.
“In this work we demonstrated a direct link between arterial-type hemogenic endothelial progenitor and definitive hematopoiesis,” Slukvin said. “These findings are important because we can now apply known pathways regulating arterial specification to improve production of lymphoid and hematopoietic stem cells from pluripotent stem cells for cancer therapies.”
The research was conducted under the umbrella of the Progenitor Cell Biology Consortium, run by the National Heart, Lung and Blood Institute, and involved a collaboration of scientists at UW-Madison, Morgridge Institute, Harvard Medical School and Fred Hutchinson Cancer Research Center.
It is also supported by The Charlotte Geyer Foundation.
The leading UW authors, in addition to Slukvin, include Gene Uenishi, Ho Sun Jung and Akhilesh Kumar.