Transsynaptic tracing and its emerging use to assess graft‐reconstructed neural circuits. (5th March 2020)

• Record Type: Journal Article
• Authors: Adler, Andrew F.; Björklund, Anders; Parmar, Malin
• Is Part Of: Stem cells. Volume 38:Number 6(2020)
• Page Start: 716
• Page End: 726
• Publication Date: 2020-03-05
• Subjects: nervous system -- Parkinson's disease -- spinal cord injury -- stem cell transplantation; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3166
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Fetal neural progenitor grafts have been evaluated in preclinical animal models of spinal cord injury and Parkinson's disease for decades, but the initial reliance on primary tissue as a cell source limited the scale of their clinical translatability. With the development of robust methods to differentiate human pluripotent stem cells to specific neural subtypes, cell replacement therapy holds renewed promise to treat a variety of neurodegenerative diseases and injuries at scale. As these cell sources are evaluated in preclinical models, new transsynaptic tracing methods are making it possible to study the connectivity between host and graft neurons with greater speed and detail than was previously possible. To date, these studies have revealed that widespread, long‐lasting, and anatomically appropriate synaptic contacts are established between host and graft neurons, as well as new aspects of host‐graft connectivity which may be relevant to clinical cell replacement therapy. It is not yet clear, however, whether the synaptic connectivity between graft and host neurons is as cell‐type specific as it is in the endogenous nervous system, or whether that connectivity is responsible for the functional efficacy of cell replacement therapy. Here, we review evidence suggesting that the new contacts established between host and graft neurons may indeed be cell‐type specific, and how transsynaptic tracing can be used in the future to further elucidate the mechanisms of graft‐mediated functional recovery in spinal cord injury and Parkinson's disease. Abstract : Monosynaptic rabies tracing can be used to map inputs to stem cell‐derived neurons grafted to models of neurodegenerative disease and injury. These studies indicate that graft neurons receive anatomically‐appropriate inputs, but it remains to be determined whether those inputs are necessary for functional recovery. Next‐generation rabies tracing is poised to address this outstanding question, which may aid ongoing translational efforts.