Open AccessMesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment
Author(s) -
Chengxiang Xia,
Tongjie Wang,
Hui Cheng,
Yong Dong,
Qitong Weng,
Guohuan Sun,
Pingwei Zhou,
Kaitao Wang,
Xiaofei Liu,
Geng Yang,
Shihui Ma,
Sha Hao,
Ling Xu,
Yuxian Guan,
Juan Du,
Xin Du,
Yangqiu Li,
Xiaofan Zhu,
Yufang Shi,
Sheng Xu,
Demin Wang,
Tao Cheng,
Jinyong Wang
Publication year - 2020
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-020-0775-3
Subject(s) - mesenchymal stem cell , leukemia , haematopoiesis , cancer research , bone marrow , tumor microenvironment , immunology , biology , stem cell , microbiology and biotechnology , immune system
Bone marrow (BM) mesenchymal stem cells (MSCs) are critical components of the BM microenvironment and play an essential role in supporting hematopoiesis. Dysfunction of MSCs is associated with the impaired BM microenvironment that promotes leukemia development. However, whether and how restoration of the impaired BM microenvironment can inhibit leukemia development remain unknown. Using an established leukemia model and the RNA-Seq analysis, we discovered functional degeneration of MSCs during leukemia progression. Importantly, intra-BM instead of systemic transfusion of donor healthy MSCs restored the BM microenvironment, demonstrated by functional recovery of host MSCs, improvement of thrombopoiesis, and rebalance of myelopoiesis. Consequently, intra-BM MSC treatment reduced tumor burden and prolonged survival of the leukemia-bearing mice. Mechanistically, donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages into arginase 1 positive phenotype with tissue-repair features. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development.