論文 - 詳細
| RRC ID | 78815 |
|---|---|
| 著者 | Gima S, Oe K, Nishimura K, Ohgita T, Ito H, Kimura H, Saito H, Takata K. |
| タイトル | Host-to-graft propagation of inoculated α-synuclein into transplanted human induced pluripotent stem cell-derived midbrain dopaminergic neurons. |
| ジャーナル | Regen Ther |
| Abstract |
INTRODUCTION:Cell therapeutic clinical trials using fetal mesencephalic tissue provided a proof-of-concept for regenerative therapy in patients with Parkinson's disease. Postmortem studies of patients with fetal grafts revealed that α-synuclein+ Lewy body (LB)-like inclusions emerged in long-term transplantation and might worsen clinical outcomes even if the grafts survived and innervated in the recipients. Various studies aimed at addressing whether host-derived α-synuclein could be transferred to the grafted neurons to assess α-synuclein+ inclusion appearance in the grafts. However, determining whether α-synuclein in the grafted neurons has been propagated from the host is difficult due to the intrinsic α-synuclein expression. METHODS:We induced midbrain dopaminergic (mDA) neurons from human induced pluripotent stem cells (hiPSCs) and transplanted them into the striatum of immunodeficient rats. The recombinant human α-synuclein preformed fibrils (PFFs) were inoculated into the cerebral cortex after transplantation of SNCA-/- hiPSC-derived mDA neural progenitors into the striatum of immunodeficient rats to evaluate the host-to-graft propagation of human α-synuclein PFFs. Additionally, we examined the incorporation of human α-synuclein PFFs into SNCA-/- hiPSC-derived mDA neurons using in vitro culture system. RESULTS:We detected human α-synuclein-immunoreactivity in SNCA-/- hiPSC-derived mDA neurons that lacked endogenous α-synuclein expression in vitro. Additionally, we observed host-to-graft α-synuclein propagation into the grafted SNCA-/- hiPSC-derived mDA neurons. CONCLUSION:We have successfully proven that intracerebral inoculated α-synuclein PFFs are propagated and incorporated from the host into grafted SNCA-/- hiPSC-derived mDA neurons. Our results contribute toward the basic understanding of the molecular mechanisms related to LB-like α-synuclein deposit formation in grafted mDA neurons. |
| 巻・号 | 25 |
| ページ | 229-237 |
| 公開日 | 2024-3-1 |
| DOI | 10.1016/j.reth.2023.12.019 |
| PII | S2352-3204(23)00152-9 |
| PMID | 38283940 |
| PMC | PMC10818157 |
| リソース情報 | |
| ラット | F344-Il2rgem1Iexas (StrainID=1295) |
| ヒト・動物細胞 | 1231A3(HPS0381) |