疾病特异性miR-145-miR-371b-5p+外泌体miRNA指纹诱导肺远端组织特异性干细胞定向分化和组织再生

文献和我们已经发表的结果及前期的实验均提示肺泡II型干/祖细胞(ATIIC)在损伤性微环境中表达的疾病特异性miR-145-miR-371b-5p+外泌体可有效诱导ATIIC的定向分化，促进损伤组织的修复。申请人拟在损伤性肺远端组织中移植可表达、分泌Lamp2b-GFP+外泌体的ATIICs ，然后通过验证、追踪ATIIC来源的Lamp2b-GFP+外泌体是否表达miR-145-miR-371b-5p+miRNAs，分析其是否可以在损伤肺组织干细胞间有效传递miR-145-miR-371b-5p+miRNAs，并探讨其促进肺组织再生的机制。此外，我们将在国际上首次制备ATIIC-特异性的Lamp2b-GFP+miR-145-miR-371b-5p+外泌体，探讨其是否可以在损伤性肺组织微环境中诱导内源性干细胞的ATIIC定向分化，促进肺组织再生，为研发严重性肺损伤的精准靶向治疗开辟新途径。

Based on the literature and our preliminary data, we hypothesize that in the injured distal lung tissue, the alveolar epithelial type II progenitor cells (ATIICs) express a disease-specific miR-145-miR-371b-5p+exosome-miRNA (Exo-miR) fingerprint to promote the ATIIC-specific differentiation for the tissue regeneration. In this proposed project, we plan to transplant the genetically modified Lamp2b-GFP+ATIICs that can efficiently express and load the Lamp2b-GFP fusion peptide to their derived exosomes. Thus, we will be able to trace the Lamp2b-GFP+miR-145—miR-371b-5p+exosome-mediated intercellular communication in the injured microenvironment in vivo to explore the mechanism underlying the disease-specific Exo-miR mediated tissue regeneration. In addition, this is the first project to generate the ATIIC-specific Lamp2b-GFP+miR-145—miR-371b-5p+exosomes to explore their therapeutic potential to induce the endogenous ATIIC-specific differentiation for tissue regeneration, which we believe will open a novel avenue for the development of precision targeted therapies for severe lung injury.