BIOMECHANICS

Blood Stem Cells Grow with the Flow

Whether on a run or at rest, the blood pulsing through our vessels seems inextricably linked with our beating hearts. That connection goes back further than you might think.

When the heart starts beating in a tiny embryo, the surging fluid rubbing against the vessel wall conjures the first wave of adult blood stem cells, as if coaxing a genie out of a lamp, two research teams report.

The greater the blood flow, the more blood stem cells form, one group found by using glowing molecular markers in live zebrafish embryos. A precisely tuned flow generated more mouse blood stem cells than a static culture dish of embryonic mouse vessel fragments, the other group showed. This phenomenon likely holds true in humans too, the researchers said.

Photo by Jan Reiss

A chemical screen in zebrafish embryos showed how blood flow could influence the production of embryonic blood stem cells. From there, co–first authors Trista North (center) and Wolfram Goessling (right), working in the lab of Leonard Zon, found that the same biomechanically stimulated pathway also works in mice.

Photo by Jan Reiss (inset courtesy Olaia Naveiras)

The shear stress of blood flow amps up production of embryonic mouse blood stem cells in culture dishes. The finding answers a century-old scientific question and suggests a new way to produce more and better blood stem cells, report co–first authors Olaia Naveiras (inset) and Luigi Adamo (center), who collaborated in the respective labs of George Daley (right) and Guillermo García-Cardeña.

If scientists can figure out how to harness these natural processes, the findings may lead to new ways of making more and better blood stem cells for research and therapy. Boosting the stem cell supply may improve patient outcomes in bone marrow transplants, which are fatal in up to 40 percent of recipients and are only used as a life-saving measure in hematological malignancies, such as leukemia, lymphoma, and other critical blood disorders. In the short term, the papers answer a century-old question about the origins of blood in our bodies.

Stubborn Stem Cells
Hematopoiesis, or blood cell development, is one of the best studied areas in stem cell research. Scientists hope to learn and recapitulate enough of the complex development steps to regenerate a person’s functional blood system. Lessons from blood stem cells will likely lead to advances in other stem cell research. Yet blood stem cells have resisted researchers’ efforts to expand their numbers or to make stem cells in the lab that can last indefinitely in a person.

Until now, stem cell researchers have focused mostly on molecular and genetic cues in stem cell growth. The newfound biomechanical cue was discovered independently by two teams of HMS researchers at Children’s Hospital Boston and Brigham and Women’s Hospital, which published their papers online May 13 in Nature and in the May 15 issue of Cell. Both teams were looking at the earliest adultlike blood stem cells that briefly emerge in the aorta, of all places, during embryonic development. The pattern is remarkably similar in every animal studied for the last 100-plus years, including humans.

Primitive blood cells first form outside the embryo, in the yolk sac, but without the full features of adult stem cells. Then adultlike blood stem cells begin emerging in the aorta just after the heart starts beating, scientists observed in the late 1800s and early 1900s. Quickly, the blood stem cell activity moves to the liver. When bones develop, it finally settles in the marrow, the source of our lifetime supply of the crucial oxygen-carrying, pathogen-fighting cells of the hematopoietic system.

Some experiments in the mid-1960s suggested the aorta was merely a pit stop in the migration of maturing blood stem cells from the outside yolk to the liver. In the mid-1970s, a French lab showed that the first adult blood stem cells did, in fact, first arise inside the embryo and not from the yolk sac.

In the last few months, other researchers have proved that blood stem cells arise from the endothelial vessel lining, which is fleetingly well-endowed with the ability to spawn blood stem cells, rather than from the surrounding vascular muscle or support tissue.

Healing Touch
In the new studies, one group started with the idea that biomechanical forces might explain why stem cells arise in embryonic vessels after the heart starts beating. Co–first authors and international graduate students Luigi Adamo, from Italy, and Olaia Naveiras, from Spain, joined forces from the respective labs of Guillermo García-Cardeña, HMS assistant professor of pathology at BWH, whose lab specializes in how biomechanical forces regulate cell fate decisions, and George Daley, HMS associate professor of biological chemistry and molecular pharmacology at Children’s, whose lab specializes in embryonic hematopoiesis.

A technically difficult series of experiments followed, initially plagued by more failures than successes. Adamo and Naveiras persisted, ultimately showing that the mechanical force could coax blood stem cells from mouse embryonic stem cells. They also showed that biomechanical stimulation could “rescue” hematopoietic activity in vessel fragments from mouse embryos with a fatal genetic defect that prevents their hearts from beating and blood from forming.

This week, Adamo defended his PhD thesis. Naveiras, now a resident in pediatric hematology in Switzerland, graduated with her doctorate from the HMS Biological and Biomedical Sciences program.

The Animal Models
Meanwhile, postdoctoral fellows Trista North and Wolfram Goessling had also been looking for ways to enhance blood stem cells in the lab of Leonard Zon, the Grousbeck professor of pediatrics at HMS and Children’s. In zebrafish, they had screened hundreds of compounds with known biological activity, one third of which were approved human drugs. The first paper on the most active compound in the biological screen, the naturally occurring compound and human drug prostaglandin E2, was published two years ago in Nature.

In an unusually quick transition from the lab to the clinic, a clinical trial testing prostaglandin E2 just enrolled its first patient at Dana-Farber Cancer Institute. The hope is to improve the outcomes of umbilical cord blood transplantation, said principal investigator Corey Cutler, HMS assistant professor of medicine at DFCI and BWH.

The next clue from the screen was not as obvious, but North, now an HMS assistant professor of pathology at Beth Israel Deaconess Medical Center, and Goessling, HMS assistant professor of medicine at DFCI and BWH, soon noticed a common theme among the drugs and other compounds that raised or lowered blood stem cell production: blood flow.

In a series of painstaking experiments in fish and then mice, they found nitric oxide, well known to be stimulated by shear stress, was also key to producing blood stem cells and might be sufficient to expand stem cells without the mechanical flow. In fact, transplantation experiments showed blood stem cells from embryonic vessel walls could not reconstitute the hematopoietic system of adult irradiated mice in the absence of nitric oxide production.

Together, the papers add a new tool for researchers to use in efforts to amplify the numbers and quality of blood stem cells, as well as a long-sought insight into how blood stem cells first arise in embryos.

—Carol Cruzan Morton

For more information, students may contact Guillermo García-Cardeña, guillermo_garcia-cardena@hms.harvard.edu; Leonard Zon, zon@enders.tch.harvard.edu; Trista North, tnorth@bidmc.harvard.edu; or Wolfram Goessling, wgoessling@partners.org.

Conflict Disclosure: Fate Therapeutics (Zon).

Funding Sources: National Institutes of Health, Netherlands Besluit Subsidies Investeringen Kennisinfrastructuur (co-author on Zon paper), Giovanni Armenise-Harvard Foundation (Adamo), Barrie de la Maza Foundation, BurroughsWellcome Fund Clinical Scientist Award in Translational Research (Daley), Howard Hughes Medical Institute (Zon and Daley).

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