Johns Hopkins researchers have discovered the earliest form of humanblood stem cells and deciphered the mechanism by which these embryonicstem cells replicate and grow. They also found a surprising biologicalmarker that pinpoints these stem cells, which serve as the progenitorsfor red blood cells and lymphocytes.
The biochemical marker, angiotensin-converting enzyme (ACE), is wellknown for its role in the regulation of blood pressure, blood vesselgrowth, and inflammation. ACE inhibitors are already widely used totreat hypertension and congestive heart failure, and the findings are,the researchers say, likely to hold promise for developing newtreatments for heart diseases, anemias, leukemia and other bloodcancers, and autoimmune diseases because they show for the first timethat ACE plays a fundamental role in the very early growth anddevelopment of human blood cells.
"We figured out how to get the 'mother' of all blood stem cellswith the right culture conditions," says Elias Zambidis, M.D., Ph.D.,of the Institute of Cell Engineering at the Johns Hopkins UniversitySchool of Medicine and the Division of Pediatric Oncology at the SidneyKimmel Comprehensive Cancer Center at Johns Hopkins.
"There is real hope that in the future we can grow billions of bloodcells at will to treat blood-related disorders, and just as criticallyif not more so, we've got ACE as a 'new' old marker to guide ourwork," Zambidis adds.
Researchers did not expect ACE to have a role in blood stem cells, henotes, "but were very pleasantly surprised to discover it as a beaconfor finding the earliest blood stem cells known, as well as new ways tofind and manipulate this marker to make them grow."
The team's findings, published Aug. 26 in the online edition of thejournal Blood, explain that these earliest stem cells marked by ACE,called hemangioblasts, first arise normally in the developing humanfetus, when a woman is three or four weeks pregnant. Hemangioblasts cannow be derived in unlimited supply experimentally from cultured humanembryonic stem cells, which are the origin of all cell types in thebody. These hemangioblasts go on to become either blood cells orendothelial cells, which form the inner lining of the heart, veins andarteries, and lymph vessels.
The research grew out of Zambidis' interest in understanding thecomplex biological processes of blood development and the transformationof embryonic stem cells into the various types of cells that make up thehuman body.
Hemangioblasts make the body's earliest form of blood in the fetalyolk sac, which nourishes a fertilized egg, and later in the fetal liverand bone marrow.However, because human embryonic cells disappear early in gestation,their role in the early production of blood could not, to theresearchers' knowledge, be studied in humans because scientists had noway to identify these human progenitor blood stems cells to follow theirdevelopment. The scientists suspected they existed in humans, however,because they have been found in mice and zebra fish.
To find the blood stem cell, Zambidis' team grew human embryonic stemcells in culture and fed them growth factors over 20 days. Each time thecell colonies expanded, the researchers sampled individual cells,searching for ones capable of making both endothelial and blood cells,the hallmark of hemangioblasts.
They plucked the newly discovered hemangioblasts from culture dishes,grew them in conditions that Zambidis and his team developed to speedreplication, and tested cells for their ability to make endothelial andblood cells. Cells capable of making endothelial cells and all theelements of blood (platelets, and white and red cells) were specificallymarked with ACE on their outer surface.
The researchers found not only that ACE was a marker forhemangioblasts, but turning off the enzyme also helps guide the cells'replication and maturation into either blood or endothelial cells. Bytreating the hemangioblasts with losartan, an ACE pathway blocking agentroutinely used to treat high blood pressure, dramatically increased therate of blood cell production.
The next step, Zambidis adds, is to test this research in animal modelsand show that "we can make lots and lots of blood cells from humanstem cells for transfusions, regenerate new vascular trees for heartdiseases, as well as create test tube factories for makingtransplantable blood cells that treat diseases. We are very far fromtreatment," Zambidis cautions, "but this is a big step."
If the new technique of mass producing progenitor blood cells iseventually proven to work in humans, it would allow patients gettingbone marrow transplants to have their own stem cells creating the bloodthey need, significantly reducing rejection risk.