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51


Cross platform validation of a unique method for deep genomic and proteomic analysis of rare immune cell populations [Meeting Abstract]

Lopez, Peter; Gregory, Michael; Miller, Kelley; Fuhrman, Kit; Ray, Karina; Hinerfeld, Douglas
ISI:000459977702034
ISSN: 0022-1767
CID: 3727632

Nascent Induced Pluripotent Stem Cells Efficiently Generate Entirely iPSC-Derived Mice while Expressing Differentiation-Associated Genes

Amlani, Bhishma; Liu, Yiyuan; Chen, Taotao; Ee, Ly-Sha; Lopez, Peter; Heguy, Adriana; Apostolou, Effie; Kim, Sang Yong; Stadtfeld, Matthias
The ability of induced pluripotent stem cells (iPSCs) to differentiate into all adult cell types makes them attractive for research and regenerative medicine; however, it remains unknown when and how this capacity is established. We characterized the acquisition of developmental pluripotency in a suitable reprogramming system to show that iPSCs prior to passaging become capable of generating all tissues upon injection into preimplantation embryos. The developmental potential of nascent iPSCs is comparable to or even surpasses that of established pluripotent cells. Further functional assays and genome-wide molecular analyses suggest that cells acquiring developmental pluripotency exhibit a unique combination of properties that distinguish them from canonical naive and primed pluripotency states. These include reduced clonal self-renewal potential and the elevated expression of differentiation-associated transcriptional regulators. Our observations close a gap in the understanding of induced pluripotency and provide an improved roadmap of cellular reprogramming with ramifications for the use of iPSCs.
PMID: 29420174
ISSN: 2211-1247
CID: 2947822

Arrested Development: Infantile Hemangioma and the Stem Cell Teratogenic Hypothesis

Harbi, Shaghayegh; Park, Hannah; Gregory, Michael; Lopez, Peter; Chiriboga, Luis; Mignatti, Paolo
BACKGROUND: Early-life programming is defined by the adaptive changes made by the fetus in response to an adverse in utero environment. Infantile hemangioma (IH), a vascular anomaly, is the most common tumor of infancy. Here we take IH as the tumor model to propose the stem cell teratogenic hypothesis of tumorigenesis and the potential involvement of the immune system. OBJECTIVES: Teratogenic agents include chemicals, heavy metals, pathogens, and ionizing radiation. To investigate the etiology and pathogenesis of IH, we hypothesized that they result from a teratogenic mechanism. Immature, incompletely differentiated, dysregulated progenitor cells (multipotential stem cells) are arrested in development with vasculogenic, angiogenic, and tumorigenic potential due to exposure to teratogenic agents such as extrinsic factors that disrupt intrinsic factors via molecular mimicry. During the critical period of immunological tolerance, environmental exposure to immunotoxic agents may harness the teratogenic potential in the developing embryo or fetus and modify the early-life programming algorithm by altering normal fetal development, causing malformations, and inducing tumorigenesis. Specifically, exposure to environmental agents may interfere with physiological signaling pathways and contribute to the generation of IH, by several mechanisms. DISCUSSION: An adverse in utero environment no longer serves as a sustainable environment for proper embryogenesis and normal development. Targeted disruption of stem cells by extrinsic factors can alter the genetic program. CONCLUSIONS: This article offers new perspectives to stimulate discussion, explore novel experimental approaches (such as immunotoxicity/vasculotoxicity assays and novel isogenic models), and to address the questions raised to convert the hypotheses into nontoxic, noninvasive treatments.
PMID: 28520518
ISSN: 1557-8585
CID: 2562922

Infantile Hemangioma Originates From A Dysregulated But Not Fully Transformed Multipotent Stem Cell

Harbi, Shaghayegh; Wang, Rong; Gregory, Michael; Hanson, Nicole; Kobylarz, Keith; Ryan, Kamilah; Deng, Yan; Lopez, Peter; Chiriboga, Luis; Mignatti, Paolo
Infantile hemangioma (IH) is the most common tumor of infancy. Its cellular origin and biological signals for uncontrolled growth are poorly understood, and specific pharmacological treatment is unavailable. To understand the process of hemangioma-genesis we characterized the progenitor hemangioma-derived stem cell (HemSC) and its lineage and non-lineage derivatives. For this purpose we performed a high-throughput (HT) phenotypic and gene expression analysis of HemSCs, and analyzed HemSC-derived tumorspheres. We found that IH is characterized by high expression of genes involved in vasculogenesis, angiogenesis, tumorigenesis and associated signaling pathways. These results show that IH derives from a dysregulated stem cell that remains in an immature, arrested stage of development. The potential biomarkers we identified can afford the development of diagnostic tools and precision-medicine therapies to "rewire" or redirect cellular transitions at an early stage, such as signaling pathways or immune response modifiers.
PMCID:5081534
PMID: 27786256
ISSN: 2045-2322
CID: 2288792

Cytometers Set Sail With Sea-Going Mobile Robots

Lopez, Peter; O'Reilly, Thomas C; Klimov, Denis
The integration of cytometers with autonomous surface and underwater vehicles can facilitate a more thorough understanding of ocean plankton types and their spatiotemporal distribution. This paper reviews existing and emerging cytometers that could potentially be integrated, with an eye toward constraints and capabilities. Vehicles have payload size and power constraints that must be considered when evaluating instrument designs for payload integration. The candidate cytometer capabilities, including dynamic range for particle-size detection, must also be taken into account to accomplish mission goals.
ISI:000357766900003
ISSN: 1948-1209
CID: 2658842

New advances in cytometric instrumentation [Meeting Abstract]

Lopez, P
The growing field of flow cytometry industry continues to produce exciting and innovative developments. Although the CyTOF mass spectrometry flow cytometer is one of the most revolutionary new developments (to be presented in another session), other advances have built upon the original FACS technology. The trends in cytometric instrumentation include smaller, easier to use analyzers and cell sorters, instrumentation capable of detecting multiple fluorescent colors even if their spectra overlap significantly, microfluidic cell sorter, analyzers that use acoustic focusing of cells in flow for potentially better precision of detection, flow cytometers that provide images and image analysis of cells in flow, and cell sorters integrated into biosafety cabinets for biohazardous work. In addition, software development has made possible the automated analysis of complete multiparametric datasets, and software is now available to aid investigators in multi-color reagent selection tailored to their specific instrument capabilities encompassing the majority of reagent and instrument vendors. These systems and their application will be presented, and the utility of these new systems in the flow cytometry core facility will be discussed
EMBASE:71779563
ISSN: 1524-0215
CID: 1476532

Overview of the new flow cytometry rg and proposed cell sorting (FACS) microarray study [Meeting Abstract]

Tighe, S; DeLay, M; Lopez, P
The Flow Cytometry Research Group (FCRG) is the latest addition to the ABRF RG family. The RG is currently in its first year and has 9 members; many of whom are flow cytometrists new to the ABRF. The initial goal of the FCRG is to describe a method for the evaluation of cell stress or other deleterious perturbations caused by cell sorting across a wide range of cell types. As an example, reports have been published demonstrating the susceptibility of dendritic cells (DCs) to phenotypic and functional changes after manipulation and isolation using techniques such as magnetic bead enrichment. To evaluate the effects of cell sorting on DCs, populations were enriched on both jet-in-air (MoFlo and FACSVantage ) and cuvette-based (FACSAria II) cell sorters, and then assessed in vitro for their ability to function as antigen presenting cells. This study showed that DC populations sorted on a cuvette sorter had decreased numbers of viable cells and decrease ability to induce antigen specific T cell proliferation, while cells sorted on jet-in-air sorters were able to induce proliferation and deemed functional. The FCRG is expanding upon this work with a 3-year research plan study which will utilize microarray analysis as an aid to identify optimal cell sorting conditions for a wide variety of cell types. This year's pilot study utilized Jurkat cells sorted through a Beckman Coulter MoFlo Legacy flow cytometer with two nozzle sizes at their respective pressures ( 50um nozzle at 70psi compared to 100um nozzle at 20psi), with and without UV laser exposure. Cells were sorted and allowed to incubate for 3 hr in RPMI media in parallel with a matched unsorted cellular control. Total RNA was extracted using Trizol and analyzed using the new Affymetrix Human Gene ST 2.0 microarrays. Results of this pilot study will be presented
EMBASE:71779562
ISSN: 1524-0215
CID: 1476542

Embracing biosafety in the flow cytometry laboratory [Meeting Abstract]

Lopez, P
Core facilities receive biological samples sourced from a variety of tissues or cell lines. This varied sample load presents a particular challenge in the flow cytometry core facility, since the cell-sorting operation relies upon the generation of droplets containing the sorted cellular material. In a failure mode (such as a nozzle clog) the cell sorter can create a significant aerosol, easily inhaled by the operator and other personnel in the area. In this session we describe the efforts and solutions proposed by ISAC, NIH and the flow cytometry community, in conjunction with biosafety officials and instrument manufacturers, to provide protective measures and best-practice guidelines for cell sorting of material ranging from primary human cells to high level biohazardous material
EMBASE:71779530
ISSN: 1524-0215
CID: 1476562

Protocadherin-18 is a novel differentiation marker and an inhibitory signaling receptor for CD8(+) effector memory T cells

Vazquez-Cintron, Edwin J; Monu, Ngozi R; Burns, Jeremy C; Blum, Roy; Chen, Gregory; Lopez, Peter; Ma, Jennifer; Radoja, Sasa; Frey, Alan B
CD8(+) tumor infiltrating T cells (TIL) lack effector-phase functions due to defective proximal TCR-mediated signaling previously shown to result from inactivation of p56(lck) kinase. We identify a novel interacting partner for p56(lck) in nonlytic TIL, Protocadherin-18 ('pcdh18'), and show that pcdh18 is transcribed upon in vitro or in vivo activation of all CD8(+) central memory T cells (CD44(+)CD62L(hi)CD127(+)) coincident with conversion into effector memory cells (CD44(+)CD62L(lo)CD127(+)). Expression of pcdh18 in primary CD8(+) effector cells induces the phenotype of nonlytic TIL: defective proximal TCR signaling, cytokine secretion, and cytolysis, and enhanced AICD. pcdh18 contains a motif (centered at Y842) shared with src kinases (QGQYQP) that is required for the inhibitory phenotype. Thus, pcdh18 is a novel activation marker of CD8(+) memory T cells that can function as an inhibitory signaling receptor and restrict the effector phase.
PMCID:3342238
PMID: 22567129
ISSN: 1932-6203
CID: 166801

Pro-tumorigenic effects of miR-31 loss in mesothelioma

Ivanov, Sergey V; Goparaju, Chandra M V; Lopez, Peter; Zavadil, Jiri; Toren-Haritan, Ginat; Rosenwald, Shai; Hoshen, Moshe; Chajut, Ayelet; Cohen, Dalia; Pass, Harvey I
The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3'-untranslated region, was consistently down-regulated by miR-31 introduction and up-regulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumor-suppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome
PMCID:2906272
PMID: 20463022
ISSN: 1083-351x
CID: 138201