中文摘要：
盡管生長因子是再生醫學的核心功能分子，但遞送體系效果不佳、信號動態調控機制尚不明確等問題，極大限制了其臨床應用。本研究探究了促炎信號對生長因子再生修復能力的影響。通過小鼠骨再生模型研究發現，兩種具有臨床應用價值的生長因子（BMP-2、PDGF-BB）的再生功能會受到白介素 - 1 受體（IL-1R1）的抑制。
機制研究表明，成骨細胞中 IL-1R1 的激活會降低細胞對生長因子的敏感性，并加速細胞衰老。此外，外源性給予生長因子會刺激巨噬細胞釋放白介素 - 1。為實現局部、長效的 IL-1R1 抑制效果，本研究對 IL-1 受體拮抗劑（IL-1Ra）進行改造，使其能夠強效結合細胞外基質（ECM）。研究證實，將生長因子與可結合細胞外基質的 IL-1Ra 聯合遞送，可顯著提升組織再生效果。
綜上，促炎信號會顯著抑制生長因子的再生活性，基于生長因子的治療策略需聯合免疫調控手段。其中，可結合細胞外基質的 IL-1Ra 能夠有效提升生長因子治療效果，具備良好的臨床轉化潛力。
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.
論文信息：
論文題目：Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling
期刊名稱：Science Advances
時間期卷：Vol 6, Issue24(2020)
在線時間：2020年6月12日
DOI: 10.1126/sciadv.aba76
產品信息：
貨號：CP-005-005
規格：5ml+5ml
品牌：Liposoma
產地：荷蘭
名稱：Clodronate Liposomes&Control Liposomes
辦事處：靶點科技
Clodronate Liposomes氯膦酸鹽脂質體清除小鼠骨再生模型里巨噬細胞。荷蘭Liposoma巨噬細胞清除劑ClodronateLiposomes見刊于Science Advances：通過局部抑制IL-1受體信號通路提升生長因子的再生修復效能。
Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質體清除巨噬細胞的材料和方法：
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.).
巨噬細胞清除材料和方法文獻截圖：通過局部抑制IL-1受體信號通路提升生長因子的再生修復效能。
