Liang Wang1,2, Huan Li1,2, Jinfu Lin1,2, Ruojie He1,2, Menglong Chen3, Yu Zhang3, Ziyu Liao1,2, Cheng Zhang4,5. 1. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, GD, China. 2. National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, No. 58 Zhongshan Road 2, Guangzhou, GD, 510080, China. 3. Department of Neurology, Guangzhou Overseas Chinese Hospital, No. 613 Huangpu Road, Guangzhou, GD, 510630, China. 4. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, 510080, GD, China. zhangch6@mail.sysu.edu.cn. 5. National Key Clinical Department and Key Discipline of Neurology, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, No. 58 Zhongshan Road 2, Guangzhou, GD, 510080, China. zhangch6@mail.sysu.edu.cn.
Abstract
BACKGROUND: Dystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments. Systemic transplantation of adipose-derived stem cells (ADSCs) is a promising treatment approach, but its low efficacy remains a challenge. Chemokine system-mediated stem cell homing plays a critical role in systemic transplantation. Here, we investigated whether overexpression of a specific chemokine receptor could improve muscle homing and therapeutic effects of ADSC systemic transplantation in dystrophic mice. METHODS: We analysed multiple microarray datasets from the Gene Expression Omnibus to identify a candidate chemokine receptor and then evaluated the protein expression of target ligands in different tissues and organs of dystrophic mice. The candidate chemokine receptor was overexpressed using the lentiviral system in mouse ADSCs, which were used for systemic transplantation into the dystrophic mice, followed by evaluation of motor function, stem cell muscle homing, dystrophin expression, and muscle pathology. RESULTS: Chemokine-profile analysis identified C-C chemokine receptor (CCR)2 as the potential target for improving ADSC homing. We found that the levels of its ligands C-C chemokine ligand (CCL)2 and CCL7 were higher in muscles than in other tissues and organs of dystrophic mice. Additionally, CCR2 overexpression improved ADSC migration ability and maintained their multilineage-differentiation potentials. Compared with control ADSCs, transplantation of those overexpressing CCR2 displayed better muscle homing and further improved motor function, dystrophin expression, and muscle pathology in dystrophic mice. CONCLUSIONS: These results demonstrated that CCR2 improved ADSC muscle homing and therapeutic effects following systemic transplantation in dystrophic mice.
BACKGROUND: Dystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments. Systemic transplantation of adipose-derived stem cells (ADSCs) is a promising treatment approach, but its low efficacy remains a challenge. Chemokine system-mediated stem cell homing plays a critical role in systemic transplantation. Here, we investigated whether overexpression of a specific chemokine receptor could improve muscle homing and therapeutic effects of ADSC systemic transplantation in dystrophic mice. METHODS: We analysed multiple microarray datasets from the Gene Expression Omnibus to identify a candidate chemokine receptor and then evaluated the protein expression of target ligands in different tissues and organs of dystrophic mice. The candidate chemokine receptor was overexpressed using the lentiviral system in mouse ADSCs, which were used for systemic transplantation into the dystrophic mice, followed by evaluation of motor function, stem cell muscle homing, dystrophin expression, and muscle pathology. RESULTS: Chemokine-profile analysis identified C-C chemokine receptor (CCR)2 as the potential target for improving ADSC homing. We found that the levels of its ligands C-C chemokine ligand (CCL)2 and CCL7 were higher in muscles than in other tissues and organs of dystrophic mice. Additionally, CCR2 overexpression improved ADSC migration ability and maintained their multilineage-differentiation potentials. Compared with control ADSCs, transplantation of those overexpressing CCR2 displayed better muscle homing and further improved motor function, dystrophin expression, and muscle pathology in dystrophic mice. CONCLUSIONS: These results demonstrated that CCR2 improved ADSC muscle homing and therapeutic effects following systemic transplantation in dystrophic mice.
Authors: Judith N Haslett; Peter B Kang; Mei Han; Alvin T Kho; Despina Sanoudou; Jay M Volinski; Alan H Beggs; Isaac S Kohane; Louis M Kunkel Journal: Mamm Genome Date: 2005-10-29 Impact factor: 2.957
Authors: Eun Ji Gang; Radbod Darabi; Darko Bosnakovski; Zhaohui Xu; Kristine E Kamm; Michael Kyba; Rita C R Perlingeiro Journal: Exp Cell Res Date: 2009-05-19 Impact factor: 3.905
Authors: Caroline Godfrey; Sofia Muses; Graham McClorey; Kim E Wells; Thibault Coursindel; Rebecca L Terry; Corinne Betts; Suzan Hammond; Liz O'Donovan; John Hildyard; Samir El Andaloussi; Michael J Gait; Matthew J Wood; Dominic J Wells Journal: Hum Mol Genet Date: 2015-05-01 Impact factor: 6.150