A research team from the University of Osaka has discovered that as certain stem cells in bone marrow die, they release chemical signals that start a multi-step process triggering living cells to proliferate. This allows bone marrow to slowly regenerate, even after severe damage from chemotherapy.

The study, published March 5 in the Journal of Experimental Medicine, is the first to identify the molecular pathways behind the regeneration of bone marrow and is an important first step in discovering how to improve this process in cancer patients.

“Patients undergoing chemotherapy against malignant diseases can suffer from insufficient bone marrow recovery following treatment, and that can lead to various troubles, including severe infectious diseases, anemia and thrombocytopenia,” said senior author Masaru Ishii, a professor of immunology and cell biology at Osaka University. 

“A considerable number of patients receiving bone marrow transplantation even die due to bone marrow failure," Ishii continued. "In this study, we wanted to understand how hematopoietic stem cells residing in the bone marrow regenerate upon chemotherapy-induced injury to recover their full function.”

To achieve this objective, the researchers focused on cells in bone marrow called hematopoietic stem and progenitor cells, or HSPCs. These cells are foundational to the circulatory and immune systems, differentiating into other types of blood cells, including red and white blood cells, platelets and plasma cells.

The constant division and differentiation of HSPCs make them particularly vulnerable to injury. However, these cells have been shown in previous studies to regenerate naturally, though often slowly, after damage.

There have also been studies researching the impacts of various treatments and biochemicals to enhance HSPC regeneration, including estrogen and immunosuppressants. However, the precise mechanism of the body’s natural regeneration of HSPCs, as well as how the cells know to begin the process, has eluded researchers.

To investigate this mystery, the researchers used a mouse model, focusing on a small subset of blood cells produced by HSPCs called group 2 innate lymphoid cells, or ILC2s. The researchers found that when mice were treated with a chemotherapeutic agent toxic to HSPCs, these ILC2s produced a chemical messenger, called granulocyte-macrophage colony-stimulating factor, that triggers living HSPCs to proliferate.

However, a step of the process was still missing. The researchers next asked how the ILC2s know to start producing this compound. They uncovered another chemical signal called interleukin (IL)-33, which HSPCs release after injury. This signal in turns activates the ILC2s. Thus, the whole pathway begins with damaged cells and ends with the proliferation of healthy cells, with ILC2s acting as sensors and mediators for the process.

“It was surprising that ILC2s form a tiny population of bone marrow cells, only about 0.1%, and yet they can produce these chemical messengers in high amounts and play an essential role in HSPC recovery,” said Ishii.

While the present study was conducted in mice, researchers hope next to start evaluating these mechanisms in humans.

“The body has developed a remarkable hematopoietic system to keep the number of cells in bone marrow stable, in which a population of cells sense the tissue damage and subsequently support their recovery,” Ishii said. “Our study implicates that adoptive transfer of cultured ILC2s might be a useful treatment to induce HSPC recovery after chemotherapy or bone marrow transplantation, and we are also going to analyze human bone marrow samples to develop a novel adjunct therapy aimed at early hematopoietic recovery.”

The study, “Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions,” published March 5 in the Journal of Experimental Medicine, was authored by Takao Sudo, Daisuke Okuzaki, Tetsuo Hasegawa, Takufumi Yokota, Hiroki Mizuno, Takahiro Matsui, Daisuke Motooka, Ryosuke Yoshizawa, Takashi Nagasawa and Yuzuru Kanakura, Osaka University; Yasutaka Motomura and Kazuyo Moro, Osaka University and RIKEN Center for Integrative Medicine; and Junichi Kikuta, Tomoka Ao and Masaru Ishii, Osaka University and National Institutes of Biomedical Innovation, Health, and Nutrition.