Diabetes induces myeloid bias in bone marrow progenitors associated with enhanced wound macrophage accumulation and impaired healing.
Diabetes induces myeloid bias in bone marrow progenitors associated with enhanced wound macrophage accumulation and impaired healing.
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DOI：
10.1002/path.5330
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Koh TJ
中科院分区：
文献类型：
--
作者：
Barman PK;Urao N;Koh TJ
糖尿病导致从祖细胞到终末分化细胞的整个髓系细胞谱系的调节失调。糖尿病的另一个并发症是持续性炎症，包括巨噬细胞的长期堆积，这导致伤口愈合受损。然而，目前尚不清楚糖尿病是否扰乱了骨髓祖细胞对外周损伤的反应，以及这种调节失调是否会导致持续的炎症和受损的愈合。在这里，我们证明了糖尿病小鼠(db/db，这里称为db)在动态平衡和损伤后表现出髓系偏向。此外，DB小鼠LSK(LIN−Sca-1+CKit+)群体中的细胞在转录水平上被预先编程为髓系承诺，并且来自DB小鼠的培养的髓系祖细胞在体外比非糖尿病小鼠产生更多的单核细胞。我们还通过白细胞介素1受体1 KO(IL1r1−/−)和DB小鼠之间的骨髓转移显示，IL-1R1信号可能不参与DB小鼠的髓系倾斜。此外，体外实验表明巨噬细胞集落刺激因子受体信号不太可能参与增强DB小鼠LSK细胞中髓系转录因子的表达。我们的发现表明，骨髓中的髓系承诺可能有助于糖尿病皮肤伤口中观察到的巨噬细胞数量的增加，而在体内平衡或创伤后调节单核细胞生成的策略可能会促进糖尿病伤口的愈合。
Diabetes induces dysregulation throughout the spectrum of myeloid lineage cells from progenitors to terminally differentiated cells. Another complication of diabetes is persistent inflammation, including prolonged accumulation of macrophages, which contributes to impaired wound healing. However, it remains unclear whether diabetes disrupts the response of bone marrow progenitors to peripheral injury and whether such dysregulation leads to sustained inflammation and impaired healing. Here, we demonstrated that diabetic mice (db/db, referred to here as DB) exhibit myeloid lineage bias during homeostasis and following injury. In addition, cells in the LSK (Lin−Sca-1+cKit+) population of DB mice are preprogrammed towards myeloid commitment at the transcriptional level, and cultured myeloid progenitors from DB mice produce more monocytes ex vivo than their non-diabetic counterparts. We also show via bone marrow transfer between interleukin-1 receptor 1 KO (Il1r1−/−) and DB mice that IL-1R1 signaling is likely not involved in myeloid skewing in DB mice. Furthermore, in vitro experiments indicated that macrophage colony-stimulating factor receptor signaling is not likely involved in enhanced myeloid transcription factor expression in LSK cells of DB mice. Our findings indicate that myeloid lineage commitment in bone marrow may contribute to increased macrophage numbers observed in diabetic skin wounds, and that strategies to regulate monopoiesis during homeostasis or post-wounding may improve diabetic wound healing.
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