State Key Laboratory of Experimental Hematology, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, 510700, China.
Leukemia. 2020 Sep;34(9):2375-2383. doi: 10.1038/s41375-020-0775-3. Epub 2020 Feb 24.
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（MSCs）是 BM 微环境的重要组成部分，在支持造血中发挥着重要作用。MSCs 的功能障碍与促进白血病发展的受损 BM 微环境有关。然而，受损 BM 微环境的恢复是否以及如何抑制白血病的发展仍不清楚。我们使用已建立的白血病模型和 RNA-Seq 分析，发现 MSCs 在白血病进展过程中存在功能退化。重要的是，BM 内而不是全身输注供体健康 MSCs 可恢复 BM 微环境，表现为宿主 MSCs 功能恢复、血小板生成改善和髓系生成再平衡。因此，BM 内 MSC 治疗可降低白血病荷瘤小鼠的肿瘤负担并延长其存活期。从机制上讲，供体 MSC 治疗可恢复宿主 MSCs 的功能，并将宿主巨噬细胞重编程为具有组织修复特征的精氨酸酶 1 阳性表型。MSC 重编程的巨噬细胞的输注在很大程度上再现了 MSC 的治疗效果。总之，我们的研究表明，供体 MSCs 可重编程宿主巨噬细胞以恢复 BM 微环境并抑制白血病的发展。
