ROCK activity and the Gβγ complex mediate chemotactic migration of mouse bone marrow-derived stromal cells

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Title: ROCK activity and the Gβγ complex mediate chemotactic migration of mouse bone marrow-derived stromal cells
Authors: Ryan, Caroline M.Brown, James A. L.Bourke, EmerPrendergast, Áine M.Kavanagh, ClaireLiu, ZhonglinOwens, PeterShaw, GeorginaKolch, WalterO'Brien, TimothyBarry, Frank P.
Permanent link: http://hdl.handle.net/10197/9159
Date: 24-Jul-2015
Online since: 2018-01-10T13:47:13Z
Abstract: Bone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells, are the focus of intensive efforts worldwide to elucidate their function and biology. Despite the importance of BMSC migration for their potential therapeutic uses, the mechanisms and signalling governing stem cell migration are still not fully elucidated. Methods: We investigated and detailed the effects of MCP-1 activation on BMSCs by using inhibitors of G protein-coupled receptor alpha beta (GPCR αβ), ROCK (Rho-associated, coiled-coil containing protein kinase), and PI3 kinase (PI3K). The effects of MCP-1 stimulation on intracellular signalling cascades were characterised by using immunoblotting and immunofluorescence. The effectors of MCP-1-mediated migration were investigated by using migration assays (both two-dimensional and three-dimensional) in combination with inhibitors. Results: We established the kinetics of the MCP-1-activated signalling cascade and show that this cascade correlates with cell surface re-localisation of chemokine (C motif) receptor 2 (CCR2) (the MCP-1 receptor) to the cell periphery following MCP-1 stimulation. We show that MCP-1-initiated signalling is dependent on the activation of βγ subunits from the GPCR αβγ complex. In addition, we characterise a novel role for PI3Kγ signalling for the activation of both PAK and ERK following MCP-1 stimulation. We present evidence that the Gβγ complex is responsible for PI3K/Akt, PAK, and ERK signalling induced by MCP-1 in BMSCs. Importantly, we found that, in BMSCs, inhibition of ROCK significantly inhibits MCP-1-induced chemotactic migration, in contrast to previous reports in other systems.Conclusions: Our results indicate differential chemotactic signalling in mouse BMSCs, which has important implications for the translation of in vivo mouse model findings into human trials. We identified novel components and interactions activated by MCP-1-mediated signalling, which are important for stem cell migration. This work has identified additional potential therapeutic targets that could be manipulated to improve BMSC delivery and homing.
Funding Details: Science Foundation Ireland
Funding Details: National Breast Cancer Research Institute
Type of material: Journal Article
Publisher: Springer Nature
Journal: Stem Cell Research and Therapy
Volume: 6
Issue: 136
Copyright (published version): 2015 the Authors
Keywords: ROCKGβγ complexMesenchymal stem cellsBMSCsMCP-1 activationMCP-1 activationGPCR αβChemotactic migrationChemotactic signallingStem cell migration
DOI: 10.1186/s13287-015-0125-y
Language: en
Status of Item: Peer reviewed
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by-nc-nd/3.0/ie/
Appears in Collections:SBI Research Collection

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