The blood stem cells that live in bone marrow divide and send their progeny down various pathways that ultimately produce red cells, white cells and platelets. These “daughter” cells must be produced at a rate of about one million cells per second in order to constantly replenish the body’s blood supply.
A nagging question is how these stem cells to persist for decades even though their progeny last for days, weeks or months before they need to be replaced. A study from the University of Pennsylvania has uncovered one of the mechanisms, and these cellular mechanisms allow these stem cells to keep dividing in perpetuity.
Dennis Discher and his colleagues in the Department of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science found that a form of a protein called “myosin,” the motor protein that allow muscles to contract, helps bone marrow stem cells divide asymmetrically. This asymmetric cell division helps one cell remains a stem cell while the other cell becomes a daughter cell. Discher’s findings might provide new insights into blood cancers, such as leukemia, and eventually lead to ways of growing transfusable blood cells in a laboratory.
The participants in this study were members of the Discher laboratory, which include lead author Jae-Won Shin, Amnon Buxboim, Kyle R. Spinler, Joe Swift, Dave P. Dingal, Irena L. Ivanovska and Florian Rehfeldt. Discher collaborated with researchers at the Univ. de Strasbourg, Lawrence Berkeley National Laboratory and Univ. of California, San Francisco. This paper was published in Cell Stem Cell.
“Your blood cells are constantly getting worn out and replaced,” Discher said. “We want to understand how the stem cells responsible for making these cells can last for decades without being exhausted.”
Presently, scientists understand the near immortality of hematopoietic stem cells (HSCs) as a result of their asymmetric cell division, although how this asymmetric cell division enables stem cell longevity was unknown. To ferret out this mechanism, Discher and his coworkers analyzed all of the genes expressed in the stem cells and compared them with the genes expression in their more rapidly dividing progeny. Those proteins that only went to one side of the dividing cell might play a role in partitioning other key factors responsible for keeping one of the cells a stem cell and the other a progeny cell.
One of the proteins that showed a distinct expression pattern was the motor protein myosin II, which has two forms, myosin A and myosin B. Myosin II is the protein that enables the body’s muscles to contract, but in nonmuscle cells also it used during cell division. During the last phase of cell division, known as cytokinesis, myosin II helps cleave and close off the cell membranes as the cell splits apart.
“We found that the stem cell has both types of myosin,” Shin said, “whereas the final red and white blood cells only had the A form. We inferred that the B form was key to splitting the stem cells in an asymmetric way that kept the B form only in the stem cell.”
With these myosins as their top candidate, Discher and others labeled key proteins in dividing stem cells with different colors and put them under the microscope.
“We could see that the myosin IIB goes to one side of the dividing cell, which causes it to cleave differently,” Discher said. ”It’s like a tug of war, and the side with the B pulls harder and stays a stem cell.”
The researchers then performed in vivo tests using mice that had human stem cells injected into their bone marrow. By genetically inhibiting myosin IIB production, Shin and others saw the stem cells and their early progeny proliferating while the amount of downstream blood cells dropped.
“Because the stem cells were not able to divide asymmetrically, they just kept making more of themselves in the marrow at the expense of the differentiated cells,” Discher said.
Discher and his team then used a drug that temporarily blocked both myosin A and myosin B. They observed that myosin inhibition increased the prevalence of non-dividing stem cells, blocking the more rapid division of progeny.
Discher believes that these findings could eventually help regrow blood stem cells after chemotherapy treatments for blood cancers or even grow blood products in the lab. Finding a drug that can temporarily shut down only the B form of myosin, while leaving the A form alone, would allow the stem cells to divide symmetrically and make more of themselves without preventing their progeny from dividing themselves.
“Nonetheless, the currently available drug that blocks both the A and B forms of myosin II could be useful in the clinic,” Shin said, “because donor bone marrow cultures can now easily be enriched for blood stem cells, and those are the cells of interest in transplants. Understanding the forces that stem cells use to divide can thus be exploited to better control these important cells.”