Impaired and limited alveolar regeneration upon injury advances pulmonary disorders and irreversibly affects millions of people worldwide. Adult mammals do not have a strong potential to regenerate functional lung tissues, while neonatal lungs robustly proliferate and regenerate the functional tissue within a week of birth upon injury. The differential composition of the extracellular matrix (ECM) of neonatal tissues favors cellular proliferation and migration, fostering lung regeneration. Regardless, conventional ECM therapies employ adult-derived tissues. Therefore, the potential differences in regenerative properties of adult and neonatal lung ECM were investigated using and lung emphysema model. Decellularization of the neonatal and adult lungs was performed using freeze-thaw cycle method. Decellularization process was structurally characterized using SEM and immunostaining. treatment of neonatal lung-derived ECM (NECM) significantly enhanced the cellular migration and proliferation compared to adult-lung derived ECM (AECM) treated cigarette smoke-extract (CSE)-stimulated A549 cells. Following the administration of AECM and NECM, we observed a significant decline in emphysematous features and an improvement in lung functions in NECM group. NECM treatment increased the ratio of HOPX/SpC cells with an active proliferation in SpC cells shown by colocalization of SpC/Ki67 and SpC/Brdu cells. Moreover, NECM treatment activated the Neureguline-1/Erbb2 signaling and fostered a regenerative environment by upregulating the expression of regenerative genes including FGF, WNTs and AXIN-2 as compared to AECM treatment. Our findings suggested the potential utilization of NECM as novel therapeutics in regenerative medicine, deviating from the conventional application of adult-derived ECM treatments in pre-clinical and clinical research.

中文翻译：

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肺气肿模型中新生儿肺源性脱细胞细胞外基质的再生能力


受伤时肺泡再生受损和有限会加剧肺部疾病，并对全世界数百万人产生不可逆转的影响。成年哺乳动物不具备再生功能性肺组织的强大潜力，而新生儿肺在受伤后出生一周内即可强劲增殖并再生功能性组织。新生儿组织细胞外基质（ECM）的不同组成有利于细胞增殖和迁移，促进肺再生。无论如何，传统的 ECM 疗法采用成人组织。因此，使用肺气肿模型研究了成人和新生儿肺 ECM 再生特性的潜在差异。使用冻融循环方法对新生儿和成人肺进行脱细胞。使用 SEM 和免疫染色对脱细胞过程进行结构表征。与成人肺源性 ECM (AECM) 处理的香烟烟雾提取物 (CSE) 刺激的 A549 细胞相比，新生儿肺源性 ECM (NECM) 的治疗显着增强了细胞迁移和增殖。给予 AECM 和 NECM 后，我们观察到 NECM 组肺气肿特征显着下降，肺功能改善。 NECM 处理增加了 HOPX/SpC 细胞的比例，SpC/Ki67 和 SpC/Brdu 细胞的共定位表明 SpC 细胞活跃增殖。此外，与 AECM 治疗相比，NECM 治疗激活了 Neureguline-1/Erbb2 信号传导，并通过上调 FGF、WNT 和 AXIN-2 等再生基因的表达来培育再生环境。 我们的研究结果表明，NECM 作为再生医学的新型疗法具有潜在的用途，这不同于临床前和临床研究中成人来源的 ECM 治疗的传统应用。