Extracellular vesicle therapeutics: the issue of one size fits all

2021 ◽  
Vol 1 (1) ◽  
pp. 35-40
Author(s):  
Naveed Akbar
Keyword(s):  
Transcription Factors ◽  
Epigenetic Regulation ◽  
Cellular Proliferation ◽  
Cell Movement ◽  
Extracellular Vesicle ◽  
Surface Proteins ◽  
Disease Models ◽  
Therapeutic Effects ◽  
Rna Transcription ◽  
Different Sources

Extracellular vesicles (EV) are mediators of intercellular communication locally in tissue microenvironments and enable distal across organ communication between cells of the same origin and those from different sources. EV surface proteins and lipids enable interaction with particular cells, whereas their internal payload of RNA, transcription factors, DNA, enzymes and metabolites functionally alters recipient cells. EV-interactions and uptake induce changes in cellular proliferation, differentiation, cell movement, as well as transcriptional and epigenetic regulation. These unique properties of EV poise them as attractive therapeutics in a broad range of pathologies, but questions remain in translating EV discoveries to effective therapies. Here, I briefly discuss the need for more stringent considerations for EV-therapeutic effects with a focus on EV biodistribution profiles in appropriate disease models and routes of EV administration with a particular focus on the vasculature.

scholarly journals Bmi1 Augments Proliferation and Survival of Cortical Bone-Derived Stem Cells after Injury through Novel Epigenetic Signaling via Histone 3 Regulation

2021 ◽  
Vol 22 (15) ◽  
pp. 7813
Author(s):  
Lindsay Kraus ◽  
Chris Bryan ◽  
Marcus Wagner ◽  
Tabito Kino ◽  
Melissa Gunchenko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Stem Cell ◽  
Histone Modification ◽  
Epigenetic Regulation ◽  
Critical Role ◽  
Proliferative Potential ◽  
Therapeutic Effects ◽  
Histone 3

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to proliferate and survive during stress. This loss of functionality is attributed to changes in histone modification, specifically histone 3 lysine 27 (H3K27). Without the proper epigenetic regulation, due to the loss of the polycomb protein in CBSCs, there is a significant decrease in cell cycle proteins, including Cyclin B, E2F, and WEE as well as an increase in DNA damage genes, including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). In conclusion, in the absence of Bmi1, CBSCs lose their proliferative potential, have increased DNA damage and apoptosis, and more cell cycle arrest due to changes in epigenetic modifications. Consequently, Bmi1 plays a critical role in stem cell proliferation and survival through cell cycle regulation, specifically in the CBSCs. This regulation is associated with the histone modification and regulation of Bmi1, therefore indicating a novel mechanism of Bmi1 and the epigenetic regulation of stem cells.

scholarly journals RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

2012 ◽  
Vol 209 (13) ◽  
pp. 2409-2422 ◽  
Author(s):  
Heiyoun Jung ◽  
Benjamin Hsiung ◽  
Kathleen Pestal ◽  
Emily Procyk ◽  
David H. Raulet
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Posttranscriptional Regulation ◽  
Cellular Proliferation ◽  
Control Cell ◽  
T Cell Subsets ◽  
Cell Cycle Entry

The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes.

scholarly journals Epigenetic regulation by the menin pathway

2017 ◽  
Vol 24 (10) ◽  
pp. T147-T159 ◽  
Author(s):  
Zijie Feng ◽  
Jian Ma ◽  
Xianxin Hua
Keyword(s):  
Transcription Factors ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Gene Transcription ◽  
Epigenetic Regulation ◽  
Posttranslational Modifications ◽  
Genetic Model ◽  
Mirna Biogenesis ◽  
Endocrine Organs

There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.

scholarly journals Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1618
Author(s):  
Kristina Kiisholts ◽  
Kaido Kurrikoff ◽  
Piret Arukuusk ◽  
Ly Porosk ◽  
Maire Peters ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cellular Proliferation ◽  
Expression Patterns ◽  
In Vitro Models ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Therapeutic Effects ◽  
Cell Penetrating ◽  
Proliferation And Invasion

Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into diseased cells. To achieve that goal, we used highly potential delivery vectors, cell-penetrating peptides (CPPs), as oligonucleotide carriers for the development of a therapeutic approach for endometriosis and cancer. Despite marked differences, both of these conditions still exhibit similarities, like excessive, uncoordinated, and autonomous cellular proliferation and invasion, accompanied by overlapping gene expression patterns. Thus, in the current study, we investigated the therapeutic effects of CPP and siRNA nanoparticles using in vitro models of benign endometriosis and malignant glioblastoma. We demonstrated that CPPs PepFect6 and NickFect70 are highly effective in transfecting cell lines, primary cell cultures, and three-dimensional spheroids. CPP nanoparticles are capable of inducing siRNA-specific knockdown of therapeutic genes, ribonucleotide reductase subunit M2 (RRM2), and vascular endothelial growth factor (VEGF), which results in the reduction of in vitro cellular proliferation, invasion, and migration. In addition, we proved that it is possible to achieve synergistic suppression of endometriosis cellular proliferation and invasion by combining gene therapy and hormonal treatment approaches by co-administering CPP/siRNA nanoparticles together with the endometriosis-drug danazol. We suggest a novel target, RRM2, for endometriosis therapy and as a proof-of-concept, we propose a CPP-mediated gene therapy approach for endometriosis and cancer.

scholarly journals Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1373 ◽  
Author(s):  
Herring ◽  
Elison ◽  
Tessem
Keyword(s):  
Transcription Factors ◽  
Family Member ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Cellular Proliferation ◽  
Nuclear Hormone Receptors ◽  
Fuel Utilization ◽  
Orphan Nuclear Receptors ◽  
Tissue Specific ◽  
Specific Effects

The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

scholarly journals Gastrointestinal transcription factors drive lineage-specific developmental programs in organ specification and cancer

2019 ◽  
Vol 5 (12) ◽  
pp. eaax8898 ◽  
Author(s):  
Roshane Francis ◽  
Haiyang Guo ◽  
Catherine Streutker ◽  
Musaddeque Ahmed ◽  
Theodora Yung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Epigenetic Regulation ◽  
Gastrointestinal Cancer ◽  
Chromatin Accessibility ◽  
Lineage Specification ◽  
Developmental Programs ◽  
Tissue Specific ◽  
Cancer Data ◽  
Gastrointestinal Tissue

Transcription factors (TFs) are spatially and temporally regulated during gut organ specification. Although accumulating evidence shows aberrant reactivation of developmental programs in cancer, little is known about how TFs drive lineage specification in development and cancer. We first defined gastrointestinal tissue–specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs. We revealed that Sox2 is not only essential for gastric specification, by maintaining chromatin accessibility at forestomach lineage loci, but also sufficient to promote forestomach/esophageal transformation upon Cdx2 deletion. By comparing our gastrointestinal lineage-specific transcriptome to human gastrointestinal cancer data, we found that stomach and intestinal lineage-specific programs are reactivated in Sox2high/Sox9high and Cdx2high cancers, respectively. By analyzing mice deleted for both Sox2 and Sox9, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.

scholarly journals Reprogramming and remodeling: transcriptional and epigenetic regulation of salicylic acid-mediated plant defense

2020 ◽  
Vol 71 (17) ◽  
pp. 5256-5268 ◽  
Author(s):  
Jian Chen ◽  
Michael Clinton ◽  
Guang Qi ◽  
Daowen Wang ◽  
Fengquan Liu ◽  
...  
Keyword(s):  
Salicylic Acid ◽  
Transcription Factors ◽  
Plant Defense ◽  
Epigenetic Regulation ◽  
Current Knowledge ◽  
Plant Immunity ◽  
Defense Responses ◽  
Transcriptional Networks ◽  
Transcriptional Reprogramming ◽  
Genomic Tools

Abstract As a plant hormone, salicylic acid (SA) plays essential roles in plant defense against biotrophic and hemibiotrophic pathogens. Significant progress has been made in understanding the SA biosynthesis pathways and SA-mediated defense signaling networks in the past two decades. Plant defense responses involve rapid and massive transcriptional reprogramming upon the recognition of pathogens. Plant transcription factors and their co-regulators are critical players in establishing a transcription regulatory network and boosting plant immunity. A multitude of transcription factors and epigenetic regulators have been discovered, and their roles in SA-mediated defense responses have been reported. However, our understanding of plant transcriptional networks is still limited. As such, novel genomic tools and bioinformatic techniques will be necessary if we are to fully understand the mechanisms behind plant immunity. Here, we discuss current knowledge, provide an update on the SA biosynthesis pathway, and describe the transcriptional and epigenetic regulation of SA-mediated plant immune responses.

scholarly journals MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

2018 ◽  
pp. 1-7
Author(s):  
Dujiao Wu ◽  
LiHao Huang ◽  
Qi Shen ◽  
Bijun Zhu
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Digestive System ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Pi3k Inhibitor ◽  
Therapeutic Effects ◽  
Potential Mechanism ◽  
Phosphoinositide 3 Kinase

Abstract: Phosphoinositide 3-kinase (PI3K) plays an important role in cellular proliferation and tumor progression. The objective of this study is to evaluate the potential mechanism and therapeutic effects of new PI3K inhibitor SHBM1009 on various cancer cells of digestive system on proliferation.  

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