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Shen, Keyue

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Shen

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Keyue

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Shen, Keyue
Author's Publications: search.filters.isAuthorOfPublication.8cf2cf2f-8a6c-4fde-b472-61acbc4e6392

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    Pharmacokinetics of Natural and Engineered Secreted Factors Delivered by Mesenchymal Stromal Cells
    (Public Library of Science, 2014) Elman, Jessica S.; Murray, Ryan M.; Wang, Fangjing; Shen, Keyue; Gao, Shan; Conway, Kevin E.; Yarmush, Martin; Tannous, Bakhos; Weissleder, Ralph; Parekkadan, Biju
    Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.
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    Resolving Cancer-Stroma Interfacial Signaling and Interventions with Micropatterned Tumor-Stromal Assays
    (2014) Shen, Keyue; Luk, Samantha; Hicks, Daniel F; Elman, Jessica S; Bohr, Stefan; Iwamoto, Yoshiko; Murray, Ryan; Pena, Kristen; Wang, Fangjing; Seker, Erkin; Weissleder, Ralph; Yarmush, Martin; Toner, Mehmet; Sgroi, Dennis; Parekkadan, Biju
    Tumor-stromal interactions are a determining factor in cancer progression. In vivo, the interaction interface is associated with spatially-resolved distributions of cancer and stromal phenotypes. Here, we establish a micropatterned tumor-stromal assay (μTSA) with laser capture microdissection to control the location of co-cultured cells and analyze bulk and interfacial tumor-stromal signaling in driving cancer progression. μTSA reveals a spatial distribution of phenotypes in concordance with human estrogen receptor-positive (ER+) breast cancer samples, and heterogeneous drug activity relative to the tumor-stroma interface. Specifically, an unknown mechanism of reversine is shown in targeting tumor-stromal interfacial interactions using ER+ MCF-7 breast cancer and bone marrow-derived stromal cells. Reversine suppresses MCF-7 tumor growth and bone metastasis in vivo by reducing tumor stromalization including collagen deposition and recruitment of activated stromal cells. This study advocates μTSA as a platform for studying tumor microenvironmental interactions and cancer field effects with applications in drug discovery and development.
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    Highly Upregulated Lhx2 in the Foxn1\(^{−/−}\) Nude Mouse Phenotype Reflects a Dysregulated and Expanded Epidermal Stem Cell Niche
    (Public Library of Science, 2013) Bohr, Stefan; Patel, Suraj; Vasko, Radovan; Shen, Keyue; Huang, Guofeng; Yarmush, Martin; Berthiaume, Francois
    Hair cycling is a prime example of stem cell dependent tissue regeneration and replenishment, and its regulatory mechanisms remain poorly understood. In the present study, we evaluated the effect of a blockage in terminal keratinocytic lineage differentiation in the Foxn1\(^{−/−}\) nude phenotype on the epithelial progeny. Most notably we found a constitutive upregulation of LIM homeobox protein 2 (Lhx2), a marker gene of epithelial stem cellness indispensible for hair cycle progression. However, histological evidence along with an erratic, acyclic rise of otherwise suppressed CyclinD1 levels along with several key markers of keratinocyte lineage differentiation indicate a frustrated expansion of epithelial stem cell niches in skin. In addition, CD49f/CD34/CD200–based profiling demonstrated highly significant shifts in subpopulations of epithelial progeny. Intriguingly this appeared to include the expansion of Oct4+ stem cells in dermal fractions of skin isolates in the Foxn1 knock-out opposed to wild type. Overall our findings indicate that the Foxn1\(^{−/−}\) phenotype has a strong impact on epithelial progeny and thus offers a promising model to study maintenance and regulation of stem cell niches within skin not feasible in other in vitro or in vivo models.