Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorigaoka, Ikeda, Osaka, 563-8577, Japan; AIST-Osaka University Advanced Photonics and Biosensing Open Innovation Laboratory, AIST, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorigaoka, Ikeda, Osaka, 563-8577, Japan.
Acta Biomater. 2024 Oct 1;187:51-65. doi: 10.1016/j.actbio.2024.08.012. Epub 2024 Aug 17.
Bilateral communication between bones and muscles is essential for healing composite bone-muscle injuries from orthopedic surgeries and trauma. However, these injuries are often characterized by exaggerated inflammation, which can disrupt bone-muscle crosstalk, thereby seriously delaying the healing of either tissue. Existing approaches are largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging, with little research conducted to date. Here we introduce collagen patches that overcome this overlooked issue by harnessing the plasticity of macrophage phenotypes. Phosphatidylserine liposomes (PSLs) capable of shifting the macrophage phenotype from inflammatory M1 into anti-inflammatory/prohealing M2 were coated on collagen patches via a layer-by-layer method. Original collagen patches failed to improve tissue healing under inflammatory conditions coordinated by M1 macrophages. In contrast, PSL-coated collagen patches succeeded in accelerating bone and muscle healing by inducing a microenvironment dominated by M2 macrophages. In cell experiments, differentiation of preosteoblasts and myoblasts was completely inhibited by secretions of M1 macrophages but unaffected by those of M2 macrophages. RNA-seq analysis revealed that type I interferon and interleukin-6 signaling pathways were commonly upregulated in preosteoblasts and myoblasts upon stimulation with M1 macrophage secretions, thereby compromising their differentiation. This study demonstrates the benefit of PSL-mediated M1-to-M2 macrophage polarization for simultaneous bone and muscle healing, offering a potential strategy toward simultaneous regeneration of multiple tissues. STATEMENT OF SIGNIFICANCE: Existing approaches for tissue regeneration, which primarily utilize growth factors, have been largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging and has been little studied. Here we demonstrate that collagen patches releasing phosphatidylserine liposomes (PSLs) promote M1-to-M2 macrophage polarization and are effective for simultaneous healing of bone and muscle. Transcriptome analysis using next-generation sequencing reveals that differentiation of preosteoblasts and myoblasts is inhibited by the secretions of M1 macrophages but promoted by those of M2 macrophages, highlighting the importance of timely regulation of M1-to-M2 polarization in tissue regeneration. These findings provide new insight to tissue healing of multiple tissues.
骨骼和肌肉之间的双向交流对于修复骨科手术和创伤引起的复合骨肌损伤至关重要。然而，这些损伤通常以炎症反应过度为特征，这可能会破坏骨肌对话，从而严重延迟任何组织的愈合。现有的方法在治疗单一组织方面大多是有效的。然而，目前同时治愈多种组织仍然具有挑战性，迄今为止研究甚少。在这里，我们介绍了胶原蛋白贴片，它通过利用巨噬细胞表型的可塑性来克服这一被忽视的问题。通过层层方法，将能够将巨噬细胞表型从炎症性 M1 转变为抗炎/促愈 M2 的磷脂酰丝氨酸脂质体 (PSL) 涂覆在胶原蛋白贴片上。原始的胶原蛋白贴片在由 M1 巨噬细胞协调的炎症条件下未能改善组织愈合。相比之下，PSL 涂层的胶原蛋白贴片通过诱导以 M2 巨噬细胞为主导的微环境成功加速了骨骼和肌肉的愈合。在细胞实验中，M1 巨噬细胞分泌的物质完全抑制了前成骨细胞和肌母细胞的分化，但不受 M2 巨噬细胞分泌的物质的影响。RNA-seq 分析表明，在受到 M1 巨噬细胞分泌物质的刺激后，I 型干扰素和白细胞介素 6 信号通路在成骨细胞和肌母细胞中普遍上调，从而损害了它们的分化。这项研究证明了 PSL 介导的 M1 向 M2 巨噬细胞极化在同时骨和肌肉愈合中的益处，为同时再生多种组织提供了一种潜在的策略。
现有组织再生方法主要利用生长因子，在治疗单一组织方面已取得很大成效。然而，同时治愈多种组织仍然具有挑战性，研究甚少。在这里，我们证明释放磷脂酰丝氨酸脂质体 (PSL) 的胶原蛋白贴片促进 M1 向 M2 巨噬细胞极化，可有效同时治疗骨骼和肌肉。使用下一代测序的转录组分析表明，M1 巨噬细胞分泌的物质抑制了前成骨细胞和肌母细胞的分化，但 M2 巨噬细胞分泌的物质促进了它们的分化，这凸显了在组织再生中及时调节 M1 向 M2 极化的重要性。这些发现为多种组织的组织愈合提供了新的见解。
