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New Research Reveals How Chemotherapy Blunts Blood Cell Regeneration

A recent study conducted in mice has shown that chemotherapy damages nerves that regulate bone marrow niches responsible for making new blood cells (hematopoiesis). The hematopoietic niche of the bone marrow supports the survival and self-renewal of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs), yet prevents the ill-timed release of these cells into the circulation. When used to treat cancers such as non-Hodgkin’s lymphoma and multiple myeloma, high-dose chemotherapy also destroys normal cells such as the HSCs and HPCs in the bone marrow. The result of chemotherapy, therefore, is a reduced hematopoietic reserve and function. However, the underlying cause remains unresolved.

This study shows for the first time that chemotherapy is toxic to the nerves that interact with (innervate) the hematopoietic niche. The experimental model assessed the ability of mice whose HSCs and HPCs have been destroyed (in this case, by irradiation) to restore their hematopoietic reserve and function under various conditions. Mice without HSCs and HPCs are likely to die unless transplanted with bone marrow cells from another normal animal. In one set of experiments, mice were or were not subjected to chemotherapy prior to irradiation and then transplanted with bone marrow cells. Compared to mice not subjected to chemotherapy, chemotherapy-treated mice were significantly more likely to die and contained fewer nerves innervating the hematopoietic niche.

To confirm that chemotherapy causes nerve toxicity in the bone marrow, the investigators studied the effect of a drug called 6-hydroxydopamine, which is known to selectively destroy “noradrenergic” nerves. Mice treated with 6-hydroxydopamine, a level of radiation that destroyed their HSCs and HPCs, and bone marrow cell transplantation showed a significant decrease in survival and delayed hematopoietic recovery compared to a group of mice not treated with the drug. Thus, this experimental model provides evidence that noradrenergic nerves are required for normal hematopoietic function. The loss of nerves contributes to the inability of the transplanted bone marrow cells to home to the bone marrow and take up residence in the hematopoietic niche.

The scientists next tested whether a known nerve protective agent such as 4-methylcatechol (4-MC) would mitigate the harmful effects of chemotherapy on hematopoietic nerves. In mice treated with chemotherapy and 4-MC, and subjected to lethal irradiation and bone marrow transplant, the number of hematopoietic nerves was significantly more than that found in mice not treated with 4-MC. In addition, the mice treated with 4-MC had improved survival. Thus the addition of 4-MC acts to maintain hematopoietic function by specifically protecting nerves which innervate the bone marrow. Overall, these results in mice may lead to future research in humans to explore ways to reduce nerve damage so as to improve blood cell regeneration after chemotherapy.