Blood grows when it flows

The physical forces exerted by a heart beat and the blood flow it produces trigger the formation of new blood cells, according to two studies published today (May 13) in Nature and Cell. Cluster of blood cells developing afterexposure to shear stressImage: Luigi Adamo, Ph.D. student inthe García-Cardeña lab at Harvard"It's very exciting work," said embryologist linkurl:Mary Dickinson;http://www.bcm.edu/db/db_fac-dickinson.html at Baylor College of Medicine in Houston, who was not in

Jef Akst

| 3 min read

The physical forces exerted by a heart beat and the blood flow it produces trigger the formation of new blood cells, according to two studies published today (May 13) in Nature and Cell.

Cluster of blood cells developing after
exposure to shear stress
Image: Luigi Adamo, Ph.D. student in
the García-Cardeña lab at Harvard

"It's very exciting work," said embryologist linkurl:Mary Dickinson;http://www.bcm.edu/db/db_fac-dickinson.html at Baylor College of Medicine in Houston, who was not involved in the research. "It's clear that mechanical forces can regulate pathways leading to differentiation that originally were only thought to be controlled by cell-to-cell signaling." Hematologist linkurl:Leonard Zon,;http://www.childrenshospital.org/cfapps/research/data_admin/Site228/mainpageS228P0.html director of the Stem Cell Program at Children's Hospital Boston, and colleagues screened a library of more than 2,500 chemicals for their effects on hematopoietic stem cell (HSC) production in thousands of zebrafish embryos. The group observed a direct correlation between a chemical's effect on blood flow and the number of HSCs in the organism: Compounds that enhanced blood flow boosted HSC numbers in the aorta, while compounds that diminished blood flow decreased the number of HSCs, they report in Cell. Results from a mutant zebrafish that never develops a heart beat -- called silent heart (sih) -- further supported the role of circulation in HSC development. sih mutants had lower expression levels of known blood stem cell markers than healthy zebra fish, suggesting that in the absence of a heartbeat, they developed fewer HSCs. In the Nature study, stem cell biologist linkurl:George Daley;http://daley.med.harvard.edu/ of the Harvard Stem Cell Institute and Children's Hospital Boston, and colleagues found similar biomechanical effects on hematopoietic precursor cells derived from mouse embryonic stem cells. They used a spinning cone-like device that propelled fluid over the cultured cells to simulate shear stress, the force that results from the friction between the blood and the wall of the blood vessel. Sheer stress -- one of several physical forces that results from circulation -- leads to enhanced blood development, they found. "One of the long term goals of stem cell research is to understand how the embryo patterns the formation of different tissues," Daley said. If blood stem cells can be generated in the lab, "we might be able to treat patients who have genetic or malignant blood diseases." Additionally, both studies suggested that nitric oxide (NO), a known modulator of hematopoiesis, may help convert the physical forces associated with blood flow into chemical signals that initiate blood cell differentiation. In zebrafish embryos, compounds that increased NO levels in the cell enhanced HSC formation -- even restoring the phenotype of the sih embryos to that of wild type zebrafish -- while in both zebrafish and mouse embryos as well as mouse cell cultures, NO inhibitors stunted HSC development. Unlike the other chemicals tested in Zon's screen, NO triggered these changes in HSC development even when administered before circulation began. This suggests that NO acts as an early signal that initiates the rest of the pathway, possibly by translating the physical forces produced by blood flow into changes in HSC formation.

Zebrafish embryo with experimentally enhanced NO levels shows
increased blood flow and elevated blood stem cell formation
Image: Trista North, Harvard

"The hope is that if we could find all the factors that an embryo needs to make blood stem cell, we would be able to convert the embryonic stem cells into a clinically useful product," said Zon. Furthermore, the two studies offer an answer to a question that has long stumped embryologists: why do HSCs originate in the aorta? Until the heart starts beating, red blood cells in the yolk sac deliver oxygen to the developing embryo, but once those blood cells die off, the embryo needs a new source of blood production. "The beauty of all this is the timing of circulation," Zon said. "The embryo waits until circulation has been established [to start making adult blood stem cells], and it knows circulation has been established because it's in the aorta, the best place to recognize a change a blood flow."
**__Related stories:__***linkurl:Blood cells filmed in formation;http://www.the-scientist.com/blog/display/55414/
[11th February 2009]*linkurl:The placental origin of HSCs;http://www.the-scientist.com/blog/display/54404/
[5th March 2008]*linkurl:Drug fishing;http://www.the-scientist.com/article/display/54781/
[July 2008]