Piezo1-mediated mechanosensation in bone marrow macrophages promotes vascular niche regeneration after irradiation injury.
Piezo1-mediated mechanosensation in bone marrow macrophages promotes vascular niche regeneration after irradiation injury.
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Piezo1介导的骨髓巨噬细胞机械感觉促进辐射损伤后血管生态位再生
作者：
Zhang X;Hou L;Li F;Zhang W;Wu C;Xiang L;Li J;Zhou L;Wang X;Xiang Y;Xiao Y;Li SC;Chen L;Ran Q;Li Z
背景：辐射破坏了造血干细胞(HSCs)所在的血管壁龛，导致延迟的造血重建。随后窦血管的恢复是血管龛再生的关键，也是造血重建的先决条件。我们推测，辐射损伤后，常驻骨髓巨噬细胞(BM-M、φ、S)负责修复骨髓间充质干细胞的壁龛。方法：检测BM-MφS在C57BL/6小鼠体内的存活和激活情况。应用免疫荧光和流式细胞术检测骨髓间充质干细胞φ的去除和辐射损伤后的造血重建和血窦血管再生情况。采用酶联免疫吸附试验和流式细胞术分析BM-MφS释放的血管内皮生长因子-A在造血干细胞生态位血管重构中的作用。用转录组测序、流式细胞术和药理学(激动剂和拮抗剂)评估血管内皮生长因子-A介导的信号转导，以确定Piezo1介导的对HSC生态位结构变化的反应的分子机制。结果：BM-MφS的缺失加重了照射后的损伤，延缓了肝窦内皮细胞和肝星状细胞的恢复。照射后，一部分BM-Mφ群体持续存在，残留的BM-Mφ表现为活化的M2样表型。照射后BM-MφS细胞，尤其是CD206+BM-MφS细胞，其肝窦再生所必需的血管内皮生长因子-A的表达上调；BM-MφS细胞，尤其是CD206+BM-MφS细胞的机械感受离子通道Piezo1的表达上调。Piezo1的上调是由辐射、Piezo1自身的激活以及细胞吞噬诱导的M2样极化所介导的。PIEZO1的激活与血管内皮生长因子-A的表达增加以及NFATC1NFATC2和HIF-1α的积聚有关。抑制钙调神经磷酸酶/神经生长因子/缺氧诱导因子-1α信号通路可抑制Piezo1介导的血管内皮细胞生长因子-A的上调。结论：BM-MφS通过感知和响应放射损伤后的结构变化，在促进血管生态位再生中发挥重要作用，为治疗促进造血重建提供了潜在的靶点。
Background: Irradiation disrupts the vascular niche where hematopoietic stem cells (HSCs) reside, causing delayed hematopoietic reconstruction. The subsequent recovery of sinusoidal vessels is key to vascular niche regeneration and a prerequisite for hematopoietic reconstruction. We hypothesize that resident bone marrow macrophages (BM-Mφs) are responsible for repairing the HSC niche upon irradiation injury. Methods: We examined the survival and activation of BM-Mφs in C57BL/6 mice upon total body irradiation. After BM-Mφ depletion via injected clodronate-containing liposomes and irradiation injury, hematopoietic reconstruction and sinusoidal vascular regeneration were assessed with immunofluorescence and flow cytometry. Then enzyme-linked immunosorbent assay (ELISA) and flow cytometry were performed to analyze the contribution of VEGF-A released by BM-Mφs to the vascular restructuring of the HSC niche. VEGF-A-mediated signal transduction was assessed with transcriptome sequencing, flow cytometry, and pharmacology (agonists and antagonists) to determine the molecular mechanisms of Piezo1-mediated responses to structural changes in the HSC niche. Results: The depletion of BM-Mφs aggravated the post-irradiation injury, delaying the recovery of sinusoidal endothelial cells and HSCs. A fraction of the BM-Mφ population persisted after irradiation, with residual BM-Mφ exhibiting an activated M2-like phenotype. The expression of VEGF-A, which is essential for sinusoidal regeneration, was upregulated in BM-Mφs post-irradiation, especially CD206+ BM-Mφs. The expression of mechanosensory ion channel Piezo1, a response to mechanical environmental changes induced by bone marrow ablation, was upregulated in BM-Mφs, especially CD206+ BM-Mφs. Piezo1 upregulation was mediated by the effects of irradiation, the activation of Piezo1 itself, and the M2-like polarization induced by the phagocytosis of apoptotic cells. Piezo1 activation was associated with increased expression of VEGF-A and increased accumulation of NFATC1, NFATC2, and HIF-1α. The Piezo1-mediated upregulation in VEGF-A was suppressed by inhibiting the calcineurin/NFAT/HIF-1α signaling pathway. Conclusion: These findings reveal that BM-Mφs play a critical role in promoting vascular niche regeneration by sensing and responding to structural changes after irradiation injury, offering a potential target for therapeutic efforts to enhance hematopoietic reconstruction.
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影响因子：
64.8
作者：
Gudipaty SA;Lindblom J;Loftus PD;Redd MJ;Edes K;Davey CF;Krishnegowda V;Rosenblatt J
通讯作者：
Rosenblatt J
影响因子：
4.1
作者：
Faure, Celine;Linossier, Marie-Therese;Guignandon, Alain
通讯作者：
Guignandon, Alain
影响因子：
23.9
作者：
Hur, Jin;Choi, Jae-Il;Kim, Hyo-Soo
通讯作者：
Kim, Hyo-Soo
影响因子：
20.1
作者：
Kim, CH;Cho, YS;Kim, MS
通讯作者：
Kim, MS
影响因子：
7.7
作者：
Caolo, Vincenza;Debant, Marjolaine;Beech, David J.
通讯作者：
Beech, David J.