Montay-Gruel Pierre, Zhu Yafeng, Petit Benoit, Leavitt Ron, Warn Mike, Giedzinski Erich, Ollivier Jonathan, Sinclair David A, Vozenin Marie-Catherine, Limoli Charles L
Department of Radiation Oncology, University of California, Irvine, CA, United States.
Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging Research, Harvard Medical School, Boston, MA, United States.
Front Oncol. 2021 Mar 2;10:602763. doi: 10.3389/fonc.2020.602763. eCollection 2020.
Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts ( < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging ( < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (, CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis.
与基于细胞的疗法相比，人干细胞衍生的细胞外囊泡（EV）在治疗功能受损的组织床和器官部位方面具有许多优势。在此，我们试图确定人胚胎干细胞（hESC）衍生的EV是否能部分解决与肺部暴露于电离辐射相关的晚期正常组织不良并发症。将hESC衍生的EV通过眶后窦系统地给予小鼠，以探索在接受高剂量胸部辐射（14 Gy）后潜在的治疗益处。数据表明，hESC衍生的EV治疗显著提高了受辐照组的总体生存率（P<0.001）。通过CBCT成像量化，生存率的提高还与肺纤维化的显著降低相关（P<0.01，辐照后2周）。定性组织学分析显示，接受EV治疗的动物中辐射诱导的肺损伤迹象减少。然后对EV进行了严格的蛋白质组学分析，以确定可能有助于改善辐射诱导的肺部正常组织毒性的潜在生物活性成分。蛋白质组学验证了几种公认的外泌体标志物（如CD68），并确定了参与核孔复合体、表观遗传学、细胞周期、生长和增殖、DNA修复、抗氧化功能以及细胞代谢（三羧酸循环和氧化磷酸化，OXYPHOS）的主要蛋白质类别。有趣的是，还发现EV含有线粒体成分（mtDNA、OXYPHOS蛋白亚基），这可能有助于辐射损伤的肺组织的代谢重编程和恢复。为了评估EV治疗在肿瘤放射治疗管理中的安全性，对携带TC1肿瘤异种移植物的小鼠进行了相同的EV治疗，结果显示可预防肺纤维化。数据表明，在一个月的时间里，治疗组和对照组的侧腹肿瘤生长没有变化。总之，目前的研究结果表明，基于EV成分分析，通过多种潜在机制，系统递送hESC衍生的EV可以改善辐射诱导的肺部正常组织并发症。
