How Blood Forms In Life’s Earliest Stages
Guillermo Garcia-Cardena, director of the Laboratory for Systems Biology of the Center for Excellence in Vascular Biology at Brigham and Women's Hospital (BWH) and George Q. Daley, MD, PhD, director of the Stem Cell Transplantation Program at Children’s Hospital Boston (CHB), along with scientists from the Indiana University School of Medicine, intrigued by the appearance of blood progenitors in the wall of the developing aorta soon after the heart starts beating, investigated the effects of mechanical stimulation on blood formation in cultured mouse embryonic stem cells.
They showed that shear stress - the frictional force of fluid flow on the surface of cells lining the embryonic aorta - increases the expression of master regulators of blood formation, including Runx1, and of genetic markers found in blood stem cells. Shear stress also increased formation of colonies of progenitor cells that give rise to specific lineages of blood cells (red cells, lymphocytes, etc.). These findings demonstrate that biomechanical forces promote blood formation.
Garcia-Cardena, Daley and colleagues also studied mouse embryos with a mutation that prevented initiation of the heartbeat. These embryos had a sharp reduction in progenitor blood cell colonies, along with reduced expression of genetic markers of blood stem cells. When specific cells from the mutant embryos were exposed in vitro to shear stress, markers of blood stem cells and numbers of blood cell colonies were restored.
Finally, the team showed that when nitric oxide production was inhibited, in both cell cultures and live mouse embryos, the effects of shear stress on blood progenitor colony formation were reduced.
“In learning how the heartbeat stimulates blood formation in embryos, we’ve taken a leap forward in understanding how to direct blood formation from embryonic stem cells in the petri dish,” says Daley, who is also affiliated with the HSCI.
“These observations reveal an unexpected role for biomechanical forces in embryonic development,” adds Garcia-Cardena. “Our work highlights a critical link between the formation of the cardiovascular and hematopoietic systems.”
The authors speculate that drugs that mimic the effects of embryonic blood flow on blood precursor cells, or molecules involved in nitric oxide signaling, might be therapeutically beneficial for patients with blood diseases. For example, nitric oxide could be used to grow and expand blood stem cells either in the culture dish or in patients after transplantation.