We have previously demonstrated that membrane enclosed microvesicles derived from murine lung cells contain lung-specific mRNA, micro RNA and protein and that these microvesicles enter murine marrow cells and effect a change in genetic phenotype manifest by expression of the lung-specific mRNAs;surfactants A-D, aquaporins and clara cell specific protein and in function manifest by increased conversion to epithelial lung cells after transplantation into lethally irradiated mice. The observed mRNA changes appear to be due to transfer of both mRNA and of a tissue specific transcriptional protein. Murine heart, liver and brain also effect tissue specific genetic changes in target marrow cells. The present proposal is a natural extension of these now published studies. We plan to elucidate the specific target cells in marrow for microvesicle genetic changes and will also study individual lung cells for their specific capacity to induce genetic change in marrow;previous studies were with whole lung. We plan to evaluate the stability of the observed genetic changes in marrow both in vitro and in vivo. Lastly, we will extend our characterization of the potential for reprogramming and attempt to identify specific transcriptional proteins or microRNA which may mediate the observed phenotype changes. To carry out these studies we will employ fluorescent activated cell sorting of cell populations, Real-time RT-PCR, immunohistochemistry, cell culture, murine marrow transplantation, SILAC to study protein transfer, lente viral vector transduction of cells and comparative 2-D gel electrophoresis and difference electrophoresis (DIGE). These studies should establish a more precise platform for studies of microvesicles, establish the stability of microvesicle induced genetic changes and begin to unravel the mechanisms behind such changes. This work could alter our thinking toward cell biology in general and open new strategies for approaching a number of diseases characterized by tissue degeneration or damage.

Public Health Relevance

The focus of this project is to determine if vesicles shed by lung cells are able to influence the identity of bone marrow cells that consume them to the point that they behave like lung cells. Such an approach could lead to new approaches for tissue regeneration and repair for a variety of lung diseases. Alternatively, by preventing the transfer of malignant behavior from cancerous cells to non-cancerous cells, novel therapies for cancer could be developed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Welniak, Lisbeth A
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Rhode Island Hospital
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Aliotta, Jason M; Pereira, Mandy; Wen, Sicheng et al. (2017) Bone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model. Stem Cells Transl Med 6:1595-1606
Hughes, Brenna L; Dutt, Riana; Raker, Christina et al. (2016) The impact of pregnancy on anti-HIV activity of cervicovaginal secretions. Am J Obstet Gynecol 215:748.e1-748.e12
Wen, S; Dooner, M; Cheng, Y et al. (2016) Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia 30:2221-2231
Quesenberry, Peter J; Goldberg, Laura R; Dooner, Mark S (2015) Concise reviews: A stem cell apostasy: a tale of four H words. Stem Cells 33:15-20
Quesenberry, Peter J; Goldberg, Laura; Aliotta, Jason et al. (2014) Marrow Hematopoietic Stem Cells Revisited: They Exist in a Continuum and are Not Defined by Standard Purification Approaches; Then There are the Microvesicles. Front Oncol 4:56
Aliotta, Jason M; Pereira, Mandy; Amaral, Ashley et al. (2013) Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice. Cardiovasc Res 100:354-62
Panagopoulos, Kiriaki; Cross-Knorr, Sam; Dillard, Christen et al. (2013) Reversal of chemosensitivity and induction of cell malignancy of a non-malignant prostate cancer cell line upon extracellular vesicle exposure. Mol Cancer 12:118
Li, Ming; Aliotta, Jason M; Asara, John M et al. (2012) Quantitative proteomic analysis of exosomes from HIV-1-infected lymphocytic cells. Proteomics 12:2203-11
Aliotta, Jason M; Lee, David; Puente, Napoleon et al. (2012) Progenitor/stem cell fate determination: interactive dynamics of cell cycle and microvesicles. Stem Cells Dev 21:1627-38
Quesenberry, Peter J; Dooner, Mark S; Goldberg, Laura R et al. (2012) A new stem cell biology: the continuum and microvesicles. Trans Am Clin Climatol Assoc 123:152-66; discussion 166

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