02 March 2022

Chemotherapy prior to hematopoietic stem cell transplantation (HSCT) can destroy microglia, a type of immune cell in the brain, French researchers have reported.

The resulting spaces are then filled with donor-derived macrophages, according to the study in Nature Medicine.

The research team was led by Dr Nathalie Cartier of INSERM and Dr Pierre-Marie Lledo of Institut Pasteur in Paris, France. They say that macrophages have been observed in mouse brains following HSCT, despite their absence in the normal brain. The mechanism of how they engraft is yet to be defined, however.

In experiments with mice, the team showed that pre-HSCT busulfan chemotherapy leads to microglia losing their regenerative capacity, entering a state of senescence (hibernation), and consequently their cell density reducing by half. This situation allows engraftment of macrophages from the HSCT donor.

“Although we observed no obvious detrimental effect with macrophage replacement of microglia, it would be important to determine whether macrophages can fulfil their role,” they write.

Dr Cartier says: “Microglial cells play an essential role in the functioning of the brain. Understanding the fate of these cells after the transplant process is essential both to clarify the consequences of chemotherapy and to develop new therapeutic strategies for serious neurodegenerative diseases.

“This study sheds light for the first time on a mechanism explaining how stem cell-derived macrophages enter the brain after bone marrow cell transplantation. This better understanding is essential for developing new strategies for gene and cell therapy applied to diseases of the central nervous system.”

Source: Sailor KA, Agoranos G, López-Manzaneda S, Tada S, Gillet-Legrand B, Guerinot C, Masson JB, Vestergaard CL, Bonner M, Gagnidze K, Veres G, Lledo PM, Cartier N. (2022) “Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain.” Nature Medicine, doi: 10.1038/s41591-022-01691-9

Link: https://www.nature.com/articles/s41591-022-01691-9

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