Cytometric analysis of high shear‐induced platelet microparticles and effect of cytokines on microparticle generation

Advanced Drug Delivery Reviews

2010

116

Cell phenotype alteration by cell-derived vesicles presents a new aspect for consideration of cell fate. Accumulating data indicates that vesicles from many cells interact with or enter different target cells from other tissues, altering their phenotype toward that of the cell releasing the vesicles. Cells may be changed by direct interactions, transfer of cell surface receptors or epigenetic reprogramming via transcriptional regulators. Induced epigenetic changes appear to be stable and result in significant functional effects. These data force a reconsideration of the cellular context in which transcription regulates the proliferative and differentiative fate of tissues and suggests a highly plastic cellular system, which might underlay a relatively stable tissue system. The capacity of marrow to convert to non-hematopoietic cells related to vesicle crosscommunication may underlie the phenomena of stem cell plasticity. Additionally, vesicles have promise in the clinical arenas of disease biomarkers, tissue restoration and control of neoplastic cell growth. KeywordsCell-derived vesicles; stem cell plasticity; epigenetic alteration; cellular injury; disease biomarker; tissue restoration IntroductionMolecular control of cellular differentiation and phenotype is well established, as is the central role of transcription factors. However, the cellular context in which this regulation takes place is less well established and concepts of the stability of cellular phenotypes may have, in fact, confused the field. The capacity of microvesicle transfer to alter genetic cell phenotype alters our perceptions of phenotype regulation and will be explored in depth here. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Mechanisms of Cellular ConversionThe capacity of cells to change phenotype has been clearly demonstrated by studies of cell fusion and nuclear transfer. Formation of heterokaryons by cell fusion showed that dormant gene expression programs can be activated [1]. Cell fusion has also been invoked to explain the phenotype shifts seen in experiments where bone marrow stem cells were transplanted into lethally irradiated mice, so-called "stem cell plasticity" [2]. Nuclear transfer was also established as another mode of dramatic alteration of cell phenotype, which in the extreme, could lead to the formation of a whole animal [3][4][5]. Organ regeneration in newts and salamanders has also been cited as examples of cellular fate change, although in these instances, production of differentiated cells from rare stem cell populations was never ruled out [6...

Section: Cell-derived Vesiclesmentioning

confidence: 99%

Cellular phenotype switching and microvesicles

Quesenberry

Advanced Drug Delivery Reviews

2010

116

“…Membrane-enclosed vesicles derived from a wide variety of cells have been shown to affect the phenotype of putative target cells under different conditions. Different terms have been used to describe these cellular-derived membrane-enclosed entities, including exosomes (106), microvesicles (107), ectosomes (108), membrane particles (109) exosome-like particles (110) and apoptotic vesicles (111). Vesicles have been characterized by size, density in a sucrose gradient, electron microscopy, sedimentation by ultracentrifugation, lipid composition, main protein markers and intracellular origin (112).…”

Section: Mechanisms Underlying Marrow Conversions To Pulmonary Epithementioning

confidence: 99%

Stem cell plasticity revisited: The continuum marrow model and phenotypic changes mediated by microvesicles

Quesenberry

Dooner

Experimental Hematology

2010

The phenotype of marrow hematopoietic stem cells is determined by cell cycle state and microvesicle entry into the stem cells. The stem cell population is continually changing based on cell cycle transit and thus can only be defined on a population basis. Purification of marrow stem cells only addresses the heterogeneity of these populations. When whole marrow is studied, the long-term repopulating stem cells are in active cell cycle. However, with some variability, when highly purified stem cells are studied, the cells appear to be dormant. Thus, the study of purified stem cells is intrinsically misleading. Tissue-derived microvesicles enhanced by injury effect the phenotype of different cell classes. We propose that previously described stem cell plasticity is due to microvesicle modulation. We further propose a stem cell population model in which the individual cell phenotypes continually changes, but the population phenotype is relatively stable. This, in turn, is modulated by microvesicle and microenvironmental influences.We and others have observed that marrow cell populations are intrinsically heterogeneous and continually changing. This phenotypic lability extends to the capacity of marrow cells to assume the phenotype of other hematopoietic cells or non-hematopoietic cells and appears to be tightly linked to the cell cycle status of the marrow stem cell.

“…Different terms have been used to describe these vesicles, including exosomes (1), microvesicles (2), ectosomes (3), membrane particles (4), exosome-like particles (5) and apoptotic vesicles (6). Vesicles have been characterized by size, density in sucrose gradients, electron microscopy, sedimentation, lipid composition, main protein markers and intracellular origin (7).…”

Section: Introductionmentioning

confidence: 99%

“…Microvesicles may be secreted by activated normal cells (3–5) and have been found to transfer CD41, integrins and CXCR4 (6,8–10) as well as HIV and prions (11,12) between cells. Embryonic stem cell-derived microvesicles have been reported to reprogram hematopoietic stem/progenitor cells by horizontal transfer of mRNA and protein (13).…”

Section: Introductionmentioning

confidence: 99%

Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription

Experimental Hematology

Pereira

Johnson

et al. 2010

185

162

Objective-Microvesicles have been shown to mediate intercellular communication. Previously, we have correlated entry of murine lung-derived microvesicles into murine bone marrow cells with expression of pulmonary epithelial cell-specific mRNA in these marrow cells. The present studies establish that entry of lung-derived microvesicles into marrow cells is a prerequisite for marrow expression of pulmonary epithelial cell-derived mRNA.Methods/Results-Murine bone marrow cells co-cultured with rat lung, but separated from them using a cell-impermeable membrane (0.4 micron pore size), were analyzed using species-specific primers (for rat or mouse). These studies revealed that surfactant B and C mRNA produced by murine marrow cells were of both rat and mouse origin. Similar results were obtained using murine lung cocultured with rat bone marrow cells or when bone marrow cells were analyzed for the presence of species-specific albumin mRNA after co-culture with rat or murine liver. These studies show that microvesicles both deliver mRNA to marrow cells and also mediate marrow cell transcription of tissue-specific mRNA. The latter likely underlies the longer term stable change in genetic phenotype which has been observed. We have also observed microRNA in lung-derived microvesicles and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest disclosureNo financial interest/relationships with financial interest relating to the topic of this article have been declared. studies with RNase-treated microvesicles indicate that microRNA negatively modulates pulmonary epithelial cell-specific mRNA levels in co-cultured marrow cells. In addition, we have also observed tissue-specific expression of brain, heart and liver mRNA in co-cultured marrow cells suggesting that microvesicle-mediated cellular phenotype change is a universal phenomena. NIH Public AccessConclusion-These studies suggest that cellular systems are more phenotypically labile then previously considered.