中文摘要：
尽管生长因子是再生医学的核心功能分子，但递送体系效果不佳、信号动态调控机制尚不明确等问题，极大限制了其临床应用。本研究探究了促炎信号对生长因子再生修复能力的影响。通过小鼠骨再生模型研究发现，两种具有临床应用价值的生长因子（BMP-2、PDGF-BB）的再生功能会受到白介素 - 1 受体（IL-1R1）的抑制。
机制研究表明，成骨细胞中 IL-1R1 的激活会降低细胞对生长因子的敏感性，并加速细胞衰老。此外，外源性给予生长因子会刺激巨噬细胞释放白介素 - 1。为实现局部、长效的 IL-1R1 抑制效果，本研究对 IL-1 受体拮抗剂（IL-1Ra）进行改造，使其能够强效结合细胞外基质（ECM）。研究证实，将生长因子与可结合细胞外基质的 IL-1Ra 联合递送，可显著提升组织再生效果。
综上，促炎信号会显著抑制生长因子的再生活性，基于生长因子的治疗策略需联合免疫调控手段。其中，可结合细胞外基质的 IL-1Ra 能够有效提升生长因子治疗效果，具备良好的临床转化潜力。
英文摘要：
Although growth factors (GFs) are key molecules for regenerative medicine, their use has been limited by issues associated with suboptimal delivery systems and incomplete understanding of their signaling dynamics. Here, we explored how proinflammatory signals affect GF regenerative potential. Using bone regeneration in mouse, we found that the regenerative capacity of two clinically relevant GFs (BMP-2 and PDGF-BB) is impaired by interleukin-1 receptor (IL-1R1). Mechanistically, IL-1R1 activation in bone-forming cells desensitizes them to GFs and accelerates senescence. Moreover, administration of the GFs triggers IL-1 release by macrophages. To provide localized and sustained IL-1R1 inhibition, we engineered IL-1R antagonist (IL-1Ra) to bind the extracellular matrix (ECM) very strongly and demonstrate that codelivering GFs with ECM-binding IL-1Ra induces superior regeneration. Thus, we highlight that GF regenerative activity is hindered by proinflammatory signals, and GF-based therapies should integrate immunomodulation. Particularly, ECM-binding IL-1Ra holds clinical translational potential by enhancing efficacy of GF therapies.
论文信息：
论文题目：Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling
期刊名称：Science Advances
时间期卷：Vol 6, Issue24(2020)
在线时间：2020年6月12日
DOI: 10.1126/sciadv.aba76
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes&Control Liposomes
办事处：靶点科技
Clodronate Liposomes氯膦酸盐脂质体清除小鼠骨再生模型里巨噬细胞。荷兰Liposoma巨噬细胞清除剂ClodronateLiposomes见刊于Science Advances：通过局部抑制IL-1受体信号通路提升生长因子的再生修复效能。
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体清除巨噬细胞的材料和方法：
In vivo macrophage depletion
One day before surgery, 200 μl of clodronate liposomes (5 mg/ml) or empty liposomes (Liposoma) was intravenously injected in C57BL/6 mice (10 to 12 weeks old). An additional 200 μl of clodronate liposomes or empty liposomes were intraperitoneally injected every 2 days until day 6. Mouse spleens were harvested and crushed, and red blood cells were lysed with red blood cell lysis buffer [ammonium chloride (8.3 g/liter) and 10 mM tris-HCl in distilled water]. Macrophage depletion was verified by resuspending splenocytes in TruStain FcX anti-CD16/32 (1 μg/ml; clone 93, BioLegend) antibodies to block nonspecific binding and 1:500 dilution of Zombie Aqua (BioLegend) diluted in PBS. Subsequently, splenocytes were labeled with the following antibodies: anti-CD11b PE (1 μg/ml; clone M1/70, BioLegend), anti-Ly6G BV421 (1 μg/ml; clone 1A8, BioLegend), and anti-F4/80 biotin (3 μg/ml; clone REA126, Miltenyi Biotech) conjugated to streptavidin APC/Fire 750 (0.4 μg/ml; BioLegend) diluted in flow cytometry buffer (PBS with 1% BSA and 5 mM EDTA). Samples were acquired on a BD FACS Fortessa X20 and analyzed with FlowJo software (TreeStar Inc.).
巨噬细胞清除材料和方法文献截图：通过局部抑制IL-1受体信号通路提升生长因子的再生修复效能。
