Melatonin may help boost the success of bone marrow transplants

The hormone that tells an organism when it is dark and prepares us for sleep also regulates the supply of stem cells in the bone marrow, according to a study involving Brazilian researchers.

By Elton Alisson  |  Agência FAPESP – Already used to treat sleep disorders and targeted in clinical trials to combat cancer and other diseases, melatonin can also help boost the success of bone marrow transplants. The hormone is produced at night by the pineal gland in the brain and performs the function of telling the organism that it is dark and preparing us for nocturnal rest. Now researchers have discovered that melatonin also regulates the availability of stem cells in the bone marrow.

The scientists who made the discovery are affiliated with the University of São Paulo’s Bioscience Institute (IB-USP) in Brazil, Israel’s Weizmann Institute of Science, and institutions in six other countries. Resulting from a research project supported by FAPESP, the study is published in the journal Cell Stem Cell.

“We discovered that stem cell proliferation and release decrease during the day, while at night, these cells are stockpiled in the bone marrow, and the melatonin produced by the organism after dark is responsible for this difference,” Regina Pekelmann Markus, a full professor at IB-USP and principal investigator for the project, told Agência FAPESP.

“The discovery suggests that the stem cell collection time may influence the success of bone marrow transplants for cancer treatment.”

Markus’s research group at IB-USP focuses on the links between melatonin and control of the immune system, referred to by Markus as the immune-pineal axis. The Weizmann group, led by Professor Tsvee Lapidot, focuses on stem cell mobilization and the role of the bone marrow in the immune system.

Previous research led by Markus had already shown that melatonin controls the flow of blood cells to healthy and infected tissue. In the case of infection, nocturnal production of melatonin is blocked, and defense cells invade the infected tissue.

The Israeli researchers observed that the progenitor cells that can differentiate into defense cells are protected by macrophages (immune system cells) in bone marrow niches. The progenitor cells continually detach themselves from these niches, proliferate, and differentiate into blood and bone cells. This ability explains their use in the treatment of cancer and other diseases.

“We performed several experiments showing that the release and proliferation of these cells, as well as their storage in bone marrow niches, are mediated by melatonin, which acts on the macrophages,” Markus said.

In the new study, the researchers measured the quantity of stem cells in the bone marrow of mice during a 24-hour period. Their analysis showed that the production of these cells peaked twice daily at 11 a.m. and 11 p.m., and the peaks were regulated by the transition between light and dark.

The stem cell production peaks were driven by increases or decreases in the levels of two substances in the bone marrow of the mice: norepinephrine (NE) and tumor necrosis factor (TNF).

“We found that TNF, which is known to cause cell death and inflammation, acts as a physiological signal for the production of melatonin in the bone marrow. This molecule appears during the transition from day to night, and vice-versa, creating peaks in the production of progenitor stem cells,” Markus said.

“The secretion of NE and TNF in the bone marrow induces cell proliferation, and this explains the two peaks of intense production, one during the day and the other at night. However, melatonin then comes into play. During the day, only local melatonin is present, and the cells leave the bone marrow and move into the bloodstream.”

When the researchers blocked NE and TNF in the mice, the peaks in the production of bone marrow stem cells vanished, suggesting that these molecules are essential for the production of undifferentiated or mature cells, depending on the time of day.

“At around 11 a.m., the bone marrow stem cells proliferate and differentiate into blood cells. They proliferate again at around 11 p.m., but in this case, they are stockpiled in bone marrow niches. This explains the daily cycle of production and replenishment of these cells in the bone marrow,” Markus said.

Transplantation strategies

In another experiment, the researchers injected melatonin into mice during the day to see if it was possible to invert the stem cell production peaks. The results confirmed this possibility. The typical nocturnal peak, during which large amounts of undifferentiated stem cells were produced, occurred in the morning instead.

When stem cells produced at night were transplanted into mice, they were found to be twice as efficient as stem cells collected during the morning peak.

“These findings can lead to strategies designed to increase the efficiency of stem cell collection for bone marrow transplants in humans,” Markus said.

One such strategy would consist of collecting stem cells from a donor’s bone marrow during the day because cells collected at night move more quickly to the bone marrow, where they are anchored and stored in niches. Another approach would be to treat bone marrow donors with melatonin before the transplant or with other molecules that regulate the light-dark cycle.

“The priority in a bone marrow transplant is to collect stem cells from the donor and have them mobilize as fast as possible in the recipient. We found that injecting melatonin during the day helps achieve this goal,” Markus said.

“The use of bone marrow stem cells in transplants could be controlled pharmacologically by means of the application of melatonin.”

Markus added that among the questions now being investigated by the group is how the bone marrow “knows” whether it is light or dark using TNF.

“We know about the influence of melatonin, but we want to find out whether it comes from the pineal gland in the brain and is conveyed to the bone marrow in the bloodstream or is produced locally in the bone marrow itself,” she said.

The article “Daily onset of light and darkness differentially controls hematopoietic stem cell differentiation and maintenance” (doi: 10.1016/j.stem.2018.08.002) by Karin Golan, Tsvee Lapidot, Regina P. Markus, et al. can be read in Cell Stem Cell at: www.sciencedirect.com/science/article/pii/S1934590918303874.