Edmund H. Sears
Brown University
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Featured researches published by Edmund H. Sears.
Stem Cells and Development | 2012
Jason M. Aliotta; David Lee; Napoleon Puente; Sam Faradyan; Edmund H. Sears; Ashley Amaral; Laura R. Goldberg; Mark S. Dooner; Mandy Pereira; Peter J. Quesenberry
We have shown that hematopoietic stem/progenitor cell phenotype and differentiative potential change throughout cell cycle. Lung-derived microvesicles (LDMVs) also change marrow cell phenotype by inducing them to express pulmonary epithelial cell-specific mRNA and protein. These changes are accentuated when microvesicles isolated from injured lung. We wish to determine if microvesicle-treated stem/progenitor cell phenotype is linked to cell cycle and to the injury status of the lung providing microvesicles. Lineage depleted, Sca-1+ (Lin-/Sca-1+) marrow isolated from mice were cultured with interleukin 3 (IL-3), IL-6, IL-11, and stem cell factor (cytokine-cultured cells), removed at hours zero (cell cycle phase G0/G1), 24 (late G1/early S), and 48 (late S/early G2/M), and cocultured with lung tissue, lung conditioned media (LCM), or LDMV from irradiated or nonirradiated mice. Alternatively, Lin-/Sca-1+ cells not exposed to exogenous cytokines were separated into G0/G1 and S/G2/M cell cycle phase populations by fluorescence-activated cell sorting (FACS) and used in coculture. Separately, LDMV from irradiated and nonirradiated mice were analyzed for the presence of adhesion proteins. Peak pulmonary epithelial cell-specific mRNA expression was seen in G0/G1 cytokine-cultured cells cocultured with irradiated lung and in late G1/early S cells cocultured with nonirradiated lung. The same pattern was seen in cytokine-cultured Lin-/Sca-1 cells cocultured with LCM and LDMV and when FACS-separated Lin-/Sca-1 cells unexposed to exogenous cytokines were used in coculture. Cells and LDMV expressed adhesion proteins whose levels differed based on cycle status (cells) or radiation injury (LDMV), suggesting a mechanism for microvesicle entry. These data demonstrate that microvesicle modification of progenitor/stem cells is influenced by cell cycle and the treatment of the originator lung tissue.
Pulmonary circulation | 2012
Edmund H. Sears; Jason M. Aliotta; James R. Klinger
Partial anomalous pulmonary venous return (PAPVR) is a rare cause of adult onset pulmonary arterial hypertension (PAH) that can present with a wide spectrum of severity from early childhood throughout adult life. We present two patients with PAH secondary to PAPVR who reflect this range of disease. The diagnosis and treatment of PAPVR and its role in pulmonary vascular disease is discussed. Cardiac and pulmonary physicians should be aware of this entity and its diagnosis and management options.
Journal of extracellular vesicles | 2012
Jason M. Aliotta; Mandy Pereira; Ming Li; Ashley Amaral; Arina Sorokina; Mark S. Dooner; Edmund H. Sears; Kate E. Brilliant; Bharat Ramratnam; Douglas C. Hixson; Peter J. Quesenberry
Background: Interest has been generated in the capacity of cellular-derived microvesicles to alter the fate of different target cells. Lung, liver, heart and brain-derived vesicles can alter the genetic phenotype of murine marrow cells; however, the stability of such changes and the mechanism of these changes remain unclear. In the present work, we show that lung-derived microvesicles (LDMV) alter the transcriptome and proteome of target marrow cells initially by mRNA and regulator(s) of transcription transfer, but that long term phenotype change is due solely to transfer of a transcriptional regulator with target cell. Methods/results: In vivo studies: Whole bone marrow cells (WBM) were co-cultured with LDMV (both isolated from male C57BL/6 mice) or cultured alone (control). One week later, cultured WBM was transplanted into lethally-irradiated female C57BL/6 mice. Recipient mice were sacrificed 6 weeks later and WBM, spleens and livers were examined for the presence of lung-specific gene expression, including surfactants A, B, C and D, aquaporin-5, and clara cell specific protein, via real-time RT-PCR. Immunohistochemistry was also performed on lungs to determine the number of transplanted marrow-derived (Y chromosome+) type II pneumocytes (prosurfactant C+). Mice transplanted with LDMV co-cultured WBM expressed pulmonary epithelial cell genes in the cells of their bone marrow, livers and spleens and over fivefold more transplanted marrow-derived Y+/prosurfactant C+cells could be found in their lungs (vs. control mice). In vitro studies: WBM (from mice or rats) was cultured with or without LDMV (from mice or rats) for 1 week then washed and cultured alone. WBM was harvested at 2-week intervals for real-time RT-PCR analysis, using species-specific surfactant primers, and for Western Blot analysis. Proteomic and microRNA microarray analyses were also performed on cells. LDMV co-cultured WBM maintained expression of pulmonary epithelial cell genes and proteins for up to 12 weeks in culture. Surfactant produced at later time points was specific only to the species of the marrow cell in culture indicating de novo mRNA transcription. These findings, in addition to the altered protein and microRNA profiles of LDMV co-cultured WBM, support a stable transcriptional mechanism for these changes. Conclusions: These data indicate that microvesicle alteration of cell fate is robust and long-term and represents an important new aspect of cellular biology.
Experimental Hematology | 2011
Michael Del Tatto; Thomas Ng; Jason M. Aliotta; Gerald A. Colvin; Mark S. Dooner; David Berz; Gerri Dooner; Elaine Papa; Douglas C. Hixson; Bharat Ramratnam; Bassam I. Aswad; Edmund H. Sears; John L. Reagan; Peter J. Quesenberry
Microvesicles have been shown to mediate varieties of intercellular communication. Work in murine species has shown that lung-derived microvesicles can deliver mRNA, transcription factors, and microRNA to marrow cells and alter their phenotype. The present studies evaluated the capacity of excised human lung cancer cells to change the genetic phenotype of human marrow cells. We present the first studies on microvesicle production by excised cancers from human lung and the capacity of these microvesicles to alter the genetic phenotype of normal human marrow cells. We studied 12 cancers involving the lung and assessed nine lung-specific mRNA species (aquaporin, surfactant families, and clara cell-specific protein) in marrow cells exposed to tissue in co-culture, cultured in conditioned media, or exposed to isolated lung cancer-derived microvesicles. We assessed two or seven days of co-culture and marrow which was unseparated, separated by ficoll density gradient centrifugation or ammonium chloride lysis. Under these varying conditions, each cancer derived from lung mediated marrow expression of between one and seven lung-specific genes. Microvesicles were identified in the pellet of ultracentrifuged conditioned media and shown to enter marrow cells and induce lung-specific mRNA expression in marrow. A lung melanoma and a sarcoma also induced lung-specific mRNA in marrow cells. These data indicate that lung cancer cells may alter the genetic phenotype of normal cells and suggest that such perturbations might play a role in tumor progression, tumor recurrence, or metastases. They also suggest that the tissue environment may alter cancer cell gene expression.
Recent Patents on Inflammation & Allergy Drug Discovery | 2010
Brian Casserly; Edmund H. Sears; Eric Gartman
The natriuretic peptides (NPs) are a family of widely distributed, but evolutionarily conserved, polypeptide mediators that exert a range of effects throughout the body. There is growing realization that NP actions go far beyond volume and blood pressure homeostasis. Their pleiotropic effects include a significant role in regulating the immune system. Localization of NP receptors in various immune organs as well as in modulation of inflammation in vascular disease supports this hypothesis. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for NPs. NPs are also involved in polarizing the immune response to allergens. NPs play an important role in shaping the early immune response to environmental antigens and appear to play a critical role in the interaction between cells of the innate and adaptive immune systems. The recent explosion of basic and clinical research has resulted in improved understanding of their molecular structure. This has facilitated development of chimeric forms of NPs as well as more convenient routes of administration. Thus, the NPs and their receptors could be exploited to develop therapeutics for the inflammatory and immune responses in wide range of diseases. Also discussed are several patents regarding NPs in the present review.
Journal of extracellular vesicles | 2015
Jason M. Aliotta; Mandy Pereira; Edmund H. Sears; Mark S. Dooner; Sicheng Wen; Laura R. Goldberg; Peter J. Quesenberry
Background Our group has previously demonstrated that murine whole bone marrow cells (WBM) that internalize lung-derived extracellular vesicles (LDEVs) in culture express pulmonary epithelial cell–specific genes for up to 12 weeks. In addition, the lungs of lethally irradiated mice transplanted with lung vesicle–modulated marrow have 5 times more WBM-derived type II pneumocytes compared to mice transplanted with unmanipulated WBM. These findings indicate that extracellular vesicle modification may be an important consideration in the development of marrow cell–based cellular therapies. Current studies were performed to determine the specific marrow cell types that LDEV stably modify. Methods Murine WBM-derived stem/progenitor cells (Lin-/Sca-1+) and differentiated erythroid cells (Ter119+), granulocytes (Gr-1+) and B cells (CD19+) were cultured with carboxyfluorescein N-succinimidyl ester (CFSE)-labelled LDEV. LDEV+ cells (CFSE+) and LDEV− cells (CFSE−) were separated by flow cytometry and visualized by fluorescence microscopy, analyzed by RT-PCR or placed into long-term secondary culture. In addition, murine Lin-/Sca-1+ cells were cultured with CFSE-labelled LDEV isolated from rats, and RT-PCR analysis was performed on LDEV+ and – cells using species-specific primers for surfactant (rat/mouse hybrid co-cultures). Results Stem/progenitor cells and all of the differentiated cell types studied internalized LDEV in culture, but heterogeneously. Expression of a panel of pulmonary epithelial cell genes was higher in LDEV+cells compared to LDEV− cells and elevated expression of these genes persisted in long-term culture. Rat/mouse hybrid co-cultures revealed only mouse-specific surfactant B and C expression in LDEV+ Lin-/Sca-1+cells after 4 weeks of culture, indicating stable de novo gene expression. Conclusions LDEV can be internalized by differentiated and more primitive cells residing in the bone marrow in culture and can induce stable de novo pulmonary epithelial cell gene expression in these cells for several weeks after internalization. The gene expression represents a transcriptional activation of the target marrow cells. These studies serve as the basis for determining marrow cell types that can be used for cell-based therapies for processes that injure the pulmonary epithelial surfaces.
Journal of Cystic Fibrosis | 2017
K.D. Gonzalez; Jonathan B. Zuckerman; Edmund H. Sears; B.S. Prato; M. Guill; Wendy Y. Craig; C. Milliard; E. Parker; T. Lever; M.M. Griffin; L.W. Leclair
Studies in cystic fibrosis (CF) patients have reported reduced rates of pulmonary exacerbation and hospitalization with probiotic use [1,2]. Furthermore, regular intake of probiotics has been associated with improvements in gastrointestinal (GI) symptoms, levels of inflammatory markers, and quality of life in this population [3]. However, little has been published about clinical use of probiotics in CF, and a recent review highlighted the need to better understand the appropriate role of these agents in long-term disease management [4]. Some patients take probiotics without supervision, and prescriptions of these formulations are not tracked in the United States Cystic Fibrosis Patient Registry (USCFPR). We therefore designed a survey to explore the rationale for patient probiotic use and to look for associations between reported intake of these products and patient characteristics, care patterns and health status within a regional consortium of CF centers in Northern New England. The study population comprised 575 adult and pediatric patients over 6 years of age at 4 CF centers (DartmouthHitchcock Medical Center, University of Vermont Medical Center, Maine Medical Center and Eastern Maine Medical Center). Surveys were completed during regularly scheduled outpatient visits, inpatient stays, or via email using an encrypted, web-based questionnaire (REDCap). Self-reported probiotic use, rationale for use/nonuse, and GI symptoms were assessed using a modified Gastrointestinal Quality of Life Index Questionnaire [3]. The USCFPR was queried for the demographic, socioeconomic, GI, and pulmonary status of each participant along with responder-specific medical therapies, microbiology and exacerbation frequency during the year of survey completion. Differences between subgroups were analyzed by t-test, Mann-Whitney U, or Chi Square test, as appropriate. The study was approved by the Institutional Review Board at each center. There were 213 responses (response rate 37%) from 75 adult and 138 pediatric patients (response rate 27% and 46%, respectively). The frequency of reported probiotic use varied between centers (24–83%, p b 0.001). The institutional policies for use of commercially available probiotic products varied
Reviews on Recent Clinical Trials | 2011
Edmund H. Sears; Eric Gartman; Brian Casserly
Medicine and health, Rhode Island | 2012
Edmund H. Sears; Jankowich; Healey Tt
american thoracic society international conference | 2011
Edmund H. Sears; Mandy Pereira; Ashley Amaral; Mark S. Dooner; Peter J. Quesenberry; Jason A. Aliotta