CD9-enriched extracellular vesicles from chemically reprogrammed basal progenitors of salivary glands mitigate salivary gland fibrosis

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL Bioactive Materials Pub Date : 2025-05-01 Epub Date: 2025-01-24 DOI:10.1016/j.bioactmat.2025.01.019

Sunyoung Park , Yeo-Jun Yoon , Yongpyo Hong , Jianning Yu , Jae-Min Cho , Ye Jin Jeong , Haeun Yu , Hyorim Jeong , Hyunjin Lee , Seungyeon Hwang , Won-Gun Koh , Ji Yeong Yang , Kyung-A Hyun , Hyo-Il Jung , Jae-Yol Lim

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Abstract

Extracellular vesicles (EVs) derived from stem cells offer promising potential for cell-free therapy. However, refining their cargo for precise disease targeting and delivery remains challenging. This study employed chemical reprogramming via dual inhibition of transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) to expand salivary gland basal progenitor cells (sgBPCs). CD9-enriched (CD9⁺) EVs were then isolated from the sgBPC secretome concentrate using a dual microfluidic chip. Notably, CD9⁺ EVs demonstrated superior uptake by salivary epithelial cells compared to CD9-depleted (CD9⁻) EVs and total EVs. In vivo studies using a salivary gland (SG) obstruction mouse model and ex vivo studies in SG fibrosis organoids revealed that CD9⁺ EVs significantly enhanced anti-fibrotic effects over CD9⁻ EVs and control treatments. The presence of miR-3162 and miR-1290 in CD9⁺ EVs supported their anti-fibrotic properties by downregulating ACVR1 expression. The chemical reprogramming culture method effectively expanded sgBPCs, enabling consistent and scalable EV production. Utilizing microfluidic chip-isolated CD9⁺ EVs and ductal delivery presents a targeted and efficient approach for anti-fibrotic SG regeneration.

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来自化学重编程的唾液腺基底祖细胞的富含cd9的细胞外囊泡减轻了唾液腺纤维化

来自干细胞的细胞外囊泡（EVs）为无细胞治疗提供了广阔的前景。然而，改进他们的货物以精确定位疾病和运送仍然具有挑战性。本研究采用化学重编程方法，通过双重抑制转化生长因子β (TGFβ)和骨形态发生蛋白（BMP）来扩增唾液腺基底祖细胞（sgBPCs）。然后用双微流控芯片从sgBPC分泌组浓缩物中分离CD9富集（CD9+） ev。值得注意的是，与CD9缺失（CD9−）ev和总ev相比，CD9+ ev表现出更强的唾液上皮细胞摄取能力。使用唾液腺（SG）阻塞小鼠模型进行的体内研究和SG纤维化类器官的体外研究表明，CD9+ ev比CD9−ev和对照治疗显著增强了抗纤维化作用。CD9+ ev中miR-3162和miR-1290的存在通过下调ACVR1表达来支持其抗纤维化特性。化学重编程培养方法有效地扩展了sgbpc，实现了一致和可扩展的电动汽车生产。利用微流控芯片分离的CD9+ ev和导管输送是抗纤维化SG再生的靶向和有效方法。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.