Exosomes derived from Induced Vascular Progenitor Cells Promote Angiogenesis in vitro and in an in vivo Rat Hindlimb Ischemia Model
angiogenesis; endothelial cell; exosome; microRNA; progenitor cell
Induced vascular progenitor cells (iVPCs) were created as an ideal cell type for regenerative medicine and have been reported to positively promote collateral blood flow and improve cardiac function in a rat model of myocardial ischemia. Exosomes have emerged as a novel biomedicine that mimics the function of the donor cells. We investigated the angiogenic activity of exosomes from induced vascular progenitor cells (iVPC-Exo) as a cell-free therapeutic approach for ischemia. Exosomes from iVPCs and rat aortic endothelial cells (RAECs) were isolated using a combination of ultrafiltration and size-exclusion chromatography. Nanoparticle tracking analysis revealed that exosome isolates fell within the exosomal diameter (<150 nm). These exosomes contained known markers Alix and TSG101, and their morphology was validated using transmission electron microscopy. Compared to RAECs, iVPCs significantly increased the secretion of exosomes. Cardiac microvascular endothelial cells and aortic ring explants were pretreated with RAEC-Exo or iVPC-Exo, and basal medium was used as a control. iVPC-Exo exerted an in vitro angiogenic effect on the proliferation, tube formation, and migration of endothelial cells and stimulated microvessel sprouting in an ex vivo aortic ring assay. Additionally, iVPC-Exo increased blood perfusion in a hindlimb ischemia model. Proangiogenic proteins (pentraxin-3 and insulin-like growth factor-binding protein-3) and microRNAs (-143-3p, -291b, and -20b-5p) were found to be enriched in iVPC-Exo, which may mediate iVPC-Exo induced vascular growth. Our findings demonstrate that treatment with iVPC-Exo promotes angiogenesis in vitro, ex vivo, and in vivo. Collectively, these findings indicate a novel cell-free approach for therapeutic angiogenesis.
Johnson Takerra K; Zhao Lina; Zhu Dihan; Wang Yang; Xiao Yan; Oguljahan Babayewa; Zhao Xueying; Kirlin Ward G; Yin Liya; Chilian William M; Liu Dong
American Journal of Physiology. Heart and Circulatory Physiology
2019
2019-08
<a href="http://doi.org/10.1152/ajpheart.00247.2019" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00247.2019</a>
Genetic Inactivation of ZCCHC6 Suppresses Interleukin‐6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice.
ANIMAL experimentation; CARTILAGE; CARTILAGE cells; DACTINOMYCIN; DNA-binding proteins; GENE expression; GENETIC aspects; IN vivo studies; INTERLEUKINS; MICE; MICRORNA; OSTEOARTHRITIS; PREVENTION; SEQUENCE analysis; SEVERITY of illness index; SYNOVITIS; TRANSCRIPTION factors
Objective: Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin‐6 (IL‐6) in patients with osteoarthritis (OA) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme ZCCHC6 (zinc‐finger CCHC domain–containing protein 6; TUT‐7) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in OA pathogenesis is unknown. The present study was undertaken to investigate whether ZCCHC6 directs the expression of IL‐6 and influences OA pathogenesis in vivo. Methods: Human and mouse chondrocytes were stimulated with recombinant IL‐1β. Expression of ZCCHC6 in human chondrocytes was knocked down using small interfering RNAs. IL‐6 transcript stability was determined by actinomycin D chase, and 3′‐uridylation of microRNAs was determined by deep sequencing. Zcchc6−/− mice were produced by gene targeting. OA was surgically induced in the knee joints of mice, and disease severity was scored using a semiquantitative grading system. Results: ZCCHC6 was markedly up‐regulated in damaged cartilage from human OA patients and from wild‐type mice with surgically induced OA. Overexpression of ZCCHC6 induced the expression of IL‐6, and its knockdown reduced IL‐6 transcript stability and IL‐1β–induced IL‐6 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6−/− mouse chondrocytes rescued the IL‐1β–induced IL‐6 expression. Knockdown of ZCCHC6 reduced the population of micro‐RNA 26b (miR‐26b) with 3′‐uridylation by 60%. Zcchc6−/− mice with surgically induced OA produced low levels of IL‐6 and exhibited reduced cartilage damage and synovitis in the joints. Conclusion: These findings indicate that ZCCHC6 enhances IL‐6 expression in chondrocytes through transcript stabilization and by uridylating miR‐26b, which abrogates repression of IL‐6. Inhibition of IL‐6 expression and significantly reduced OA severity in Zcchc6−/− mice identify ZCCHC6 as a novel therapeutic target to inhibit disease pathogenesis. [ABSTRACT FROM AUTHOR]
Ansari Mohammad Y; Khan Nazir M; Ahmad Nashrah; Green Jonathan; Novak Kimberly; Haqqi Tariq M
Arthritis & Rheumatology
2019
2019-04
<a href="http://doi.org/10.1002/art.40751" target="_blank" rel="noreferrer noopener">10.1002/art.40751</a>
MicroRNAs and lung cancer: Biology and applications in diagnosis and prognosis.
gene expression; lung cancer; Carcinogenesis; microRNA
MicroRNAs are tiny non-coding RNA molecules which play important roles in the epigenetic control of cellular processes by preventing the translation of proteins from messenger RNAs (mRNAs). A single microRNA can target different mRNAs, and an mRNA can be targeted by multiple microRNAs. Such complex interplays underlie many molecular pathways in cells, and specific roles for many microRNAs in physiological as well as pathological phenomena have been identified. Changes in expression of microRNAs have been associated with a wide variety of disease conditions, and microRNA-based biomarkers are being developed for the identification and monitoring of such states. This review provides a general overview of the current state of knowledge about the biology of microRNAs, and specific information about microRNAs with regard to the diagnosis and prognosis of lung cancer.
Mallick Reema; Patnaik Santosh Kumar; Yendamuri Sai
Journal of carcinogenesis
2010
2010-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.4103/1477-3163.67074" target="_blank" rel="noreferrer noopener">10.4103/1477-3163.67074</a>