Patsalos Andreas, Pap Attila, Varga Tamas, Trencsenyi Gyorgy, Contreras Gerardo Alvarado, Garai Ildiko, Papp Zoltan, Dezso Balazs, Pintye Eva, Nagy Laszlo
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032, Hungary.
Scanomed LTD, Debrecen, Hungary.
J Physiol. 2017 Sep 1;595(17):5815-5842. doi: 10.1113/JP274361. Epub 2017 Aug 8.
The in situ phenotypic switch of macrophages is delayed in acute injury following irradiation. The combination of bone marrow transplantation and local muscle radiation protection allows for the identification of a myeloid cell contribution to tissue repair. PET-MRI allows monitoring of myeloid cell invasion and metabolism. Altered cellular composition prior to acute sterile injury affects the in situ phenotypic transition of invading myeloid cells to repair macrophages. There is reciprocal intercellular communication between local muscle cell compartments, such as PAX7 positive cells, and recruited macrophages during skeletal muscle regeneration.
Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for clearance of necrotic debris and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6C ) to a repair (Ly6C ) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging, we show that preserved muscle integrity and cell composition prior to the injury is necessary for the repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions shape the macrophage in situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics.
照射后急性损伤中巨噬细胞的原位表型转换延迟。骨髓移植与局部肌肉辐射防护相结合，有助于确定骨髓细胞对组织修复的贡献。正电子发射断层扫描-磁共振成像（PET-MRI）可监测骨髓细胞的浸润和代谢。急性无菌损伤前细胞组成的改变会影响入侵的骨髓细胞向修复性巨噬细胞的原位表型转变。在骨骼肌再生过程中，局部肌肉细胞区室（如PAX7阳性细胞）与募集的巨噬细胞之间存在相互的细胞间通讯。
骨骼肌再生是包括入侵巨噬细胞在内的多种细胞类型之间的复杂相互作用。急性无菌损伤后它们被募集到受损组织对于清除坏死碎片和协调组织再生是必要的。这个高度动态的过程的特征是浸润的单核细胞从炎症性（Ly6C⁺）向修复性（Ly6C⁻）巨噬细胞表型的原位转变。巨噬细胞表型转变以及损伤后组织再生过程中局部肌肉组织与浸润巨噬细胞之间的相互作用的重要性尚未完全了解，并且对它们的研究缺乏适当的方法。在这里，我们使用急性无菌骨骼肌损伤模型，结合照射、骨髓移植和体内成像，表明损伤前保留的肌肉完整性和细胞组成对于修复性巨噬细胞表型转变以及随后正常和完全的组织再生是必要的。重要的是，通过使用体内消融PAX7阳性细胞的模型，我们表明这个对辐射敏感的骨骼肌祖细胞池在急性无菌肌肉损伤后有助于巨噬细胞表型转变。此外，照射期间通过铅屏蔽进行局部肌肉组织辐射防护可保持正常的巨噬细胞转变动态，进而促进肌肉组织再生。综上所述，我们的数据表明在组织损伤时，包括卫星细胞在内的肌肉组织区室与浸润的骨髓细胞之间存在更广泛和相互的相互作用。这些相互作用塑造了巨噬细胞的原位表型转变，这对于正常肌肉组织修复动态是不可或缺的。
