Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution
Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution
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DOI：
10.1242/dev.071696
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发表时间：
2012-01-15
期刊：
影响因子：
4.6
通讯作者：
Schedin, Pepper
中科院分区：
文献类型：
--
作者：
O'Brien, Jenean;Martinson, Holly;Schedin, Pepper
乳腺发育依赖于巨噬细胞，正如青春期和妊娠扩张阶段对巨噬细胞的需求所证明的那样。同样引人注目的组织重组发生在哺乳后，此时腺体通过大量程序性上皮细胞死亡和基质再生而退化到组织学上类似于怀孕前的状态。产后复旧的特点是类似伤口愈合的事件，包括具有 M2 特征的巨噬细胞的涌入。巨噬细胞水平在上皮细胞死亡的初始波后达到峰值，表明细胞死亡的启动和执行与巨噬细胞无关。为了解决巨噬细胞在断奶引起的乳腺退化过程中的作用，在 Mafia 小鼠模型断奶前开始有条件地系统性删除表达集落刺激因子 1 受体 (CSF1R) 的巨噬细胞。 CSF1R(+)巨噬细胞的耗竭导致乳腺复旧延迟，表现为断奶后7天溶酶体介导的上皮细胞凋亡和细胞凋亡的丧失、肺泡退化的缺乏以及脂肪细胞再生的缺乏。在存在乳汁停滞和 STAT3 激活的情况下，无法执行复旧，这表明在没有 CSF1R(+) 巨噬细胞的情况下，两者都不足以启动复旧。将野生型骨髓源性巨噬细胞 (BMDM) 或 M2 分化的巨噬细胞注射到巨噬细胞耗尽的乳腺中足以挽救复旧，包括细胞凋亡、肺泡退化和脂肪细胞再生。暴露于产后乳房复旧环境的 BMDM 上调了 M2 标记物精氨酸酶 1 和甘露糖受体。这些数据证明了巨噬细胞对于正常产后乳腺退化期间上皮细胞死亡的必要性，并暗示 M2 极化巨噬细胞。
Mammary gland development is dependent on macrophages, as demonstrated by their requirement during the expansion phases of puberty and pregnancy. Equally dramatic tissue restructuring occurs following lactation, when the gland regresses to a state that histologically resembles pre-pregnancy through massive programmed epithelial cell death and stromal repopulation. Postpartum involution is characterized by wound healing-like events, including an influx of macrophages with M2 characteristics. Macrophage levels peak after the initial wave of epithelial cell death, suggesting that initiation and execution of cell death are macrophage independent. To address the role of macrophages during weaning-induced mammary gland involution, conditional systemic deletion of macrophages expressing colony stimulating factor 1 receptor (CSF1R) was initiated just prior to weaning in the Mafia mouse model. Depletion of CSF1R(+) macrophages resulted in delayed mammary involution as evidenced by loss of lysosomal-mediated and apoptotic epithelial cell death, lack of alveolar regression and absence of adipocyte repopulation 7 days post-weaning. Failure to execute involution occurred in the presence of milk stasis and STAT3 activation, indicating that neither is sufficient to initiate involution in the absence of CSF1R(+) macrophages. Injection of wild-type bone marrow-derived macrophages (BMDMs) or M2-differentiated macrophages into macrophage-depleted mammary glands was sufficient to rescue involution, including apoptosis, alveolar regression and adipocyte repopulation. BMDMs exposed to the postpartum mammary involution environment upregulated the M2 markers arginase 1 and mannose receptor. These data demonstrate the necessity of macrophages, and implicate M2-polarized macrophages, for epithelial cell death during normal postpartum mammary gland involution.