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Targeting Reprogrammed Cancer-Associated Fibroblasts with Engineered Mesenchymal Stem Cell Extracellular Vesicles for Pancreatic Cancer Treatment.
Zhou, Pengcheng; Ding, Xian'guang; Du, Xuanlong; Wang, Lianhui; Zhang, Yewei.
Afiliación
  • Zhou P; School of Medicine, Southeast University, Nanjing 210000, China.
  • Ding X; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
  • Du X; State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China.
  • Wang L; School of Medicine, Southeast University, Nanjing 210000, China.
  • Zhang Y; State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China.
Biomater Res ; 28: 0050, 2024.
Article en En | MEDLINE | ID: mdl-39099892
ABSTRACT

Background:

As one of the most aggressive and lethal cancers, pancreatic cancer is highly associated with cancer-associated fibroblasts (CAFs) that influence the development and progression of cancer. Targeted reprogramming of CAFs may be a promising strategy for pancreatic cancer. This study aims to construct engineered extracellular vesicles (EVs) with surface modification of integrin α5 (ITGA5)-targeting peptide and high internal expression of miR-148a-3p by endogenous modification for targeted reprogramming of pancreatic CAFs.

Methods:

Bone marrow mesenchymal stem cells (BMSCs) and pancreatic CAFs were cocultured to examine the effect of BMSC-derived EVs on the expression levels of CAF markers. miR-148a-3p was identified as a functional molecule. The mechanism of miR-148a-3p was elucidated using the dual-luciferase reporter assay. BMSCs were infected with TERT-encoding and miR-148a-3p-encoding lentiviruses. Subsequently, BMSCs were modified with ITGA5-specific targeting peptide. The supernatant was ultracentrifuged to obtain the engineered EVs (ITGA5-EVs-148a), which were used to reprogram CAFs.

Results:

BMSCs modulated CAF marker expressions through EVs. miR-148a-3p was up-regulated in BMSCs. The expression of miR-148a-3p in pancreatic CAFs was down-regulated when compared with that in normal fibroblasts (NFs). Mechanistically, ITGA5-EVs-148a effectively suppressed the proliferation and migration of pancreatic CAFs by targeting ITGA5 through the TGF-ß/SMAD pathway. ITGA5-EVs-148a was associated with enhanced cellular uptake and exhibited enhanced in vitro and in vivo targeting ability. Moreover, ITGA5-EVs-148a exerted strong reconfiguration effects in inactivating CAFs and reversing tumor-promoting effects in 3D heterospheroid and xenograft pancreatic cancer models.

Conclusions:

This targeted CAF reprogramming strategy with genetically engineered ITGA5-EVs-148a holds great promise as a precision therapeutics in clinical settings.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomater Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomater Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos