Chronic myeloproliferative neoplasms

Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment

Abstract

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.

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Fig. 1: Impaired bone marrow MSCs in mice with NrasG12D mutation-induced leukemia.
Fig. 2: Intra-BM transfusion of donor MSCs prolongs survival of leukemia-bearing mice.
Fig. 3: Characterization of recovered host MSCs from MSC-treated leukemia-bearing mice.
Fig. 4: Characterization of MSC-reprogrammed BM resident macrophages isolated from leukemia-bearing mice.
Fig. 5: Intra-BM transfusion of MSC-reprogrammed macrophages largely rescues the therapeutic effects of MSC treatment in leukemic mice.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2019YFA0110200), the Strategic Priority Research Program of Chinese Academy of Sciences (XDA16010601), the Chinese Ministry of Science and Technology (2015CB964401, 2016YFA0100601, 2016YFA0100600, 2017YFA0103401, and 2015CB964902), the Major Research and Development Project of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110104006 and 2018GZR0201008), the CAS Key Research Program of Frontier Sciences (QYZDB-SSW-SMC057), the Health and Medical Care Collaborative Innovation Program of Guangzhou Scientific and Technology (201803040017), CAMS Innovation Fund for Medical Sciences (2016-12M-1-002), the General Program from Guangzhou Scientific and Technological Project (201707010157), the Science and Technology Planning Project of Guangdong Province (2017B030314056 and 2017B020230004), the grants from the National Natural Science Foundation of China (Grant nos. 81925002, 81970099, 31471117, 31271457, 81470281, 81421002, 81730006, 31600948, and 81861148029), the CAMS Initiative for Innovative Medicine (2016-I2M-1-017), and the grants from NIH, USA (AI079087, DW and HL130724, DW).

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CXX performed research, analyzed data, and wrote the manuscript; YD and QTW analyzed RNA-Seq data; TJW, HC, PQZ, KTW, XFL, YG, SHM, LX, and YXG performed experiments; SH, JD, XD, YQL, XFZ, YFS, and SX discussed the manuscript; DW discussed the project and wrote the manuscript; and TC and JYW designed the research and wrote the manuscript.

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Correspondence to Tao Cheng or Jinyong Wang.

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Xia, C., Wang, T., Cheng, H. et al. Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment. Leukemia (2020). https://doi.org/10.1038/s41375-020-0775-3

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