hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease

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Abstract

Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
  • Cell and Molecular Biology

Keywords

  • brain repair, cell replacement therapy, cell transplantation, grafting, monosynaptic tracing, Parkinson's disease, stem cells
Original languageEnglish
Pages (from-to)3462-3473.e5
JournalCell Reports
Volume28
Issue number13
Publication statusPublished - 2019 Sep 24
Publication categoryResearch
Peer-reviewedYes