Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, BMC A10, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Stem Cell Reports. 2022 Jan 11;17(1):159-172. doi: 10.1016/j.stemcr.2021.11.014. Epub 2021 Dec 30.
Transplantation in Parkinson's disease using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons is a promising future treatment option. However, many of the mechanisms that govern their differentiation, maturation, and integration into the host circuitry remain elusive. Here, we engrafted hESCs differentiated toward a ventral midbrain DA phenotype into the midbrain of a preclinical rodent model of Parkinson's disease. We then injected a novel DA-neurotropic retrograde MNM008 adeno-associated virus vector capsid, into specific DA target regions to generate starter cells based on their axonal projections. Using monosynaptic rabies-based tracing, we demonstrated for the first time that grafted hESC-derived DA neurons receive distinctly different afferent inputs depending on their projections. The similarities to the host DA system suggest a previously unknown directed circuit integration. By evaluating the differential host-to-graft connectivity based on projection patterns, this novel approach offers a tool to answer outstanding questions regarding the integration of grafted hESC-derived DA neurons.
使用人胚胎干细胞（hESC）衍生的多巴胺能（DA）神经元进行帕金森病移植是一种很有前途的未来治疗选择。然而，许多控制其分化、成熟和整合到宿主回路的机制仍然难以捉摸。在这里，我们将向帕金森病临床前啮齿动物模型的中脑移植了向腹侧中脑 DA 表型分化的 hESC。然后，我们将一种新型的 DA 神经滋养性逆行 MNM008 腺相关病毒载体衣壳注入特定的 DA 靶区，根据其轴突投射生成起始细胞。使用单突触狂犬病毒追踪，我们首次证明移植的 hESC 衍生的 DA 神经元根据其投射接收明显不同的传入输入。与宿主 DA 系统的相似性表明存在以前未知的定向电路整合。通过评估基于投射模式的宿主到移植物的连接的差异，这种新方法为回答有关移植的 hESC 衍生的 DA 神经元整合的未解决问题提供了一种工具。
