4.3 Review

Signal transduction pathways alter the molecular cargo of extracellular vesicles: implications in regenerative medicine

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Article Oncology

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

Patricia Gonzalez-Callejo et al.

Summary: Tumor-secreted extracellular vesicles play a crucial role in the establishment and growth of metastatic tumors. The diversity among these vesicles, particularly in triple-negative breast cancer, has not been fully explored. This study found that vesicles secreted by cancer stem cells and differentiated cancer cells have distinct effects on the tumor microenvironment, promoting different aspects of tumor growth and metastasis.

INTERNATIONAL JOURNAL OF CANCER (2023)

Article Cell & Tissue Engineering

Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model

Rabea J. Madel et al.

Summary: Extracellular vesicles (EVs) derived from human mesenchymal stromal cells (MSCs) have the potential to suppress acute inflammation and promote tissue regeneration. However, there are variations in the immunomodulatory capabilities of different MSC-EV preparations. Therefore, the therapeutic potency of each individual MSC-EV preparation should be evaluated before clinical application.

CYTOTHERAPY (2023)

Review Oncology

Cancer as an infective disease: the role of EVs in tumorigenesis

Lucia Robado de Lope et al.

Summary: Cancer is considered an evolutionary disease where tumor cells adapt to the environment and eventually form metastasis. Communication between tumor cells and the surrounding microenvironment via extracellular vesicles (EVs) is crucial for the success of the metastatic process. Recent studies suggest that tumor-derived EVs not only modify the microenvironment to facilitate tumor progression but also induce malignant transformation in cells outside the primary tumor. Further research is needed to understand the role of EVs in cancer progression and metastasis, which may have implications for novel cancer treatments.

MOLECULAR ONCOLOGY (2023)

Review Cell & Tissue Engineering

Mesenchymal Stem Cells-Derived Apoptotic Extracellular Vesicles (ApoEVs): Mechanism and Application in Tissue Regeneration

Yufan Zhu et al.

Summary: Mesenchymal stem cells (MSCs) are commonly used for cellular therapy due to their immunosuppressive and regenerative effects. However, MSCs undergo extensive apoptosis after transplantation. During apoptosis, MSCs generate apoptotic extracellular vesicles (MSCs-ApoEVs), which play a critical role in intercellular communication and tissue regeneration. This review provides a detailed overview of the production, release, isolation, functionality, and potential clinical applications of MSCs-ApoEVs.

STEM CELLS (2023)

Article Cell Biology

Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy

Simon Heidegger et al.

Summary: Tumor-derived extracellular vesicles (EVs) play a role in immune evasion and tumor progression through the RNA-sensing receptor RIG-I. Activation of RIG-I releases EVs that promote dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a are necessary for the generation of immunostimulatory EVs. The composition of the EV RNA cargo, including small non-coding stimulatory RNAs, is regulated by active intrinsic RIG-I signaling. Increased transcriptional activity of EV pathway genes and RIG-I in melanoma samples is associated with prolonged patient survival and positive response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses.

CELL REPORTS MEDICINE (2023)

Article Multidisciplinary Sciences

Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires

Akira Yokoi et al.

Summary: Cancer cell-derived extracellular vesicles (EVs) could be potential targets for disease biomarkers due to their unique protein profiles. Analysis of small EVs (sEVs) and medium/large EVs (m/lEVs) revealed that both subtypes had distinct proteomic characteristics. Specific sEV proteins (FRa, Claudin-3, and TACSTD2) for high-grade serous ovarian carcinoma (HGSOC) were identified, while no candidates were found for m/lEVs. Additionally, a microfluidic device using polyketone-coated nanowires (pNWs) was developed for efficient sEV isolation and showed specific detectability in cancer patients and predicted clinical status.

SCIENCE ADVANCES (2023)

Article Oncology

MEK/ERK-mediated oncogenic signals promote secretion of extracellular vesicles by controlling lysosome function

Tomoya Hikita et al.

Summary: Cancer cells secrete EVs derived from MVBs, and the MEK/ERK pathway controls MVB fate and promotes EV production in cancer cells by inactivating lysosomal function.

CANCER SCIENCE (2022)

Article Cell & Tissue Engineering

Oral Progenitor Cell Line-Derived Small Extracellular Vesicles as a Treatment for Preferential Wound Healing Outcome

Rob Knight et al.

Summary: Researchers have developed an immortalized oral progenitor cell line that produces small extracellular vesicles (sEVs) capable of promoting wound healing and inhibiting scar formation. These oral sEVs show higher potency and functionality compared to sEVs derived from other cell sources, making them a preferred product for therapeutic development. This study provides a new option for non-scarring wound healing in clinical settings.

STEM CELLS TRANSLATIONAL MEDICINE (2022)

Review Chemistry, Multidisciplinary

Extracellular Vesicles for Regenerative Medicine Applications

Raphael J. Crum et al.

Summary: Tissue engineering and regenerative medicine focus on developing new techniques, devices, and materials to replace or repair injured or diseased tissue and organs. These approaches use cells, scaffolds, and signaling molecules to promote repair and regeneration. Extracellular vesicles have emerged as key mediators of tissue regeneration and repair.

APPLIED SCIENCES-BASEL (2022)

Review Neurosciences

Extracellular vesicles through the blood-brain barrier: a review

Hector M. Ramos-Zaldivar et al.

Summary: Extracellular vesicles (EVs) are non-replicative particles released from cells. The mechanism of bidirectional EVs transport across the blood-brain barrier (BBB) is poorly understood. Current research lacks direct visualization of EVs transcytosis through the BBB in mammals, with most studies relying on in vitro models that do not consider the combined effect of all cellular layers constituting the BBB. Further research using in vitro and in vivo methodologies is needed to clarify these issues.

FLUIDS AND BARRIERS OF THE CNS (2022)

Article Cell Biology

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

Alessio Lanna et al.

Summary: It was discovered that some T cells can elongate telomeres by acquiring telomere vesicles from antigen-presenting cells, independently of telomerase action, which contributes to delaying the aging process.

NATURE CELL BIOLOGY (2022)

Review Biology

Extracellular signals regulate the biogenesis of extracellular vesicles

Yong Jin et al.

Summary: Extracellular vesicles (EVs) are naturally released membrane vesicles that act as carriers of proteins and RNAs for intercellular communication. With high efficiency and specificity, EVs provide a novel form of information transfer compared to classical signal transduction. In addition, EVs can collect extracellular information, extending the concept of signal transduction. The functions of EVs have been extensively studied and show great potential for clinical applications. However, the biogenesis of EVs and the regulation of this process by extracellular signals remain unclear.

BIOLOGICAL RESEARCH (2022)

Article Cell & Tissue Engineering

The Intercellular Communication Between Mesenchymal Stromal Cells and Hematopoietic Stem Cells Critically Depends on NF-κB Signalling in the Mesenchymal Stromal Cells

Shalmali Pendse et al.

Summary: Mesenchymal stromal cells (MSCs) regulate the fate of hematopoietic stem cells (HSCs) through cell-cell interactions and paracrine mechanisms. CoCl2-treated MSCs have inhibited growth due to activation of the NF-kappa B signaling pathway, which also blocks their communication with co-cultured HSCs. This communication is essential for effective hematopoiesis, as it involves adhesion molecules and HSC-supportive factors in the MSCs.

STEM CELL REVIEWS AND REPORTS (2022)

Review Biochemistry & Molecular Biology

Membrane Microvesicles as Potential Vaccine Candidates

Layaly Shkair et al.

Summary: The prevention and control of infectious diseases is crucial, with vaccination being an effective approach. Microvesicles are suggested as potential vehicles for antigen delivery, carrying various immunogenic molecules directly to target cells.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

Article Biochemical Research Methods

Isolation and characterization of extracellular vesicle subpopulations from tissues

Rossella Crescitelli et al.

Summary: This study presents a protocol for isolating multiple EV subpopulations directly from tissues, including enzymatic treatment, ultracentrifugation, density separation, electron microscopy characterization, etc., which can be completed in 22 hours. The approach can be applied to tissues such as human melanoma metastases and can be adopted by researchers experienced with cell culture and EV isolation.

NATURE PROTOCOLS (2021)

Review Oncology

The forces driving cancer extracellular vesicle secretion

Maarten P. Bebelman et al.

Summary: The discovery of cancer cells releasing large quantities of extracellular vesicles (EVs) has sparked a rapid growth in the field, leading to research on their functions in cancer and potential therapeutic interventions. However, understanding the mechanisms behind EV biogenesis in cancer cells and identifying targets distinct from normal physiology remain key challenges in this area of study.

NEOPLASIA (2021)

Article Biology

Cryopreservation of mesenchymal stromal cell-derived extracellular vesicles using trehalose maintains their ability to expand hematopoietic stem cells in vitro

Pallavi Budgude et al.

Summary: Mesenchymal stromal cells (MSCs) have been highlighted as a promising source for regenerative therapies, with studies showing their therapeutic effects through the secretion of extracellular vesicles (EVs). Optimizing cryopreservation strategies for EVs could aid in their long-term storage and development as off-the-shelf biologics, improving their functionality for ex vivo expansion of hematopoietic stem cells (HSCs) in regenerative medicine.

CRYOBIOLOGY (2021)

Review Nanoscience & Nanotechnology

A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes

Sangiliyandi Gurunathan et al.

Summary: Exosomes are nanoscale membrane vesicles secreted by cells, which play important roles in intercellular communication and disease diagnosis. Research on exosomes has great potential in biomedical fields, but the underlying biological mechanisms require further exploration.

INTERNATIONAL JOURNAL OF NANOMEDICINE (2021)

Article Cell & Tissue Engineering

Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use

Renato M. S. Cardoso et al.

Summary: The article presents an optimized and scalable process for isolating extracellular vesicles (EV) smaller than 200 nm, secreted by umbilical cord blood mononuclear cells (UCB-MNC), providing a method foundation for further research in regenerative medicine. The use of ultrafiltration and size exclusion chromatography (UF/SEC) showed superior benefits compared to traditional ultracentrifugation (UC), allowing for increased vesicle yield and potential for mass production in a clinical setting.

STEM CELLS TRANSLATIONAL MEDICINE (2021)

Review Cell Biology

Tissue-derived extracellular vesicles in cancers and non-cancer diseases: Present and future

Su-Ran Li et al.

Summary: Extracellular vesicles (EVs) are lipid-bilayer membrane structures secreted by most cell types, acting as messengers through the transfer of lipids, proteins, and nucleic acids to influence cellular processes. Tissue-derived EVs (Ti-EVs) offer advantages such as tissue specificity and accurate reflection of the tissue microenvironment, playing important roles in intercellular communication and disease development insights. Current research on Ti-EVs is limited compared to body fluid or cell culture-derived EVs, highlighting the need for further exploration in basic and clinical applications.

JOURNAL OF EXTRACELLULAR VESICLES (2021)

Article Multidisciplinary Sciences

High-grade extracellular vesicles preparation by combined size-exclusion and affinity chromatography

Cristina Bellotti et al.

Summary: A new two-step fast performance liquid chromatography (FPLC) protocol has been developed for the purification of large numbers of extracellular vesicles (EVs), resulting in higher purity and more selective enrichment of exosomes. The method combines size exclusion chromatography with immobilized metal affinity chromatography for efficient separation of different types of EVs. This new approach holds promise for the isolation of defined subpopulations of EVs with preserved biological function that can be easily scaled up for production of larger amounts of EVs.

SCIENTIFIC REPORTS (2021)

Review Oncology

Restoring Tissue Homeostasis at Metastatic Sites: A Focus on Extracellular Vesicles in Bone Metastasis

Domenica Giannandrea et al.

Summary: Bone is a common site for cancer metastasis, with spread to the bone associated with poor prognosis, pain, increased fracture risk, and hypercalcemia. Extracellular vesicles (EVs) play a role in this metastatic process, potentially affecting tumor metastasis formation.

FRONTIERS IN ONCOLOGY (2021)

Review Cell & Tissue Engineering

Extracellular Vesicles in Regenerative Medicine: Potentials and Challenges

Ji Yong Lee et al.

Summary: Regenerative medicine aims to restore damaged tissues and organs, with extracellular vesicles (EVs) being a promising approach due to their ability to overcome limitations of cell therapies and be engineered for specific purposes. Over the past decade, EVs have emerged as a therapeutic agent for various diseases and conditions due to their multifaceted biological functions.

TISSUE ENGINEERING AND REGENERATIVE MEDICINE (2021)

Review Cell Biology

From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm

Jancy Johnson et al.

Summary: MSCs, as a leading cell source for stem cell therapy, have regenerative and immunomodulatory properties, but face challenges in clinical applications. EVs and EEVs, as potential cell-free alternatives, may overcome these challenges in the clinical application of MSCs.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

Article Oncology

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism

Susana Garcia-Silva et al.

Summary: Peinado and colleagues demonstrate that melanoma-secreted small extracellular vesicles (sEVs) and NGFR cargo can induce lymphangiogenesis and promote lymph node pre-metastatic niche formation, facilitating melanoma metastasis. Targeting NGFR could potentially prevent this process in pre-clinical settings.

NATURE CANCER (2021)

Review Biotechnology & Applied Microbiology

Mechanism of cargo sorting into small extracellular vesicles

Yiwen Chen et al.

Summary: Extracellular vesicles are membranous structures released by cells to transport biomolecules and signaling molecules between cells, with small sEVs and larger EVs being the two main types categorized by size. These vesicles are no longer considered waste products, but rather regulators of intercellular communication with specific cargos sorted into them through different mechanisms.

BIOENGINEERED (2021)

Article Cell & Tissue Engineering

Pharmacological Inhibition of p38 MAPK Rejuvenates Bone Marrow Derived-Mesenchymal Stromal Cells and Boosts their Hematopoietic Stem Cell-Supportive Ability

Pallavi Budgude et al.

Summary: Research has shown that ex vivo expanded MSCs display activated p38 MAPK signaling and increased oxidative stress, leading to compromised hematopoietic stem cell support functions. Priming MSCs with a p-38 MAPK inhibitor can enhance their niche-supportive abilities, improving the outcome of regenerative therapies involving in vitro cultured MSCs.

STEM CELL REVIEWS AND REPORTS (2021)

Review Chemistry, Multidisciplinary

Isolation and characterization of extracellular vesicles for clinical applications in cancer - time for standardization?

Nikki Salmond et al.

Summary: EVs are nanometer sized particles released by cells, playing important roles in cell communication and therapeutic delivery. However, lack of standardization in isolating and characterizing EVs calls for more rigorous methods and standardization.

NANOSCALE ADVANCES (2021)

Article Pharmacology & Pharmacy

Preserving extracellular vesicles for biomedical applications: consideration of storage stability before and after isolation

Fumin Yuan et al.

Summary: Extracellular vesicles (EVs) are nanovesicles released by various cell types, known for their potent biological activities. While -80 degrees C is considered as the most favorable condition for storage, challenges remain in understanding the impact of storage conditions on EVs, indicating further research is needed.

DRUG DELIVERY (2021)

Review Biochemical Research Methods

Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles

Andrew M. Leidal et al.

METHODS (2020)

Article Cell & Tissue Engineering

Extracellular vesicles for acute kidney injury in preclinical rodent models: a meta-analysis

Chao Liu et al.

STEM CELL RESEARCH & THERAPY (2020)

Review Pharmacology & Pharmacy

Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations

Natalia L. Klyachko et al.

PHARMACEUTICS (2020)

Review Biochemistry & Molecular Biology

Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking

Daniel E. Murphy et al.

EXPERIMENTAL AND MOLECULAR MEDICINE (2019)

Review Cell Biology

Shedding light on the cell biology of extracellular vesicles

Guillaume van Niel et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2018)

Review Pharmacology & Pharmacy

Biogenesis and function of extracellular vesicles in cancer

Maarten P. Bebelman et al.

PHARMACOLOGY & THERAPEUTICS (2018)

Review Medicine, Research & Experimental

The biology and function of exosomes in cancer

Raghu Kalluri

JOURNAL OF CLINICAL INVESTIGATION (2016)

Editorial Material Cardiac & Cardiovascular Systems

Exosomes as Potential Alternatives to Stem Cell Therapy in Mediating Cardiac Regeneration

Sang-Ging Ong et al.

CIRCULATION RESEARCH (2015)

Article Multidisciplinary Sciences

Tumour exosome integrins determine organotropic metastasis

Ayuko Hoshino et al.

NATURE (2015)

Article Cell Biology

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Bruno Costa-Silva et al.

NATURE CELL BIOLOGY (2015)

Article Biochemistry & Molecular Biology

C-elegans Ciliated Sensory Neurons Release Extracellular Vesicles that Function in Animal Communication

Juan Wang et al.

CURRENT BIOLOGY (2014)

Article Biochemistry & Molecular Biology

Sorting signal targeting mRNA into hepatic extracellular vesicles

Natalia Szostak et al.

RNA BIOLOGY (2014)