Hematopoiesis could be improved by correcting aberrant bone marrow macrophages polarization in aplastic anemia patients.

The immune-mediated destruction of hematopoietic stem cells (HSCs) is the most recognized mechanism of aplastic anemia (AA); however, the unfavorable therapeutic effect of immunosuppressive therapy (IST) has shown that the pathogenesis of AA is still unclear. Our previous studies revealed that M1 and M2 macrophages (MΦs) in the bone marrow (BM) microenvironment exert opposite effects on hematopoiesis and that their aberrant polarization is involved in poor hematopoietic reconstitution after transplantation. To determine whether aberrant BM MΦs polarization is involved in the occurrence of AA, we established a classic mouse model of AA and performed a prospective case-control study involving AA patients and age-matched healthy controls (HCs). BM MΦs polarization was analyzed by flow cytometry. RNA-seq, PCR and Western blot were performed to investigate the underlying mechanism involved. To clarify the effect of thrombopoietin receptor agonist (TPO-RA) on BM MΦs polarization and subsequent impact on hematopoiesis and immunity, we established in vitro coculture assays of HSCs/T cells and BM MΦs treated with or without hetrombopag (HET), a novel TPO-RA. We found that in mice with AA, aberrant BM MΦs polarization, characterized by increased M1 MΦs number and decreased M2 MΦs number, accompanied by hematopoietic failure, was observed. Consistently, aberrant BM MΦs polarization, which is related to the downregulation of the PI3K/AKT pathway, was observed in AA patients. HET corrected the aberrant polarization of BM MΦs in AA patients and therefore improved their impaired functions, especially their hematopoiesis-supporting and immune-regulatory abilities, which may be related to the activation of the PI3K/AKT pathway. Although further validation is needed, our data suggest that remodeling BM MΦs polarization may be one of the reasons for the better clinical response to the combination of HET and IST in AA patients.