Abi3bp Is a Multifunctional Autocrine/Paracrine Factor that Regulates Mesenchymal Stem Cell Biology

Authors

  • Conrad P. Hodgkinson,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Vinogran Naidoo,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Karl G. Patti,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Jose A. Gomez,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Jeffrey Schmeckpeper,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Zhiping Zhang,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Bryce Davis,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Richard E. Pratt,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Maria Mirotsou,

    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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  • Victor J. Dzau

    Corresponding author
    1. Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
    • Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA===

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    • Telephone: 919-684-2255; Fax: 919-681-7020


  • Author contributions: C.P.H.: conception and design, collection of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; V.N., K.G.P., J.G., J.S., Z.Z., and B.D.: collection and/or assembly of data; R.P.: data analysis and interpretation; M.M.: conception and design, manuscript writing, and final approval of manuscript; V.J.D.: conception and design, manuscript writing, data analysis and interpretation, and final approval of manuscript.

Abstract

Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over-expressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp toward MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin-mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress-fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt-MSC proliferation, promoting S-phase entry via cyclin-d1, ERK1/2, and Src. Upon Abi3bp binding to integrin-β1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs. STEM Cells 2013;31:1669–1682

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