bims-engexo 2024-12-29 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2024–12–29
eleven papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Exosomes, their sources, and possible uses in cancer therapy in the era of personalized medicine.
Exosomes derived from hypoxic mesenchymal stem cells restore ovarian function by enhancing angiogenesis.
Modulating exosomal communication between macrophages and melanoma cancer cells via cyclodextrin-based nanosponges loaded with doxorubicin.
Tadalafil Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells-Derived Exosomes in Pulmonary Hypertension by Upregulating miR-29a-3p.
Advances in the combination of stem cell exosomes with medical devices-the new direction for combination products.
Exosomal PVRL4 Promotes Lung Adenocarcinoma Progression by Enhancing the Generation of Myeloid-Derived Suppressor Cell-Secreted TGF-β1.
Isolation and Identification of Brain Tissue Extracellular Vesicles for Translational Proteomics.
MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis.
Exosomal ANXA2 facilitates ovarian cancer peritoneal metastasis by activating peritoneal mesothelial cells through binding with TLR2.
Brain-Derived Exosomal miR-9-5p Induces Ferroptosis in Traumatic Brain Injury-Induced Acute Lung Injury by Targeting Scd1.
Epidermal growth factor receptor ligands enriched in follicular fluid exosomes promote oncogenesis of fallopian tube epithelial cells.

J Cancer Res Clin Oncol. 2024 Dec 26. 151(1): 16

Exosomes, their sources, and possible uses in cancer therapy in the era of personalized medicine.

Tomas Zemanek, Lubos Danisovic, Andreas Nicodemou.

  Despite significant advances in immunotherapy, its efficacy in solid tumors remains limited. Exosomes, a primary type of extracellular vesicles, can transport diverse intracellular molecules to nearby or distant cells and organs, facilitating numerous biological functions. Research has shown that exosomes have the dual ability to both activate and suppress the immune system. Their potential as anticancer vaccines arise from the capacity to carry antigens and major histocompatibility complex (MHC) molecules. Exosomes derived from blood, saliva, urine, and cerebrospinal fluid serve as promising biomarkers for cancer diagnosis and prognosis. Recent advancements in exosome-based therapy have highlighted its utility in drug delivery and immunotherapy. This review examines the composition and sources of exosomes within the immune microenvironment of solid tumors and delves into the mechanisms and pathways through which exosomes impact immunotherapy. We further explore the clinical potential of engineered exosomes and exosome vaccines in solid tumor immunotherapy. These insights may pave the way for exosome-based strategies in cancer diagnosis, treatment, and prognosis, enhancing the effectiveness of immunotherapy for solid tumors.

Keywords:  Cancer; Cell therapy; Exosomes; Immunotherapy; Personalized medicine; Tumor

DOI:  https://doi.org/10.1007/s00432-024-06066-w
Stem Cell Res Ther. 2024 Dec 21. 15(1): 496

Exosomes derived from hypoxic mesenchymal stem cells restore ovarian function by enhancing angiogenesis.

Qingxi Qu, Linghong Liu, Limei Wang, Yuqian Cui, Chunxiao Liu, Xuanxuan Jing, Xiaoxuan Xu.

   BACKGROUND: hucMSC-exosomes can be engineered to strengthen their therapeutic potential, and the present study aimed to explore whether hypoxic preconditioning can enhance the angiogenic potential of hucMSC-exosomes in an experimental model of POF.
METHODS: Primary hucMSCs and ROMECs were isolated from fresh tissue samples and assessed through a series of experiments. Exosomes were isolated from hucMSCs under normoxic or hypoxic conditions (norm-Exos and hypo-Exos, respectively) and then characterized using classic experimental methods. Based on a series of angiogenesis-related assays, we found that hypo-Exos significantly promoted ROMEC proliferation, migration, and tube formation and increased angiogenesis-promoting molecules in vitro. Histology, immunohistochemistry, and immunofluorescence experiments in a rat model of POF demonstrated that hypoxia pretreatment strengthens the therapeutic angiogenic effect of hucMSC-exosomes in vivo. Subsequently, high-throughput miRNA sequencing, qRT‑PCR analysis, and western blotting were employed to identify the potential molecular mechanism.
RESULTS: We found that hypo-Exos enhance endothelial function and angiogenesis via the transfer of miR-205-5p in vitro and in vivo. Finally, based on the results of bioinformatics analysis, dual luciferase reporter assays, and gain- and loss-of-function studies, we found evidence indicating that exosomal miR-205-5p enhances angiogenesis by targeting the PTEN/PI3K/AKT/mTOR signalling pathway. These results indicated for the first time that exosomes derived from hypoxia-conditioned hucMSCs strongly enhance angiogenesis via the transfer of miR-205-5p by targeting the PTEN/PI3K/AKT/mTOR signalling pathway.
CONCLUSIONS: Our findings provide a theoretical basis and demonstrate the potential application of a novel cell-free approach with stem cell-derived products in the treatment of POF.

Keywords:  Angiogenesis; Exosomes; Hypoxic preconditioning; Mesenchymal stem cells; PTEN; Premature ovarian failure; miR-205-5p

DOI:  https://doi.org/10.1186/s13287-024-04111-6
Nanotoxicology. 2024 Dec 27. 1-11

Modulating exosomal communication between macrophages and melanoma cancer cells via cyclodextrin-based nanosponges loaded with doxorubicin.

Mohammad Mahmoudian, Shokoufeh Alizadeh, Darya Lotfi, Yousef Khazaei Monfared, Mahdi Mahdipour, Francesco Trotta, Parvin Zakeri-Milani, Ziba Islambulchilar.

  The cellular components of the tumor microenvironment (TME) comprise cancer cells and nonmalignant cells including stromal and immune cells. Exosomes are extracellular vesicles secreted by various types of cells that play a crucial role in intercellular communications within TME. The main goal of this study was to elucidate how exosomes of macrophage cells treated with doxorubicin (DOX) and DOX-loaded cyclodextrin-based nanosponges (DOX-CDNSs), affect melanoma cancer cell proliferation. For this aim, the exosomes of the murine macrophage cell line (RAW 264.7) were isolated and characterized after treating the cells with DOX and DOX-CDNSs. The results demonstrated that DOX-CDNSs at a treatment concentration of 1 µg/mL, were nontoxic for macrophages and remarkably toxic against cancer cells. However, DOX was nontoxic for both cell types at the same treatment concentration. DOX and DOX-CDNSs remarkably declined the viability of both cell types at higher concentrations (25 and 50 µg/mL). Intriguingly, the exosomes of DOX-CD-NSs treated macrophages promoted the viability of cancer cells at the treatment concentrations of 1, 20, and 40 µg/mL. While the exosomes of DOX-treated macrophages increased cell viability of cancer cells only at the lowest concentration. In conclusion, this study suggests that utilization of CD-NSs may augment the toxicity of DOX against cancer cells, while it could direct macrophages toward secreting exosomes that favor the growth of cancer cells.

Keywords:  Exosomes; cyclodextrin (CD)-based nanosponges; doxorubicin; macrophages; melanoma cancer cells

DOI:  https://doi.org/10.1080/17435390.2024.2446553
Int J Nanomedicine. 2024 ;19 13525-13546

Tadalafil Enhances the Therapeutic Efficacy of Mesenchymal Stem Cells-Derived Exosomes in Pulmonary Hypertension by Upregulating miR-29a-3p.

Yi Liu, Changqing He, Quanhai Zhong, Xianbao Shi, Hongyan Li, Gaoge Fu, Lixuan Guo, Churong Zhao, Lei Tian, Xin Li, Xue Jiao, Lina Shan.

   Introduction: Pulmonary hypertension (PH) is a progressive and life-threatening condition. Recent research has demonstrated that exosomes derived from mesenchymal stem cells (MSC) exhibit significant therapeutic potential in the treatment of PH. The composition of these exosomes is often substantially influenced by the characteristics of their parental cells. This study aimed to identify an intervention strategy to enhance the efficacy of mesenchymal stem cell exosomes in treating PH.
Methods: Exosomes were isolated from control MSC and tadalafil-pretreated MSCs. In vitro and in vivo studies were conducted.
Results: MSCTAD-Exo attenuated macrophage inflammation and improved endothelial cell (EC) apoptosis while also reducing pulmonary arterial pressure in a hypoxia-induced rat model. Furthermore, MSC exosomes can mitigate hypoxia-induced proliferation and migration of smooth muscle cells (SMC) by influencing the secretion of endothelial exosomes. MiR-29a-3p has been identified as a crucial mediator in this process, with its expression regulated by cAMP responsive element binding protein 1 (CREB1). MiR-29a-3p exerts anti-inflammatory effects by modulating the expression of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2). Notably, the anti-inflammatory and anti-vascular remodeling activities of exosomes were diminished following the depletion of MiR-29a-3p.
Discussion: MSC treated with tadalafil can secrete better exosomes. MSCTAD-Exo may enhance anti-inflammatory and anti-vascular remodeling properties by upregulating mir-29a-3p expression, providing a novel idea for PH therapy. Future studies could explore the clinical application of this finding.

Keywords:  exosome; hypoxia pulmonary hypertension; mesenchymal stem cell; miR-29a-3p; tadalafil

DOI:  https://doi.org/10.2147/IJN.S493047
Chin J Nat Med. 2024 Dec;pii: S1875-5364(24)60637-0. [Epub ahead of print]22(12): 1067-1075

Advances in the combination of stem cell exosomes with medical devices-the new direction for combination products.

Yuewen Zhai, Fang He, Ji Fang, Siwen Li.

  Exosomes (exos), nanoscale extracellular vesicles, play a critical role in tissue development and function. Stem cell-derived exos, containing various tissue repair components, show promise as natural therapeutic agents in disease treatment and regenerative medicine. However, challenges persist in their application, particularly in targeted delivery and controlled release, which are crucial for enhancing their biological efficacy. The integration of medical devices may provide a superior platform for improving drug bioavailability. Consequently, the combination products of stem cell-derived exos and medical devices present novel opportunities for expanding the therapeutic potential of exosomes. This review offers a comprehensive overview of the current research frontier in stem cell-derived exos combined with medical devices and discusses the prospective challenges and future prospects in this field.

Keywords:  Combination products; Medical devices; Stem cell exosomes; Tissue repair

DOI:  https://doi.org/10.1016/S1875-5364(24)60637-0
Thorac Cancer. 2024 Dec 26.

Exosomal PVRL4 Promotes Lung Adenocarcinoma Progression by Enhancing the Generation of Myeloid-Derived Suppressor Cell-Secreted TGF-β1.

Yahai Liang, Jinmei Li, Lihua Zhang, Jinling Zhou, Meilian Liu, Xiaoxia Peng, Weizhen Zheng, Zhennan Lai.

   BACKGROUND: The cancer cell marker poliovirus receptor-like protein 4 (PVRL4) has been shown to be highly expressed in many cancers, including lung cancer. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells with immunosuppressive roles that can attenuate the anticancer response. Here, the precise functions and the relationship between PVRL4 and MDSCs in lung adenocarcinoma (LUAD) progression were investigated.
METHODS: Detection of levels of mRNAs and proteins was conducted using qRT-PCR and western blotting. The CCK-8, colony formation, transwell, wound healing assays, and flow cytometry were used to explore cell growth, invasion, migration, and apoptosis, respectively. ELISA analysis detected TGF-β1 contents. LUAD mouse models were established for in vivo assay. Exosomes were isolated by ultracentrifugation. MDSCs were induced from peripheral blood mononuclear cells (PBMCs) by cytokine or co-culture with cancer cells.
RESULTS: LUAD tissues and cells showed high PVRL4 expression, and PVRL4 deficiency suppressed LUAD cell proliferation, invasion, migration, and induced cell apoptosis in vitro, and impeded LUAD growth in vivo. Thereafter, we found that PVRL4 was packaged into exosomes in LUAD cells, and could be transferred into PBMCs to promote MDSC induction and the expression of MDSC-secreted TGF-β1. Functionally, the silencing of exosomal PVRL4 impaired LUAD cell proliferation, invasion, migration, and evoked cell apoptosis, which could be reversed by the incubation of TGF-β1-overexpressed MDSCs.
CONCLUSION: Exosomal PVRL4 promoted LUAD progression by inducing the secretion of TGF-β1 in MDSCs, indicating a novel direction for LUAD immunotherapy.

Keywords:  LUAD; MDSCs; PBMCs; PVRL4; TGF‐β1; exosome; immunosuppressive activity

DOI:  https://doi.org/10.1111/1759-7714.15495
Methods Mol Biol. 2025 ;2884 225-239

Isolation and Identification of Brain Tissue Extracellular Vesicles for Translational Proteomics.

Michelle V Lihon, Nathan A Tuchscherer, W Andy Tao.

  Extracellular vesicles (EVs) are small membrane-bound structures that play important roles in intercellular communication and the transfer of biomolecules between cells. EVs have become a topic of interest for research in translational proteomics for disease biomarker discovery due to their ability to reflect changes in the cellular proteome, including diseases affecting the brain. Utilizing the proteome analysis of EVs to its fullest potential requires proper isolation and purity. In this chapter, we describe a detailed method for the isolation and identification of brain tissue EVs for translational proteomics using our in-house chemical affinity magnetic bead-based (non-antibody) method, the EVtrap. We also discuss various methods for quantification, characterization, and functional analysis of isolated brain tissue EVs, including western blotting, and proteomic profiling of post-translational modifications (PTMs) involved in neurodegenerative diseases, such as protein N-terminal acetylation. This protocol provides a valuable resource for studies conducted on brain tissue EVs and their potential as biomarkers and therapeutic targets for neurological diseases.

Keywords:  Brain tissue; DDA; EVtrap; Exosomes; Extracellular vesicles (EVs); Label-free proteomics; Mass spectrometry; Relative quantitative proteomics; Tissue

DOI:  https://doi.org/10.1007/978-1-0716-4298-6_15
Commun Biol. 2024 Dec 26. 7(1): 1700

MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis.

Zheng Wang, Hongbo Xu, Bichen Xue, Lian Liu, Yulin Tang, Zhichao Wang, Kai Yao.

Diabetic foot ulcer (DFU) is a common but devastating complication of diabetes mellitus and might ultimately lead to amputation. Elucidating the regulatory mechanism of wound healing in DFU is quite important for developing DFU management strategies. Here, we show, mecenchymal stem cell (MSC)-derived exosomes promoted the proliferation, migration and angiogenesis of high glucose-treated endothelial cells and reduced cell apoptosis. These effects were further enhanced by MSC-derived exosomes carrying circMYO9B overexpression. Mechanistically, circMYO9B promoted the translocation of hnRNPU from nucleus to cytoplasm and consequently destabilized CBL, thereby reducing the ubiquitination and degradation of KDM1A to promote VEGFA expression in endothelial cells. MSC-derived exosomes carrying circMYO9B promotes angiogenesis and thus accelerates diabetic wound healing through regulating the hnRNPU/CBL/KDM1A/VEGFA axis, indicating potential therapeutic targets and strategies for DFU treatment.

DOI: https://doi.org/10.1038/s42003-024-07367-z
Cell Commun Signal. 2024 Dec 21. 22(1): 616

Exosomal ANXA2 facilitates ovarian cancer peritoneal metastasis by activating peritoneal mesothelial cells through binding with TLR2.

Jingni Zhang, Hongmei Liu, Qiulei Wu, Tong Liu, Xiaoli Liu, Jing Cai, Xiaoqing Yi, Zehua Wang, Lingling Gao.

   BACKGROUND: Peritoneal dissemination of ovarian cancer (OvCa) can be largely attributed to the formation of a metastatic microenvironment driven by tumoral exosomes. Here, we aimed to elucidate the mechanisms through which exosomal annexin A2 (ANXA2) derived from OvCa cells induces an HPMC phenotypic shift in favour of peritoneal metastasis.
METHODS: Immunohistochemistry and orthotopic and intraperitoneal OvCa xenograft mouse models were used to clarify the relationship between tumour ANXA2 expression and peritoneal metastasis. Exosomes were isolated from OvCa cell lines via ultracentrifugation. Functional experiments on cell proliferation and motility, and western blot were performed to investigate the activation of HPMCs and its impact on tumour cell in vitro. High-throughput transcriptional sequencing and rescue experiments in which ANXA2 inhibitor (LCKLSL) or the toll-like receptor 2 (TLR2) inhibitor (C29) was used to co-culture the HPMCs with exosome were employed to identify the crucial functional molecules through which exosomal ANXA2 activates HPMCs. The impact of exosomal ANXA2-activated HPMCs on tumour progression was assessed via functional experiments.
RESULTS: Primary OvCa samples with high ANXA2 expression exhibited a stronger tendency to metastasize to the abdominal cavity. Tumoral ANXA2 promoted OvCa peritoneal metastasis through the secretion of exosomes carrying ANXA2. ANXA2-loaded exosomes activated HPMCs through exosomal ANXA2 binding to TLR2, shifting the phenotype of HPMCs towards mesenchymal cells, increasing their migration and invasion capacities, and elevating the expression of lipocalin 2 (LCN2). High LCN2 expression in HPMCs promoted OvCa cell adhesion, proliferation, motility, and lipid metabolism reprogramming.
CONCLUSION: Exosomal ANXA2 secreted by tumour cells activates HPMCs and induces the expression of LCN2, which in turn promotes the peritoneal metastasis of OvCa.

Keywords:  Annexin A2; Exosome; Human peritoneal mesothelial cell; Lipocalin 2; Ovarian cancer; Toll-like receptor 2

DOI:  https://doi.org/10.1186/s12964-024-01987-y
CNS Neurosci Ther. 2024 Dec;30(12): e70189

Brain-Derived Exosomal miR-9-5p Induces Ferroptosis in Traumatic Brain Injury-Induced Acute Lung Injury by Targeting Scd1.

Yi Zhang, Chang Sun, Bailun Wang, Angran Gu, Ziyi Zhou, Changping Gu.

   AIMS: This study aimed to explore the role and underlying mechanisms of brain-derived exosomes in traumatic brain injury-induced acute lung injury (TBI-induced ALI), with a particular focus on the potential regulation of ferroptosis through miRNAs and Scd1.
METHODS: To elucidate TBI-induced ALI, we used a TBI mouse model. Exosomes were isolated from the brains of these mice and characterized using TEM and NTA. LC-MS analysis revealed an increase in the level of ferroptosis in the lung tissues of mice with TBI. Subsequent miRNA and mRNA sequencing revealed the upregulation of miR-9-5p and the downregulation of Scd1 in the pulmonary tissues of these mice. Ferroptosis was assessed by quantifying the levels of ROS, MDA, and Fe2+ and the expression of proteins associated with ferroptosis.
RESULTS: TBI led to the release of exosomes enriched with miR-9-5p, which targeted Scd1 in lung tissue, thereby promoting ferroptosis. Treatment with antagomir 9-5p reduced the level of ALI in TBI mice, indicating that exosomal miR-9-5p plays a significant role in TBI-induced ALI.
CONCLUSION: This study revealed that brain-derived exosomal miR-9-5p mediates ferroptosis in TBI-induced ALI by targeting Scd1. These findings may provide new insights into the complex interplay between TBI and ALI and highlight the potential of miR-9-5p as a target for the development of novel therapeutic strategies.

Keywords:  Ferroptosis; Scd1; TBI‐induced ALI; exosomes; miR‐9‐5p

DOI:  https://doi.org/10.1111/cns.70189
Cancer Cell Int. 2024 Dec 21. 24(1): 424

Epidermal growth factor receptor ligands enriched in follicular fluid exosomes promote oncogenesis of fallopian tube epithelial cells.

Aye Aye Khine, Pao-Chu Chen, Ying-Hsi Chen, Sung-Chao Chu, Hsuan-Shun Huang, Tang-Yuan Chu.

   BACKGROUND: Incessant ovulation is the main etiologic factor of ovarian high-grade serous carcinomas (HGSC), which mostly originate from the fallopian tube epithelium (FTE). Receptor tyrosine kinase (RTK) ligands essential for follicle development and ovulation wound repair were abundant in the follicular fluid (FF) and promoted the transformation of FTE cells. This study determined whether RTK ligands are present in FF exosomes and whether epidermal growth factor receptor (EGFR) signaling is essential for oncogenic activity.
METHODS: The FF of women undergoing in vitro fertilization was fractionated based on the richness of exosomes and tested for transformation toward FTE cells under different RTK inhibitors. EGFR ligands in FF exosomes were identified, and downstream signaling proteins in FTE cells were characterized.
RESULTS: The transforming activity of FF was almost exclusively enriched in exosomes, which possess a high capacity to induce anchorage-independent growth, clonogenicity, migration, invasion, and proliferation of FTE cells. EGFR inhibition abolished most of these activities. FF and FF exosome exposure markedly increased EGFR phosphorylation and the downstream signal proteins, including AKT, MAPK, and FAK. Multiple EGF family growth factors, such as amphiregulin, epiregulin, betacellulin, and transforming growth factor-alpha, were identified in FF exosomes.
CONCLUSIONS: Our results demonstrate that FF exosomes serve as carriers of EGFR ligands as well as ligands of other RTKs that mediate the transformation of FTE cells and underscore the need to further explore the content and roles of FF exosomes in HGSC development.

Keywords:  Epidermal growth factor receptor (EGFR); Follicular fluid (FF); High-grade serous carcinomas (HGSC); Ovulation; exosome

DOI:  https://doi.org/10.1186/s12935-024-03614-9