Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury.

Autor:	Gao S; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Guo X; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Zhao S; iHuman Institute, Shanghai Science and Technology University, Shanghai, 201210, China., Jin Y; Shanghai Public Health Clinical Center, Fudan University, JinShan, Shanghai, 201508, China., Zhou F; Department of Neurology, Third Affiliated Hospital of Navy Military Medical University, Shanghai, 200438, China., Yuan P; Tongji hospital affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200065, China., Cao L; Shanghai Eighth People's Hospital Affiliated to Jiangsu University, Shanghai, 200233, China., Wang J; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Qiu Y; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Sun C; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Kang Z; Department of Orthopaedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 200137, China., Gao F; Zhoupu hospital, Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China., Xu W; Tongji hospital affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200065, China., Hu X; Tongji hospital affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200065, China., Yang D; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Qin Y; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China., Ning K; Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK., Shaw PJ; Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK., Zhong G; iHuman Institute, Shanghai Science and Technology University, Shanghai, 201210, China. zhongsh@shanghaitech.edu.cn., Cheng L; Tongji hospital affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200065, China. chlm.d@163.com., Zhu H; Tianjin Hospital, Tianjin, 300211, China. hongwen_zhu@126.com.; BOE Technology Group Co., Ltd., Beijing, 100176, China. hongwen_zhu@126.com., Gao Z; Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. zhengliang_gao@tongji.edu.cn., Chen X; Shanghai Eighth People's Hospital Affiliated to Jiangsu University, Shanghai, 200233, China. CXWP65@163.com., Xu J; East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China. xunymc2000@yahoo.com.
Jazyk:	angličtina
Zdroj:	Cell death & disease [Cell Death Dis] 2019 Aug 08; Vol. 10 (8), pp. 597. Date of Electronic Publication: 2019 Aug 08.
DOI:	10.1038/s41419-019-1772-1
Abstrakt:	Human adipose-derived stem cells (hADSCs) are increasingly presumed to be a prospective stem cell source for cell replacement therapy in various degenerative and/or traumatic diseases. The potential of trans-differentiating hADSCs into motor neuron cells indisputably provides an alternative way for spinal cord injury (SCI) treatment. In the present study, a stepwise and efficient hADSC trans-differentiation protocol with retinoic acid (RA), sonic hedgehog (SHH), and neurotrophic factors were developed. With this protocol hADSCs could be converted into electrophysiologically active motoneuron-like cells (hADSC-MNs), which expressed both a cohort of pan neuronal markers and motor neuron specific markers. Moreover, after being primed for neuronal differentiation with RA/SHH, hADSCs were transplanted into SCI mouse model and they survived, migrated, and integrated into injured site and led to partial functional recovery of SCI mice. When ablating the transplanted hADSC-MNs harboring HSV-TK-mCherry overexpression system with antivirial Ganciclovir (GCV), functional relapse was detected by motor-evoked potential (MEP) and BMS assays, implying that transplanted hADSC-MNs participated in rebuilding the neural circuits, which was further confirmed by retrograde neuronal tracing system (WGA). GFP-labeled hADSC-MNs were subjected to whole-cell patch-clamp recording in acute spinal cord slice preparation and both action potentials and synaptic activities were recorded, which further confirmed that those pre-conditioned hADSCs indeed became functionally active neurons in vivo. As well, transplanted hADSC-MNs largely prevented the formation of injury-induced cavities and exerted obvious immune-suppression effect as revealed by preventing astrocyte reactivation and favoring the secretion of a spectrum of anti-inflammatory cytokines and chemokines. Our work suggests that hADSCs can be readily transformed into MNs in vitro, and stay viable in spinal cord of the SCI mouse and exert multi-therapeutic effects by rebuilding the broken circuitry and optimizing the microenvironment through immunosuppression.
Databáze:	MEDLINE
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