PT  - JOURNAL ARTICLE
AU  - Chengxiang Xia
AU  - Tongjie Wang
AU  - Hui Cheng
AU  - Yong Dong
AU  - Qitong Weng
AU  - Guohuan Sun
AU  - Peiqing Zhou
AU  - Kaitao Wang
AU  - Xiaofei Liu
AU  - Yang Geng
AU  - Shihui Ma
AU  - Sha Hao
AU  - Ling Xu
AU  - Yuxian Guan
AU  - Juan Du
AU  - Xin Du
AU  - Yangqiu Li
AU  - Xiaofan Zhu
AU  - Yufang Shi
AU  - Sheng Xu
AU  - Demin Wang
AU  - Tao Cheng
AU  - Jinyong Wang
TI  - Mesenchymal stem cells restore local microenvironment and systemically suppress leukemia via reprogramming macrophages
AID  - 10.1101/661298
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 661298
4099  - http://biorxiv.org/content/early/2019/06/05/661298.short
4100  - http://biorxiv.org/content/early/2019/06/05/661298.full
AB  - 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 high-throughput 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, thus systemically changing cytokine expression patterns, improving normal hematopoiesis, reducing tumor burden, and ultimately prolonging survival of the leukemia-bearing mice. Donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages to fulfill tissue-repair function. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Further, we found that donor MSCs reprogrammed macrophages to reduce leukemia burden through autocrine effects of IL-6. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development, thus validating local MSC application as a potentially effective therapy for leukemia.