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Project

Astrocyte subtype specific transplantation for promoting synaptogenesis after cervical SCI

Funder: Craig H Neilsen Foundation

Funding period
USD 150 K
Funding amount
Abstract
Astrocyte lineage cell transplantation is a powerful and innovative strategy for the treatment of spinal cord injury (SCI). Astrocytes play many critical roles in the central nervous system (CNS), including promoting synaptogenesis in the developing CNS. Importantly, the heterogeneity of astrocytes both across and within various CNS regions is gaining appreciating. For example, one subpopulation of mature cortical astrocytes significantly enhances synaptogenesis in vitro (i.e. Type C astrocytes) as compared with other CNS astrocytes. To date, astrocytes have been approached as a homogeneous population in the context of therapeutic cell transplantation, not accounting for potential differences in therapeutically relevant properties across various astrocyte subpopulations. Here, we propose that the specialized function of Type C astrocytes can be used to restore synaptic connectivity after cervical SCI. Phrenic motor neurons (PhMNs) innervating the diaphragm muscle receive input from the rostral Ventral Respiratory Group (rVRG) neurons, whose cell bodies reside in the brainstem. Denervation of the PhMNs as a result of severing the rVRG axons in cervical SCI results in loss of diaphragm function, compromising overall respiration. Our lab has shown that inhibiting the PTEN signaling pathway, involved in the developmental downregulation of axonal growth in vivo, is sufficient to induce regeneration of rVRG axons after SCI. However, relatively low synaptic innervation of PhMNs by rVRG axons occurs, resulting in a modest recovery of respiratory function, suggesting the need for improved synaptogenesis after SCI. Due to the synaptogenic properties of Type C astrocytes, we hypothesize that transplantation of Type C astrocytes after cervical SCI will promote synaptogenesis between regenerating rVRG axons and PhMNs or pre-phrenic interneurons, leading to improved respiratory function. This study is the first to use the specific function of a subtype of astrocytes to treat SCI. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Regenerative Medicine

  • RCDC

    Neurosciences

  • RCDC

    Lung

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science