Extracellular Vesicles: A New Prospective in Crosstalk between Microenvironment and Stem Cells in Hematological Malignancies

The bone marrow (BM) microenvironment in hematological malignancies (HMs) comprises heterogeneous populations of neoplastic and nonneoplastic cells. Cancer stem cells (CSCs), neoplastic cells, hematopoietic stem cells (HSCs), and mesenchymal stromal/stem cells (MSCs) are all components of this microenvironment. CSCs are the HM initiators and are associated with neoplastic growth and drug resistance, while HSCs are able to reconstitute the entire hematopoietic system; finally, MSCs actively support hematopoiesis. In some HMs, CSCs and neoplastic cells compromise the normal development of HSCs and perturb BM-MSCs. In response, “reprogrammed” MSCs generate a favorable environment to support neoplastic cells. Extracellular vesicles (EVs) are an important cell-to-cell communication type in physiological and pathological conditions. In particular, in HMs, EV secretion participates to unidirectional and bidirectional interactions between neoplastic cells and BM cells. The transfer of EV molecular cargo triggers different responses in target cells; in particular, malignant EVs modify the BM environment in favor of neoplastic cells at the expense of normal HSCs, by interfering with antineoplastic immunity and participating in resistance to treatment. Here, we review the role of EVs in BM cell communication in physiological conditions and in HMs, focusing on the effects of BM niche EVs on HSCs and MSCs.

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The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

Cells ◽

10.3390/cells10092316 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2316

Author(s):

Lucia Catani ◽

Michele Cavo ◽

Francesca Palandri

Keyword(s):

Extracellular Vesicles ◽

Immune Escape ◽

Myeloproliferative Neoplasms ◽

Cell Communication ◽

Bioactive Molecules ◽

Driver Genes ◽

Hematopoietic Stem ◽

Increased Risk ◽

Patients Experience

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.

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The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.635189 ◽

2021 ◽

Vol 9 ◽

Author(s):

Laura Mosteo ◽

Joanna Storer ◽

Kiran Batta ◽

Emma J. Searle ◽

Delfim Duarte ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Hematopoietic Stem ◽

Vascular Niche ◽

Dynamic Interface ◽

Bone Marrow Vascular Niche ◽

Bidirectional Interactions ◽

Vascular Compartment

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in “inflamm-aging” and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

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Very Long-Chain C24:1 Ceramide Is Increased in Serum Extracellular Vesicles with Aging and Can Induce Senescence in Bone-Derived Mesenchymal Stem Cells

Cells ◽

10.3390/cells8010037 ◽

2019 ◽

Vol 8 (1) ◽

pp. 37 ◽

Cited By ~ 21

Author(s):

Andrew Khayrullin ◽

Priyanka Krishnan ◽

Luis Martinez-Nater ◽

Bharati Mendhe ◽

Sadanand Fulzele ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Cardiovascular Health ◽

Rhesus Macaques ◽

Cell Communication ◽

Size Exclusion ◽

Target Cells ◽

Serum Samples

Extracellular vesicles (EVs), including exosomes and microvesicles, function in cell-to-cell communication through delivery of proteins, lipids and microRNAs to target cells via endocytosis and membrane fusion. These vesicles are enriched in ceramide, a sphingolipid associated with the promotion of cell senescence and apoptosis. We investigated the ceramide profile of serum exosomes from young (24–40 yrs.) and older (75–90 yrs.) women and young (6–10 yrs.) and older (25–30 yrs.) rhesus macaques to define the role of circulating ceramides in the aging process. EVs were isolated using size-exclusion chromatography. Proteomic analysis was used to validate known exosome markers from Exocarta and nanoparticle tracking analysis used to characterize particle size and concentration. Specific ceramide species were identified with lipidomic analysis. Results show a significant increase in the average amount of C24:1 ceramide in EVs from older women (15.4 pmol/sample) compared to those from younger women (3.8 pmol/sample). Results were similar in non-human primate serum samples with increased amounts of C24:1 ceramide (9.3 pmol/sample) in older monkeys compared to the younger monkeys (1.8 pmol/sample). In vitro studies showed that primary bone-derived mesenchymal stem cells (BMSCs) readily endocytose serum EVs, and serum EVs loaded with C24:1 ceramide can induce BMSC senescence. Elevated ceramide levels have been associated with poor cardiovascular health and memory impairment in older adults. Our data suggest that circulating EVs carrying C24:1 ceramide may contribute directly to cell non-autonomous aging.

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Stem cells and extracellular vesicles: biological regulators of physiology and disease

AJP Cell Physiology ◽

10.1152/ajpcell.00017.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. C155-C166 ◽

Cited By ~ 7

Author(s):

Theodor Borgovan ◽

Lorin Crawford ◽

Chibuikem Nwizu ◽

Peter Quesenberry

Keyword(s):

Stem Cells ◽

Extracellular Vesicles ◽

Cell Types ◽

Target Cells ◽

Malignant Phenotype ◽

Marrow Mesenchymal Stem Cells ◽

Physiological Homeostasis ◽

Clinical Advances ◽

Machine Learning Models

Many different subpopulations of subcellular extracellular vesicles (EVs) have been described. EVs are released from all cell types and have been shown to regulate normal physiological homeostasis, as well as pathological states by influencing cell proliferation, differentiation, organ homing, injury and recovery, as well as disease progression. In this review, we focus on the bidirectional actions of vesicles from normal and diseased cells on normal or leukemic target cells; and on the leukemic microenvironment as a whole. EVs from human bone marrow mesenchymal stem cells (MSC) can have a healing effect, reversing the malignant phenotype in prostate and colorectal cancer, as well as mitigating radiation damage to marrow. The role of EVs in leukemia and their bimodal cross talk with the encompassing microenvironment remains to be fully characterized. This may provide insight for clinical advances via the application of EVs as potential therapy and the employment of statistical and machine learning models to capture the pleiotropic effects EVs endow to a dynamic microenvironment, possibly allowing for precise therapeutic intervention.

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Extracellular Vesicles from Mesenchymal Stem Cells as Potential Treatments for Osteoarthritis

Cells ◽

10.3390/cells10061287 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1287

Author(s):

Nur Azira Mohd Noor ◽

Asma Abdullah Nurul ◽

Muhammad Rajaei Ahmad Mohd Zain ◽

Wan Khairunnisaa Wan Nor Aduni ◽

Maryam Azlan

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Cartilage Regeneration ◽

Target Cells ◽

Inflammatory Drugs ◽

Degenerative Disorder ◽

Intercellular Communications

Osteoarthritis (OA) is a chronic degenerative disorder of the joint and its prevalence and severity is increasing owing to ageing of the population. Osteoarthritis is characterized by the degradation of articular cartilage and remodeling of the underlying bone. There is little understanding of the cellular and molecular processes involved in pathophysiology of OA. Currently the treatment for OA is limited to painkillers and anti-inflammatory drugs, which only treat the symptoms. Some patients may also undergo surgical procedures to replace the damaged joints. Extracellular vesicles (EV) play an important role in intercellular communications and their concentration is elevated in the joints of OA patients, although their mechanism is unclear. Extracellular vesicles are naturally released by cells and they carry their origin cell information to be delivered to target cells. On the other hand, mesenchymal stem cells (MSCs) are highly proliferative and have a great potential in cartilage regeneration. In this review, we provide an overview of the current OA treatments and their limitations. We also discuss the role of EV in OA pathophysiology. Finally, we highlight the therapeutic potential of MSC-derived EV in OA and their challenges.

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Cell Interplay in Osteoarthritis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.720477 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zihao Li ◽

Ziyu Huang ◽

Lunhao Bai

Keyword(s):

Stem Cells ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Cell Communication ◽

Synovial Fibroblasts ◽

Health Concern ◽

Common Chronic Disease ◽

Cell Tissue ◽

Induced Pluripotent

Osteoarthritis (OA) is a common chronic disease and a significant health concern that needs to be urgently solved. OA affects the cartilage and entire joint tissues, including the subchondral bone, synovium, and infrapatellar fat pads. The physiological and pathological changes in these tissues affect the occurrence and development of OA. Understanding complex crosstalk among different joint tissues and their roles in OA initiation and progression is critical in elucidating the pathogenic mechanism of OA. In this review, we begin with an overview of the role of chondrocytes, synovial cells (synovial fibroblasts and macrophages), mast cells, osteoblasts, osteoclasts, various stem cells, and engineered cells (induced pluripotent stem cells) in OA pathogenesis. Then, we discuss the various mechanisms by which these cells communicate, including paracrine signaling, local microenvironment, co-culture, extracellular vesicles (exosomes), and cell tissue engineering. We particularly focus on the therapeutic potential and clinical applications of stem cell-derived extracellular vesicles, which serve as modulators of cell-to-cell communication, in the field of regenerative medicine, such as cartilage repair. Finally, the challenges and limitations related to exosome-based treatment for OA are discussed. This article provides a comprehensive summary of key cells that might be targets of future therapies for OA.

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The Role of Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles (MSC-EVs) in Normal and Abnormal Hematopoiesis and Their Therapeutic Potential

Journal of Clinical Medicine ◽

10.3390/jcm9030856 ◽

2020 ◽

Vol 9 (3) ◽

pp. 856 ◽

Cited By ~ 8

Author(s):

Aristea K. Batsali ◽

Anthie Georgopoulou ◽

Irene Mavroudi ◽

Angelos Matheakakis ◽

Charalampos G. Pontikoglou ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Biological Effects ◽

Potential Contribution ◽

Scale Production ◽

Hematopoietic Stem ◽

The Impact

Mesenchymal stem cells (MSCs) represent a heterogeneous cellular population responsible for the support, maintenance, and regulation of normal hematopoietic stem cells (HSCs). In many hematological malignancies, however, MSCs are deregulated and may create an inhibitory microenvironment able to induce the disease initiation and/or progression. MSCs secrete soluble factors including extracellular vesicles (EVs), which may influence the bone marrow (BM) microenvironment via paracrine mechanisms. MSC-derived EVs (MSC-EVs) may even mimic the effects of MSCs from which they originate. Therefore, MSC-EVs contribute to the BM homeostasis but may also display multiple roles in the induction and maintenance of abnormal hematopoiesis. Compared to MSCs, MSC-EVs have been considered a more promising tool for therapeutic purposes including the prevention and treatment of Graft Versus Host Disease (GVHD) following allogenic HSC transplantation (HSCT). There are, however, still unanswered questions such as the molecular and cellular mechanisms associated with the supportive effect of MSC-EVs, the impact of the isolation, purification, large-scale production, storage conditions, MSC source, and donor characteristics on MSC-EV biological effects as well as the optimal dose and safety for clinical usage. This review summarizes the role of MSC-EVs in normal and malignant hematopoiesis and their potential contribution in treating GVHD.

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Algal Cells-Derived Extracellular Vesicles: A Review With Special Emphasis on Their Antimicrobial Effects

Frontiers in Microbiology ◽

10.3389/fmicb.2021.785716 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fereshteh Bayat ◽

Alireza Afshar ◽

Neda Baghban

Keyword(s):

Stem Cells ◽

Extracellular Vesicles ◽

Culture Medium ◽

Cell Communication ◽

Medicinal Uses ◽

Antimicrobial Effects ◽

Plant Stem ◽

Stem Cell Niches ◽

Plant Stem Cells

Extracellular vesicles (EVs) originated from different cells of approximately all kinds of organisms, recently got more attention because of their potential in the treatment of diseases and reconstructive medicine. To date, lots of studies have been performed on mammalian-derived vesicles, but little attention has been paid to algae and marine cells as valuable sources of EVs. Proving the promising role of EVs in medicine requires sufficient resources to produce qualified microvesicles. Algae, same as its other sister groups, such as plants, have stem cells and stem cell niches. Previous studies showed the EVs in plants and marine cells. So, this study was set out to talk about algal extracellular vesicles. EVs play a major role in cell-to-cell communication to convey molecules, such as RNA/DNA, metabolites, proteins, and lipids within. The components of EVs depends on the origin of the primitive cells or tissues and the isolation method. Sufficient resources are needed to produce high-quality, stable, and compatible EVs as a drug or drug delivery system. Plant stem cells have great potential as a new controllable resource for the production of EVs. The EVs secreted from stem cells can easily be extracted from the cell culture medium and evaluated for medicinal uses. In this review, the aim is to introduce algae stem cells as well as EVs derived from algal cells. In the following, the production of the EVs¸ the properties of EVs extracted from these sources and their antimicrobial effects will be discussed.

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Role of Extracellular Vesicles in Hematological Malignancies

BioMed Research International ◽

10.1155/2015/821613 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Stefania Raimondo ◽

Chiara Corrado ◽

Lavinia Raimondi ◽

Giacomo De Leo ◽

Riccardo Alessandro

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Hematological Malignancies ◽

Predictive Biomarkers ◽

Cell Types ◽

Target Cells ◽

Specific Cell ◽

Cell Of Origin ◽

Cell Functions

In recent years the role of tumor microenvironment in the progression of hematological malignancies has been widely recognized. Recent studies have focused on how cancer cells communicate within the microenvironment. Among several factors (cytokines, growth factors, and ECM molecules), a key role has been attributed to extracellular vesicles (EV), released from different cell types. EV (microvesicles and exosomes) may affect stroma remodeling, host cell functions, and tumor angiogenesis by inducing gene expression modulation in target cells, thus promoting cancer progression and metastasis. Microvesicles and exosomes can be recovered from the blood and other body fluids of cancer patients and contain and deliver genetic and proteomic contents that reflect the cell of origin, thus constituting a source of new predictive biomarkers involved in cancer development and serving as possible targets for therapies. Moreover, due to their specific cell-tropism and bioavailability, EV can be considered natural vehicles suitable for drug delivery. Here we will discuss the recent advances in the field of EV as actors in hematological cancer progression, pointing out the role of these vesicles in the tumor-host interplay and in their use as biomarkers for hematological malignancies.

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Extracellular Vesicles as Innovative Tool for Diagnosis, Regeneration and Protection against Neurological Damage

International Journal of Molecular Sciences ◽

10.3390/ijms21186859 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6859

Author(s):

Pavle Andjus ◽

Maja Kosanović ◽

Katarina Milićević ◽

Mukesh Gautam ◽

Seppo J. Vainio ◽

...

Keyword(s):

Extracellular Vesicles ◽

Neural Development ◽

Cell Communication ◽

Target Cells ◽

Liquid Biopsies ◽

Wide Range ◽

Distant Target ◽

Innovative Tool ◽

Therapeutic Perspective

Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown to carry cargoes of signaling proteins, RNA species, DNA and lipids. Once released, their content is selectively taken up by near or distant target cells, influencing their behavior. Exosomes are involved in cell–cell communication in a wide range of embryonic developmental processes and in fetal–maternal communication. In the present review, an outline of the role of EVs in neural development, regeneration and diseases is presented. EVs can act as regulators of normal homeostasis, but they can also promote either neuroinflammation/degeneration or tissue repair in pathological conditions, depending on their content. Since EV molecular cargo constitutes a representation of the origin cell status, EVs can be exploited in the diagnosis of several diseases. Due to their capability to cross the blood–brain barrier (BBB), EVs not only have been suggested for the diagnosis of central nervous system disorders by means of minimally invasive procedures, i.e., “liquid biopsies”, but they are also considered attractive tools for targeted drug delivery across the BBB. From the therapeutic perspective, mesenchymal stem cells (MSCs) represent one of the most promising sources of EVs. In particular, the neuroprotective properties of MSCs derived from the dental pulp are here discussed.

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