Raúl E. Russo, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay

Understanding the reaction of endogenous progenitor cells to improve self -repair after spinal cord injury

Funded in: 2017, 2018, 2019, 2020

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Problem: The capacity for repair by endogenous progenitor cells is not enough to reach a meaningful functional recovery.

Target: Investigation of cell intrinsic genetic programs to reactivate self-repair capabilities of ependymal cells

Goal: Modulation of the ependymal cells for a more adaptive injury response thereby improving functional recovery.

Although the mammalian spinal cord lacks the ability for self-repair, some cells in the ependyma react to injury by proliferating and migrating towards the lesion. Most differentiate into astrocytes with a few becoming oligodendrocytes (OLs). The ependyma-derived cells seem beneficial as they produce growth factors -helping neurons around the lesion to survive- and do not generate inhibitors of axonal growth. Thus, optimizing the reaction of the ependyma to injury seems a promising strategy to facilitate endogenous repair. To reach this goal, we need to understand the mechanisms that regulate ependymal cells with heterogeneous functional properties. We speculate that injury re-activates genetic programs that lead ependymal cells to recapitulate some of the behaviors of progenitors in the neural tube. The reaction of ependymal cells and the fate of their progeny would be in turn regulated by specific intrinsic properties (e.g., K+ channels, transcription factors, etc.) and the “milieu” produced by tissue damage. Because ATP is massively released after injury, we hypothesize that purinergic signaling is a major regulator of the response of progenitors in the ependyma. To test these hypotheses, we will apply a multi-technical approach combining electrophysiology, transcriptomics, immunohistochemistry and electron microscopy using transgenic mice that allow the tracking of ependymal cells and their progeny after injury. We will pursue the following aims: 1) to study the functional and transcriptional response of ependymal cells to injury; 2) to study purinergic signaling in ependymal cells and its injury-related plasticity; 3) to explore the nature of ependyma-derived astrocytes and OLs and their potential for repair. The proposed research will provide information on the mechanisms that “awake” ependymal cells after injury and may reveal useful clues to manipulate these progenitors for a more adaptive reaction (e.g., increased production of re-myelinating oligodendrocytes over reactive astrocytes) thereby improving functional recovery.



The video shows a progenitor-like cell with an endfoot in contact with the central canal lumen (lower left). The cell is filled with the calcium indicator Fluo4. When the P2X7 receptor agonist BzATP is applied close to the central canal (timing of the application signaled by lettering) a calcium wave propagates from the endfoot towards the cell body and distal process of the cell.