Blood-forming stem cells, which reside in their bone marrow niches and give rise to the entire immune system, are continuously woken up to replenish the blood with mature cells that have a finite life span. The wake up call can come in the form of reactive oxygen molecules called free radicals, produced in the mitochondria as a byproduct of the manufacture of cellular fuel. Our team has now discovered a mechanism that sends an awakening message to these stem cells via the mitochondria.

The heart of the message is a protein known as MTCH2 – or “Mitch,” as the scientists call it – which sits on the membranes of mitochondria and acts as a molecular switch. When we discovered MTCH2 more than a decade ago, we showed that this protein can function as a receptor that regulates cellular suicide: Under conditions of severe stress, “Mitch” conveys a suicide message that prompts the mitochondria to develop holes and disintegrate, ultimately causing the cell to die. In the new study, postdoctoral fellow Dr. Maria Maryanovich and other members of the lab – Dr. Yehudit Zaltsman and Ph.D. students Antonella Ruggiero and Andres Goldman – found that in blood-forming stem cells, MTCH2 has an additional role: It suppresses the activity of the mitochondria for as long as the cells need to remain in their dormant state.

When we created genetically engineered mice that lacked MTCH2 in their entire blood system, we found that the mitochondria in the blood-forming stem and progenitor cells underwent major changes. These organelles more than doubled in size, and their activity increased almost four-fold. As a result, the stem cells became activated, apparently awoken by the free radicals generated in the mitochondria. The cells left their niches and began to mature in such large numbers that their supply in the bone marrow was exhausted. These findings suggest that enhancing the activity of the mitochondria (by decreasing MTCH2) can awaken the stem cells when their supply is needed.
This clever control mechanism of the stem cell cycle – awakening the cells by enhancing their metabolism – ensures that the cells have sufficient energy for growing and maturing. Just as a traveler who wakes up in the morning won’t survive a long journey without essential provisions, so sleepy stem cells need energy to survive their new journey after having been awoken. We have found that turning on mitochondria metabolism supplies the cells with precisely such energy.” Taking part in the study were Dr. Smadar Levin Zaidman of Chemical Research Support, Dr. Ziv Porat of the Biological Services Unit and Prof. Tsvee Lapidot and Dr. Karin Golan of the Immunology Department.

In addition to shedding new light on the basic biology of the stem cell cycle, our study may lead to new ways of controlling the activity of stem cells in research and in the clinic. The findings suggest that it may be possible to wake up stem cells by altering their metabolism rather than by manipulating their genes, as is done today. In addition, the findings open up a new avenue of research into leukemia. They suggest that defects in the control of cellular metabolism in blood-forming stem cells and at various stages of their maturation may lead to the abnormal cellular proliferation observed in leukemia. If this is indeed found to be the case, it may be possible to treat leukemia by correcting such metabolic defects.