Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, Kamla Nehru Nagar, Ghaziabad, UP, 201002, India.
Centre for Advance Research (CFAR), Faculty of Medical Sciences, King George's Medical University, Lucknow, India.
J Control Release. 2024 Aug;372:234-250. doi: 10.1016/j.jconrel.2024.05.043. Epub 2024 Jun 23.
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 in vitro and in vivo 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. In vitro 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.
肺损伤导致的肺泡再生受损和受限会导致多种肺部疾病,并不可逆转地影响全球数百万人。成年哺乳动物没有很强的能力来再生功能性肺组织,而新生肺在出生后一周内受到损伤时会强烈增殖并再生功能性组织。新生组织的细胞外基质(ECM)的差异组成有利于细胞增殖和迁移,促进肺再生。然而,传统的 ECM 治疗方法采用的是成年组织。因此,使用体外和体内肺气肿模型研究了成年和新生肺 ECM 的再生特性的潜在差异。使用冻融循环法对新生和成年肺进行脱细胞处理。使用 SEM 和免疫染色对脱细胞过程进行结构表征。与用香烟烟雾提取物(CSE)刺激的 A549 细胞处理的成年肺衍生 ECM(AECM)相比,新生肺衍生 ECM(NECM)的体外处理显著增强了细胞迁移和增殖。在给予 AECM 和 NECM 后,我们观察到 NECM 组肺气肿特征明显下降,肺功能得到改善。NECM 处理增加了 HOPX/SpC 细胞的比例,SpC 细胞中的 SpC/Ki67 和 SpC/Brdu 细胞共定位显示 SpC 细胞具有活跃的增殖。此外,与 AECM 处理相比,NECM 处理通过上调包括 FGF、WNTs 和 AXIN-2 在内的再生基因的表达,激活了 Neuregulin-1/Erbb2 信号,并促进了再生环境的形成。我们的研究结果表明,NECM 具有作为再生医学中新型治疗方法的潜力,这与传统应用成年衍生 ECM 治疗在临床前和临床研究中的应用不同。