Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex
Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex
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DOI：
10.1302/2046-3758.810.bjr-2018-0231.r2
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发表时间：
2019-10-01
影响因子：
4.6
通讯作者：
Goodman, S. B.
中科院分区：
文献类型：
--
作者：
Nathan, K.;Lu, L. Y.;Goodman, S. B.
目的多达10%的骨折会导致不良后果，而女性是危险因素。细胞性别差异与这些不同的愈合过程有关。更好地了解骨愈合的潜在机制和这一过程中的性别差异是改善临床结果的关键。本研究利用巨噬细胞-间充质干细胞(MSC)共培养系统来确定：1)促进炎症(M1)向抗炎(M2)巨噬细胞转变以获得最佳骨形成的确切时间；以及2)这种免疫调节是如何受男性和女性共培养的影响的。方法采用原代小鼠巨噬细胞-MSC共培养体系，证明从M1巨噬细胞到M2巨噬细胞(M1与IL-4极化)的最佳转变时间，以最大限度地促进男性和女性MSCs的基质矿化。结果我们发现男性混合培养中96小时的M1表型允许最大的基质矿化，而女性联合培养中为72小时。在男性组和女性组中，随着IL-4的加入，ALP活性和骨钙素的分泌也随之增加。结论：1)72-96小时的促炎环境对于最佳基质矿化是至关重要的；2)在这种共培养环境中，由于性别的不同，免疫学上存在差异。优化骨折愈合过程中的免疫调节可能会增强和加速骨再生反应。这些发现为精确的免疫调节增强骨愈合提供了洞察力，这是性别特有的。
ObjectivesUp to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures.MethodsA primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion.ResultsWe found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis.ConclusionThese results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.