Intracellular trafficking and endocytosis of CXCR4 in fetal mesenchymal stem/stromal cells

Pelekanos, Rebecca A., Ting, Michael J., Sardesai, Varda S., Ryan, Jennifer M., Lim, Yaw-Chyn, Chan, Jerry K. Y. and Fisk, Nicholas M. (2014) Intracellular trafficking and endocytosis of CXCR4 in fetal mesenchymal stem/stromal cells. BMC Cell Biology, 15 1: . doi:10.1186/1471-2121-15-15

Author Pelekanos, Rebecca A.
Ting, Michael J.
Sardesai, Varda S.
Ryan, Jennifer M.
Lim, Yaw-Chyn
Chan, Jerry K. Y.
Fisk, Nicholas M.
Title Intracellular trafficking and endocytosis of CXCR4 in fetal mesenchymal stem/stromal cells
Journal name BMC Cell Biology   Check publisher's open access policy
ISSN 1471-2121
Publication date 2014-05-16
Year available 2014
Sub-type Article (original research)
DOI 10.1186/1471-2121-15-15
Open Access Status DOI
Volume 15
Issue 1
Total pages 15
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Fetal mesenchymal stem/stromal cells (MSC) represent a developmentally-advantageous cell type with translational potential.

To enhance adult MSC migration, studies have focussed on the role of the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12), but more recent work implicates an intricate system of CXCR4 receptor dimerization, intracellular localization, multiple ligands, splice variants and nuclear accumulation. We investigated the intracellular localization of CXCR4 in fetal bone marrow-derived MSC and role of intracellular trafficking in CXCR4 surface expression and function.

We found that up to 4% of human fetal MSC have detectable surface-localized CXCR4. In the majority of cells, CXCR4 is located not at the cell surface, as would be required for ‘sensing’ migratory cues, but intracellularly. CXCR4 was identified in early endosomes, recycling endosomes, and lysosomes, indicating only a small percentage of CXCR4 travelling to the plasma membrane. Notably CXCR4 was also found in and around the nucleus, as detected with an anti-CXCR4 antibody directed specifically against CXCR4 isoform 2 differing only in N-terminal sequence. After demonstrating that endocytosis of CXCR4 is largely independent of endogenously-produced SDF-1, we next applied the cytoskeletal inhibitors blebbistatin and dynasore to inhibit endocytotic recycling. These increased the number of cells expressing surface CXCR4 by 10 and 5 fold respectively, and enhanced the number of cells migrating to SDF1 in vitro (up to 2.6 fold). These molecules had a transient effect on cell morphology and adhesion, which abated after the removal of the inhibitors, and did not alter functional stem cell properties.

We conclude that constitutive endocytosis is implicated in the regulation of CXCR4 membrane expression, and suggest a novel pharmacological strategy to enhance migration of systemically-transplanted cells.
Keyword Fetal mesenchymal stromal cells
Bone marrow
Chemokine receptor
Chemokine receptor
Small molecule
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Online article no. 15

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2015 Collection
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 8 times in Scopus Article | Citations
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