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.

骨髓（BM）间充质干细胞（MSC）是BM微环境的关键组成部分，在支持造血过程中起着至关重要的作用。MSCs的功能障碍与促进白血病发展的BM微环境受损有关。然而，受损的BM微环境的恢复是否以及如何抑制白血病的发展尚不清楚。使用已建立的白血病模型和RNA-Seq分析，我们发现了白血病进展过程中MSC的功能退化。重要的是，通过供体健康MSC的BM内而非全身输注可以恢复BM微环境，这可以通过宿主MSC的功能恢复，血小板生成改善和骨髓生成的重新平衡来证明。因此，BM-MSC内治疗减少了荷瘤小鼠的肿瘤负担并延长了其生存期。从机制上讲，供体MSC处理可恢复宿主MSC的功能，并将宿主巨噬细胞重新编程为具有组织修复功能的精氨酸酶1阳性表型。MSC重新编程的巨噬细胞的输血很大程度上概括了MSC的治疗效果。两者合计，我们的研究表明供体MSC重新编程宿主巨噬细胞，以恢复BM微环境和抑制白血病的发展。