Browsing by Subject "Cellular proliferation"

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    Human adipose derived stromal/stem cells (hASCs) protect against STZ-induced hyperglycemia; analysis of hASC-derived paracrine effectors
    (Wiley, 2014-07) Kono, Tatsuyoshi M.; Sims, Emily K.; Moss, Dan R.; Yamamoto, Wataru; Ahn, Geonyoung; Diamond, Julie; Tong, Xin; Day, Kathleen H.; Territo, Paul R.; Hanenberg, Helmut; Traktuev, Dmitry O.; March, Keith L.; Evans-Molina, Carmella; Department of Medicine, IU School of Medicine
    Adipose-derived stromal/stem cells (ASCs) ameliorate hyperglycemia in rodent models of islet transplantation and autoimmune diabetes, yet the precise human ASC (hASC)-derived factors responsible for these effects remain largely unexplored. Here, we show that systemic administration of hASCs improved glucose tolerance, preserved β cell mass, and increased β cell proliferation in streptozotocin-treated nonobese diabetic/severe combined immunodeficient mice. Coculture experiments combining mouse or human islets with hASCs demonstrated that islet viability and function were improved by hASCs following prolonged culture or treatment with proinflammatory cytokines. Analysis of hASC-derived factors revealed vascular endothelial growth factor and tissue inhibitor of metalloproteinase 1 (TIMP-1) to be highly abundant factors secreted by hASCs. Notably, TIMP-1 secretion increased in the presence of islet stress from cytokine treatment, while TIMP-1 blockade was able to abrogate in vitro prosurvival effects of hASCs. Following systemic administration by tail vein injection, hASCs were detected in the pancreas and human TIMP-1 was increased in the serum of injected mice, while recombinant TIMP-1 increased viability in INS-1 cells treated with interleukin-1beta, interferon-gamma, and tumor necrosis factor alpha. In aggregate, our data support a model whereby factors secreted by hASCs, such as TIMP-1, are able to mitigate against β cell death in rodent and in vitro models of type 1 diabetes through a combination of local paracrine as well as systemic effects.
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    Identification of Specific Lysines and Arginines That Mediate Angiomotin Membrane Association
    (American Chemical Society, 2019-04-30) Hall, Le’Celia; Donovan, Emily; Araya, Michael; Idowa, Eniola; Jiminez-Segovia, Ilse; Folck, Anthony; Wells, Clark D.; Kimble-Hill, Ann C.; Biochemistry and Molecular Biology, School of Medicine
    The family of Angiomotin (Amot) proteins regulate several biological pathways associated with cellular differentiation, proliferation, and migration. These adaptor proteins target proteins to the apical membrane, actin fibers, or the nucleus. A major function of the Amot coiled-coil homology (ACCH) domain is to initiate protein interactions with the cellular membrane, particularly those containing phosphatidylinositol lipids. The work presented in this article uses several ACCH domain lysine/arginine mutants to probe the relative importance of individual residues for lipid binding. This identified four lysine and three arginine residues that mediate full lipid binding. Based on these findings, three of these residues were mutated to glutamates in the Angiomotin 80 kDa splice form and were incorporated into human mammary cell lines. Results show that mutating three of these residues in the context of full-length Angiomotin reduced the residence of the protein at the apical membrane. These findings provide new insight into how the ACCH domain mediates lipid binding to enable Amot proteins to control epithelial cell growth.