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

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.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model

“…One possible reason involves trophic effects of progenitor cells in rVM. Previous studies have reported that only VM into syngeneic recipients has the ability to improve apomorphine-induced rotational behavior in hemiparkinsonian rats and induce the recovery in the striatal uptakes of [ 18 F] DOPA after transplantation [ 37 , 63 ], suggesting that progenitor cells in rVM tissues are able to synthesize dopamine in the lesioned striatum to alleviate 6-OHDA-induced behavior alternations. However, the striatal uptake of [ 18 F] FE-PE2I was not recovered significantly in rVM-implanted striatum, implying that these cells in rVM tissues are still exhibited as DA precursor cells, not developed into DAT-expressed matured DA neurons [ 37 ].…”

“…Previous studies have reported that only VM into syngeneic recipients has the ability to improve apomorphine-induced rotational behavior in hemiparkinsonian rats and induce the recovery in the striatal uptakes of [ 18 F] DOPA after transplantation [ 37 , 63 ], suggesting that progenitor cells in rVM tissues are able to synthesize dopamine in the lesioned striatum to alleviate 6-OHDA-induced behavior alternations. However, the striatal uptake of [ 18 F] FE-PE2I was not recovered significantly in rVM-implanted striatum, implying that these cells in rVM tissues are still exhibited as DA precursor cells, not developed into DAT-expressed matured DA neurons [ 37 ]. While rhCDNF treatment did not further alleviate behavior alternations at an earlier time point, which might be reflective of DA precursor cell function, this therapeutic application could predominantly promote DA maturation representative of increase in [ 18 F] FE-PE2I uptake in rVM-implanted striatum.…”

“…As previously stated, the hemiparkinsonian model rats were generated [ 37 ]. In brief, eight-week-old male SD rats were given 6-OHDA (20 μg in 4 μL of 0.02% ascorbic acid−holding saline) (Sigma-Aldrich, Saint Louis, MO, USA) unilaterally to the medial forebrain bundle (7.8 mm below the dura, 1.2 mm lateral to the midline, and 4.4 mm posterior to the bregma).…”

“…The Department of Nuclear Medicine native to National Taiwan University Hospital synthesized and provided [ 18 F] DOPA [ 37 ]. [ 18 F] FE-PE2I was synthesized with minor modification, as previously described.…”

“…The PET imaging procedure for small animals was based on previous research [ 37 ]. In brief, PET imaging was performed on rats using PET scanner (BIOPET 105, BIOSCAN, Santa Clara, CA, USA) at one week before the 6-OHDA lesion was produced, three weeks after the 6-OHDA lesion was created; four- and eight-weeks following transplantation.…”