Purinergic Receptors in Spinal Cord-Derived Ependymal Stem/Progenitor Cells and Their Potential Role in Cell-Based Therapy for Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a major cause of paralysis with no current therapies. Following SCI, large amounts of ATP and other nucleotides are released by the traumatized tissue leading to the activation of purinergic receptors that, in coordination with growth factors, induce lesion remodeling and repair. We found that adult mammalian ependymal spinal cord-derived stem/progenitor cells (epSPCs) are capable of responding to ATP and other nucleotidic compounds, mainly through the activation of the ionotropic P2X 4 , P2X 7 , and the metabotropic P2Y 1 and P2Y 4 purinergic receptors. A comparative study between epSPCs from healthy rats versus epSPCis, obtained after SCI, shows a downregulation of P2Y 1 receptor together with an upregulation of P2Y 4 receptor in epSPCis. Moreover, spinal cord after severe traumatic contusion shows early and persistent increases in the expression of P2X 4 and P2X 7 receptors around the injury, which are completely reversed when epSPCis were ectopically transplanted. Since epSPCi transplantation significantly rescues neurological function after SCI in parallel to inhibition of the induced P2 ionotropic receptors, a potential avenue is open for therapeutic alternatives in SCI treatments based on purinergic receptors and the endogenous reparative modulation.

Purinergic signalling in a latent stem cell niche of the rat spinal cord

“…Ca 2+ waves) as possible targets to manipulate the response of the ependymal stem cell niche to ATP released by spinal cord injury. In line with this idea, recent work showed increased P2X7 expression in the spinal cord after injury [41]. Whether the tuning of purinergic signalling in the latent CC stem cell niche may modulate the healing induced by ependymal cells [7,34] will require the combination of in vivo and in vitro animal models to target selectively P2X7 receptors within the niche.…”

Intertwining extracellular nucleotides and their receptors with Ca2+in determining adult neural stem cell survival, proliferation and final fate

“…However, fate-mapping analysis of ECs following SCI in vivo revealed generation of astrocytes and oligodendrocytes only [43] (see also §3). Although no generation of new neurons has been observed, acute transplantation of undifferentiated ECs fully reverted the pathological increase in P2X4Rs and P2X7Rs observed after SCI and led to a partial recovery of locomotor activity [39], thus suggesting a possible bystander role played by ECs.…”

“…However, after spinal cord injury (SCI) or hypoxia, ECs proliferate, migrate towards the injury site and start expressing GFAP, a marker of multipotency [38,40]. Interestingly, ECs reveal downregulation of P2Y 1 Rs in parallel with upregulation of P2Y 4 Rs one week after SCI, suggesting that the panel of expression of P2YRs may play a critical role in the modulation of neural progenitor cell expansion [39]. Activated ECs generate a high number of neurospheres and give rise to astrocytes, oligodendrocytes and, under some conditions, motoneurons when exposed to differentiating agents rstb.royalsocietypublishing.org Phil.…”

“…They stain positive for markers of immature neural cells, such as nestin, vimentin and the transcription factor Sox2, and of ciliated cells such as Fox1 and Crocc [38]. Moreover, a very recent paper showed for the first time that spinal cord ECs express ionotropic P2X4Rs and P2X7Rs, and metabotropic P2Y 1 Rs and P2Y 4 Rs, all functionally coupled to [Ca 2þ ] i transients [39]. They also stain positive for the dualistic receptor GPR17 [40], which responds to both extracellular nucleotides and cysteinyl-leukotrienes and plays a fundamental role not only in the differentiation of NG2-glia to mature myelinating oligodendrocytes (see also below), but also in their alternative switch towards a neurogenic fate [41].…”

Diadenosine tetraphosphate (Ap4A) inhibits ATP-induced excitotoxicity: a neuroprotective strategy for traumatic spinal cord injury treatment

“…According to Wang and colleagues [10], ATP release is strongly increased in peritraumatic areas during the first 6 h following the trauma, activating purinergic receptors in some cases overexpressed after SCI (vg. P2X 4 and P2X 7 [102,103]). Signaling through purinergic receptors increases the concentration of intracellular calcium and induces excitotoxic death of neurons and oligodendrocytes [10], as well as modulates the acute and chronic inflammation and neuropathic pain [104,105].…”