Connexin Signaling Is Involved in the Reactivation of a Latent Stem Cell Niche after Spinal Cord Injury

Abstract

The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P Ͼ 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.

Expression of Connexins 37, 43 and 45 in Developing Human Spinal Cord and Ganglia

“…Ependymal cells in the adult SC are latent progenitors that react to injury to support some degree of endogenous repair. Cx blockade reduced the injury-induced proliferation of ependymal cells [ 39 ]. Moreover, Russo and collaborators observed a high density of Cx43 on the end-feet of central canal-contacting cells in the turtle, which supported a key role of functional clustering via Cx43 in the SC neurogenesis [ 40 ].…”

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

“…Extrinsic signals guiding adult neurogenesis in the spinal cord include connexin, Notch and Wnt signaling pathways [18,53]. Intrinsic signals include neural progenitor transcription factors Nkx6.1, Pax6, and Olig6 [54][55][56].…”

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

“…Extrinsic signals guiding adult neurogenesis in the spinal cord include connexin, Notch and Wnt signaling pathways [40,41]. Intrinsic signals include neural progenitor transcription factors Nkx6.1, Pax6, and Olig6 [39,42,43].…”

“…SCI affects the NSPC stem cell niche in models of contusive, surgical stab, and slice injury at any anatomical level of the spinal cord [41]. Common clinical SCI damages disturbs the niche due to equidistant dorsal and ventral positioning of the central canal [15].…”