Expression of a Distinct Set of Chemokine Receptors in Adipose Tissue-Derived Stem Cells is Responsible for In Vitro Migration Toward Chemokines Appearing in the Major Pelvic Ganglion Following Cavernous Nerve Injury

Maarten Albersen; Joost Berkers; Philip Dekoninck; Jan Deprest; Tom F Lue; Petter Hedlund; Ching-Shwun Lin; Trinity J Bivalacqua; Hendrik Van Poppel; Dirk De Ridder; Frank Van der Aa

doi:10.1002/sm2.1

Expression of a Distinct Set of Chemokine Receptors in Adipose Tissue-Derived Stem Cells is Responsible for In Vitro Migration Toward Chemokines Appearing in the Major Pelvic Ganglion Following Cavernous Nerve Injury

Sex Med. 2013 Aug;1(1):3-15. doi: 10.1002/sm2.1.

Authors

Affiliations

¹ Laboratory of Experimental Urology, Department of Development and Regeneration, University of Leuven Leuven, Belgium ; Laboratory of Experimental Gynecology, Department of Development and Regeneration, University of Leuven Leuven, Belgium.
² Laboratory of Experimental Urology, Department of Development and Regeneration, University of Leuven Leuven, Belgium.
³ Laboratory of Experimental Gynecology, Department of Development and Regeneration, University of Leuven Leuven, Belgium.
⁴ Knuppe Molecular Urology Laboratory, Department of Urology, University of California San Francisco, CA, USA.
⁵ Department of Urology, Urological Research Institute, Vita-Salute San Raffaele University Milan, Italy.
⁶ Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions Baltimore, MD, USA.

PMID: 25356281
PMCID: PMC4184711
DOI: 10.1002/sm2.1

Abstract

Introduction: Adipose tissue-derived stem cells (ADSCs) herald tremendous promise for clinical application in a wide range of injuries and diseases. Several preclinical reports demonstrate their efficacy in the treatment of cavernous nerve (CN) injury-induced erectile dysfunction in rats. It was recently illustrated that these effects were established as a result of ADSC migration to the major pelvic ganglion (MPG) where these cells induced neuroregeneration in loco.

Aims: The study aims to identify chemotactic factors in the MPG following injury and to match upregulated chemokines to their respective receptors in human ADSC on the genomic, structural, and functional levels.

Methods: Quantitative real-time polymerase chain reaction, fluorescence-activated cell sorting (FACS), intracellular FACS, immunofluorescence microscopy, migration assays, and calcium imaging were used in this study.

Main outcome measures: The main outcomes are chemokine expression in the MPG following CN injury, and the functional and structural presence of chemokine receptors in ADSC.

Results: CCR4, CX3CR1, and XCR1 are functionally and structurally present in human ADSC, and are activated by the chemokines CCL2, CX3CL1, and XCL1 respectively, which are upregulated in the MPG following CN injury. CXCR4 and its ligand CXCL12 (SDF1) are likely no major homing factors for ADSC. Expression of chemokine receptor mRNA in ADSC did not necessarily translate into receptor presence at the cell surface and/or functional activation of these receptors. Most of the expressed chemokine receptors were detected in the intracellular compartment of these cells.

Conclusions: We identified the ligand/chemokine receptor pairs CCL2/CCR4, CX3CL1/CX3CR1, and XCL1/XCR1 as potentially responsible for ADSC homing toward the MPG following CN injury. The intracellular localization of various chemokine receptors likely indicates redirecting of chemokine receptors to the cell surface under specific cellular conditions. Furthermore, modification of expression of these receptors at the genomic level may potentially lead to improved migration toward injury sites and thus enhancement of treatment efficacy. Albersen M, Berkers J, Dekoninck P, Deprest J, Lue TF, Hedlund P, Lin C-S, Bivalacqua TJ, Van Poppel H, De Ridder D, and Van der Aa F. Expression of a distinct set of chemokine receptors in adipose tissue-derived stem cells is responsible for in vitro migration toward chemokines appearing in the major pelvic ganglion following cavernous nerve injury. Sex Med 2013;1:3-15.

Keywords: Adipose Tissue-Derived Stem Cells; Cavernous Nerve Injury; Cell Surface; Chemokine Receptors; Chemokines; Erectile Dysfunction; Intracellular; Migration.