P2X7 purinoceptors contribute to the death of Schwann cells transplanted into the spinal cord

Abstract

The potential to use Schwann cells (SCs) in neural repair for patients suffering from neurotrauma and neurodegenerative diseases is well recognized. However, significant cell death after transplantation hinders the clinical translation of SC-based therapies. Various factors may contribute to the death of transplanted cells. It is known that prolonged activation of P2X7 purinoceptors (P2X7R) can lead to death of certain types of cells. In this study, we show that rat SCs express P2X7R and exposure of cultured SCs to high concentrations of ATP (3–5 mM) or a P2X7R agonist, 2′(3′)-O-(4-benzoylbenzoyl)ATP (BzATP) induced significant cell death rapidly. High concentrations of ATP and BzATP increased ethidium uptake by SCs, indicating increased membrane permeability to large molecules, a typical feature of prolonged P2X7R activation. SC death, as well as ethidium uptake, induced by ATP was blocked by an irreversible P2X7R antagonist oxidized ATP (oxATP) or a reversible P2X7R antagonist A438079. oxATP also significantly inhibits the increase of intracellular free calcium induced by minimolar ATP concentrations. Furthermore, ATP did not cause death of SCs isolated from P2X7R-knockout mice. All these results suggest that P2X7R is responsible for ATP-induced SC death in vitro. When rat SCs were treated with oxATP before transplantation into uninjured rat spinal cord, 35% more SCs survived than untreated SCs 1 week after transplantation. Moreover, 58% more SCs isolated from P2X7R-knockout mice survived after being transplanted into rat spinal cord than SCs from wild-type mice. This further confirms that P2X7R is involved in the death of transplanted SCs. These results indicate that targeting P2X7R on SCs could be a potential strategy to improve the survival of transplanted cells. As many other types of cells, including neural stem cells, also express P2X7R, deactivating P2X7R may improve the survival of other types of transplanted cells.

Up-regulation of P2X7 receptors mediating proliferation of Schwann cells after sciatic nerve injury

“…Previous studies have presented evidence that P2X7R are expressed in the paranodal membrane of rat Schwann cells in vivo [15], in cultured mouse Schwann cells [8,21,24], in longitudinal sciatic nerve sections of rat and mouse [20] and in cross and longitudinal sciatic nerve sections of mouse [12]. In this study, we clearly demonstrate localization of P2X7R ir in two types of Schwann cells in longitudinal sciatic nerve sections.…”

“…Previous data has shown that the Schwann cells mainly express P2X7R [20,21,24]. Early electrophysiological and pharmacological data showed that P2X7R are functionally expressed in myelinating Schwann cells of peripheral nerves [15].…”

“…With methods of patch-clamp recording, fluorescent dye uptake and immunocytochemistry, P2X7R were detected in cultured mouse Schwann cells [8]. Recent data has shown that P2X7R control myelination in sciatic nerves and contribute to the death of Schwann cells transplanted into the spinal cord [12,20].…”

Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists

“…As such, inhibition of the P2X7R offers protection against ATP-mediated cell death in a number of cells expressing the P2X7R [12], [30], [36]. Therefore, C23, C40 and C60 compounds were finally tested for their effectiveness in preventing ATP-induced cell death in hP2X7R-expressing HEK293 cells to provide further supporting evidence for their action on the hP2X7R.…”

Purinergic neurone-glia signalling in cognitive-related pathologies

“…Schwann cells(Luo et al, 2013) and oligodendrocytes(Matute, 2011) that myelinate, respectively, peripheral and central neurones, also possess P2X 7 receptors. In Schwann cells P2X 7 receptors are involved in control of myelination in development(Faroni et al, 2014).…”