U of M researchers identify a protein that is important for blood-forming stem cell division

Researchers at the University of Michigan have discovered a protein called Lkb1, which is known to regulate cellular metabolism, is also necessary for normal cell division in blood-forming stem cells. Loss of the protein results in an abnormal number of chromosomes and a high rate of cell death. This finding demonstrates that stem cells are metabolically different from other blood-forming cells, which can divide without Lkb1. This metabolic difference could someday be used to better control the behavior of blood-forming stem cells used in disease treatments.

Sean Morrison, director of the U-M Center for Stem Cell Biology (based at the Life Sciences Institute), and Howard Hughes Medical Institute researcher said “This raises the possibility that, in the future, we may be able to modulate stem cell function –when treating degenerative diseases or when performing cell therapies—by altering the metabolism of the cells… It opens up a whole new area of inquiry that, until now, had not been recognized.”

Lkb1 is a protein kinase that acts as a “tumor suppressor.” A “kinase” is a molecule that attach phosphates to other molecules.  Creatine kinase, for example, attaches phosphate groups to creatine to form phosphocreatine.  Tumor suppressor gene products regulate cell growth and proliferation and loss of function of these gene products causes cells to grow uncontrollably. Lkb1 helps coordinate cellular metabolism with cell growth, and it does this in combination with another protein kinase called AMPK. Together, these two kinases help maintain a balance between a cell’s internal energy production and the process of cell division. They send signals to halt division when a cell lacks the energy needed to execute the process. Few studies have examined stem cell metabolism. There’s been a widespread assumption among biologists that basic metabolic processes are broadly similar in most cell types.

In many types of cells, deletion of the genes that encode Lkb1 and AMPK leads to tissue overgrowth and the formation of tumors, presumably because the cells no long receive signals telling them to stop dividing. Morrison’s team have deleted the two genes in blood-forming stem cells of mice—the first time these genes have been “knocked out” in stem cells—then observed and measured the effects. Their results are reported in the Dec. 2 edition of the journal Nature.

“One obvious prediction you’d make, based on the outcome of previous studies, is that the cells would start to hyper-proliferate,” said Daisuke Nakada, a research fellow at the U-M Life Sciences Institute and first author of the Nature paper. “But that’s not what we saw at all,” Morrison said. “Deletion of the Lkb1 gene induced cell death in blood-forming stem cells, and the cells disappeared faster than anything we’ve ever seen before.”

The observed cell death is likely due to defects in energy production within the stem cells, as well as another effect observed by Morrison’s team. They found that knocking out the Lkb1 gene derailed the cell division process; it led to unhealthy daughter cells with the wrong number of chromosomes. Normal cell division, or mitosis, results in the separation of replicated chromosomes and the formation of two daughter nuclei with identical sets of chromosomes and genes. Inside the dividing cell’s nucleus, a structure called a mitotic spindle pulls chromosomes into the daughter cells in an orderly fashion.

Morrison’s team found that deleting Lkb1 resulted in mitotic chaos. Multiple mitotic spindles formed, pulling the chromosomes into a tangled mess. “The cells that survive this mayhem have an abnormal number of chromosomes, which we think leads to the death of a lot of cells,” Morrison said.  Thus Lkb1 is acutely required for blood-forming stem cells to divide properly.

Australian group discovers interaction between stem cells and their progeny

Australian stem cell researchers at the Walter and Eliza Hall Institute in Melbourne have shown that mature blood cells can communicate with, and influence the behavior of, their stem cell ‘parents’. The discovery of a blood cell ‘feedback loop’ in the body opens up new avenues of research into diseases caused by stem cell disorders, and the potential for new disease treatments. This research was led by Carolyn de Graaf and Doug Hilton from the Molecular Medicine division and Warren Alexander from the Cancer and Hematology division led the research.

These findings reveal a relationship between the blood cells that wasn’t known to exist until now. Doug Hilton said, “We know that blood stem cells give rise to all the mature blood cells, but the standard assumption was that external factors control blood cell production and the two populations exist in isolation… “This study shows that the mature cells actually communicate back to the stem cells, changing their gene expression and influencing their behavior.”

Blood cell disorders can cause disturbances in the feedback loop, with profound effects on the blood stem cells. This group initially examined the effects of the loss of the Myb gene. This vitally essential gene encodes a transcription factor that represses platelet production. Loss of the Myb gene caused laboratory animals to have very high numbers of platelets in their blood, which caused changes in the signaling pathways that control stem cell maintenance. Rather than being maintain in a resting state, the stem cells continually cycled and produced mature blood cells. The stem cells were eventually exhausted and blood disorders developed because there were not enough stem cells to produce new red and white blood cells.

This research team utilized new generation genomic technologies to identify gene signatures in the blood stem cells that were caused by defective signaling. They then used these gene signatures to diagnose the disease. They postulate that such molecular signatures could be eventually used to diagnose and treat blood-based diseases.

Carolyn de Graaf noted that “If we can understand the genes important for stem cell maintenance and blood cell production, then we can start to look at ways of improving transplantation techniques and therapies for blood disorders.”

Patients with stem cell failures could also potentially benefit. What to do next is to determine whether some of these stem cell failures are due to miscommunication between mature blood cells and stem cells. This might lead to new ways to treat these disorders down the track.