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Potential functional applications of extracellular vesicles: a report by the NIH Common Fund Extracellular RNA Communication Consortium.

Quesenberry PJ, Aliotta J, Camussi G, Abdel-Mageed AB, Wen S, Goldberg L, Zhang HG, Tetta C, Franklin J, Coffey RJ, Danielson K, Subramanya V, Ghiran I, Das S, Chen CC, Pusic KM, Pusic AD, Chatterjee D, Kraig RP, Balaj L, Dooner M - J Extracell Vesicles (2015)

Bottom Line: Background information and details of the projects are presented.Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed.The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA; pquesenberry@lifespan.org.

ABSTRACT
The NIH Extracellular RNA Communication Program's initiative on clinical utility of extracellular RNAs and therapeutic agents and developing scalable technologies is reviewed here. Background information and details of the projects are presented. The work has focused on modulation of target cell fate by extracellular vesicles (EVs) and RNA. Work on plant-derived vesicles is of intense interest, and non-mammalian sources of vesicles may represent a very promising source for different therapeutic approaches. Retro-viral-like particles are intriguing. Clearly, EVs share pathways with the assembly machinery of several other viruses, including human endogenous retrovirals (HERVs), and this convergence may explain the observation of viral-like particles containing viral proteins and nucleic acid in EVs. Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed. These studies show restoration of injured cell function and the importance of heterogeneity of different vesicle populations. The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described. The tremendous clinical potential of EVs underlies many of these projects, and the importance of regulatory issues and the necessity of general manufacturing production (GMP) studies for eventual clinical trials are emphasized. Clinical trials are already being pursued and should expand dramatically in the near future.

No MeSH data available.


Related in: MedlinePlus

CMs stained with CellTracker™ Red were washed and cultured in serum free media for 48 hours. EVs were isolated from media using ultracentrifugation and visualized being taken up by cardiac fibroblasts using an Olympus BX62 microscope with Qimaging EMc2 EMCCD cooled camera (red, cell tracker red for membrane; blue, hoechst 33,342 for nucleus).
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Figure 0001: CMs stained with CellTracker™ Red were washed and cultured in serum free media for 48 hours. EVs were isolated from media using ultracentrifugation and visualized being taken up by cardiac fibroblasts using an Olympus BX62 microscope with Qimaging EMc2 EMCCD cooled camera (red, cell tracker red for membrane; blue, hoechst 33,342 for nucleus).

Mentions: EV release from CMs was first reported by Gupta and Knowlton in primary cultures of adult rat CMs, and appeared to be regulated by hypoxia (104). In a second study, hypoxia led to the release of the 26 kDa transmembrane form of TNF-α in CD63+ EVs. Exposure of healthy CMs to these EVs induced apoptosis, suggesting that stress may lead to deleterious signalling between CMs (105). A recent study also demonstrated the transfer of DNA and RNA from CMs to fibroblasts (102). EVs released by HL-1 cells were found to contain DNA and RNA, as labelled with acridine orange, and when added to NIH-3T3 cultures, could transfer the acridine orange staining into NIH-3T3 fibroblasts nuclei, thereby demonstrating EV-mediated transfer of genetic information from CMs to fibroblasts. Cargo present within the EVs included ribosomal RNA and mRNA coding for proteins, and transfer of this produced changes in gene expression within the fibroblasts. Our own recent work demonstrates clear uptake of EVs derived from primary neonatal rat CM cultures into cardiac fibroblasts (Fig. 1), suggesting that EVs may indeed be an important mode of paracrine signalling among cells of the cardiovascular system. Interestingly, a recent study demonstrated that cardiac fibroblast-derived EVs also transfer information to CMs (103). Cardiac fibroblast-derived EVs contained many passenger strand miRNAs that are normally subjected to intracellular degradation. These miRNAs were shown to be potent pro-hypertrophic factors in the CMs, and inhibition of one of these, miR-21-3p, attenuated pathology (Fig. 1).


Potential functional applications of extracellular vesicles: a report by the NIH Common Fund Extracellular RNA Communication Consortium.

Quesenberry PJ, Aliotta J, Camussi G, Abdel-Mageed AB, Wen S, Goldberg L, Zhang HG, Tetta C, Franklin J, Coffey RJ, Danielson K, Subramanya V, Ghiran I, Das S, Chen CC, Pusic KM, Pusic AD, Chatterjee D, Kraig RP, Balaj L, Dooner M - J Extracell Vesicles (2015)

CMs stained with CellTracker™ Red were washed and cultured in serum free media for 48 hours. EVs were isolated from media using ultracentrifugation and visualized being taken up by cardiac fibroblasts using an Olympus BX62 microscope with Qimaging EMc2 EMCCD cooled camera (red, cell tracker red for membrane; blue, hoechst 33,342 for nucleus).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553260&req=5

Figure 0001: CMs stained with CellTracker™ Red were washed and cultured in serum free media for 48 hours. EVs were isolated from media using ultracentrifugation and visualized being taken up by cardiac fibroblasts using an Olympus BX62 microscope with Qimaging EMc2 EMCCD cooled camera (red, cell tracker red for membrane; blue, hoechst 33,342 for nucleus).
Mentions: EV release from CMs was first reported by Gupta and Knowlton in primary cultures of adult rat CMs, and appeared to be regulated by hypoxia (104). In a second study, hypoxia led to the release of the 26 kDa transmembrane form of TNF-α in CD63+ EVs. Exposure of healthy CMs to these EVs induced apoptosis, suggesting that stress may lead to deleterious signalling between CMs (105). A recent study also demonstrated the transfer of DNA and RNA from CMs to fibroblasts (102). EVs released by HL-1 cells were found to contain DNA and RNA, as labelled with acridine orange, and when added to NIH-3T3 cultures, could transfer the acridine orange staining into NIH-3T3 fibroblasts nuclei, thereby demonstrating EV-mediated transfer of genetic information from CMs to fibroblasts. Cargo present within the EVs included ribosomal RNA and mRNA coding for proteins, and transfer of this produced changes in gene expression within the fibroblasts. Our own recent work demonstrates clear uptake of EVs derived from primary neonatal rat CM cultures into cardiac fibroblasts (Fig. 1), suggesting that EVs may indeed be an important mode of paracrine signalling among cells of the cardiovascular system. Interestingly, a recent study demonstrated that cardiac fibroblast-derived EVs also transfer information to CMs (103). Cardiac fibroblast-derived EVs contained many passenger strand miRNAs that are normally subjected to intracellular degradation. These miRNAs were shown to be potent pro-hypertrophic factors in the CMs, and inhibition of one of these, miR-21-3p, attenuated pathology (Fig. 1).

Bottom Line: Background information and details of the projects are presented.Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed.The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA; pquesenberry@lifespan.org.

ABSTRACT
The NIH Extracellular RNA Communication Program's initiative on clinical utility of extracellular RNAs and therapeutic agents and developing scalable technologies is reviewed here. Background information and details of the projects are presented. The work has focused on modulation of target cell fate by extracellular vesicles (EVs) and RNA. Work on plant-derived vesicles is of intense interest, and non-mammalian sources of vesicles may represent a very promising source for different therapeutic approaches. Retro-viral-like particles are intriguing. Clearly, EVs share pathways with the assembly machinery of several other viruses, including human endogenous retrovirals (HERVs), and this convergence may explain the observation of viral-like particles containing viral proteins and nucleic acid in EVs. Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed. These studies show restoration of injured cell function and the importance of heterogeneity of different vesicle populations. The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described. The tremendous clinical potential of EVs underlies many of these projects, and the importance of regulatory issues and the necessity of general manufacturing production (GMP) studies for eventual clinical trials are emphasized. Clinical trials are already being pursued and should expand dramatically in the near future.

No MeSH data available.


Related in: MedlinePlus