The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson's Disease.

Yun-Ting Jhao,Yi-Wen Lin,Yu-Ten Ju,Chyng-Yann Shiue,Shinn-Chih Wu,Cheng-Yi Cheng,Kuo-Hsing Ma,Chien-Fu F Chen,Ruoh-Fang Yan,Ta-Kai Chou,Sheau-Huei Chueh,Chuang-Hsin Chiu,Christer Halldin

doi:10.3390/cells8111420

Abstract

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson’s disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.

Highlights

Parkinson’s disease (PD) is typified by selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta and is a prevalent neurodegenerative disorder [1]
An increase in net rotation was noted in hemiparkinsonian rats, whereas no behavioral improvement was observed in the sham (n = 3) and Sertoli cells (SCs) groups (n = 6)
Co-transplantation of SCs in allo- and xenotransplantation of ventral mesencephalic (VM) tissue led to improved DA function in the rats (n = 6/group)

Summary

Introduction

Parkinson’s disease (PD) is typified by selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta and is a prevalent neurodegenerative disorder [1]. Pharmacological and surgical treatment, such as deep brain stimulation, can partially alleviate these symptoms [2]. Intra-striatal transplantation of cells harvested from human fetal ventral mesencephalic (hVM) tissue have been shown to restore striatal dopamine concentration in PD patients and provide long-lasting relief of the symptoms [5,6,7]. HVM tissues are unlikely to become a major PD therapy in that the supply of human fetal tissues is limited and there are serious ethical issues to consider. DA cells derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can, in theory, resolve the supply issue and have been heavily tested in PD animal models [8,9,10]

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