Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice

Abstract

Embryonic stem (ES) cells have been investigated in repair of the CNS following neuronal injury and disease; however, the efficacy of these cells in treatment of postinjury pain is far from clear. In this study, we evaluated the therapeutic potential of predifferentiated mouse ES cells to restore sensory deficits following spinal cord injury (SCI) in mice. The pain model used unilateral intraspinal injection of quisqualic acid (QUIS) into the dorsal horn between vertebral levels T13 and L1. Seven days later, 60,000 predifferentiated ES cells or media were transplanted into the site of the lesion. Histological analysis at 7, 14, and 60 days posttransplantation revealed that animals receiving ES cell transplants suffered significantly less tissue damage than animals receiving media alone. Transplanted cells provided immediate effects on both spontaneous and evoked pain behaviors. Treatment with ES cells resulted in 0% (n = 28) excessive grooming behavior versus 60% (18 of 30) in media-treated animals. In the acetone test (to assess thermal allodynia), mice recovered to preinjury levels by 12 days after ES cell transplant, whereas control animals injected with media after SCI did not show any improvement up to 60 days. Similarly, the von Frey test (to assess mechanical allodynia) and the formalin test (to assess nociceptive hyperalgesia) showed that transplantation of predifferentiated ES cells significantly reduced these pain behaviors following injury. Here we show that predifferentiated ES cells act in a neuroprotective manner and provide antinociceptive and therapeutic effects following excitotoxic SCI.

Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain

“…Although the reasons for reduced GABA signaling after peripheral or central nerve injury are still matter of debate (57,58,60), several studies showed that transplantation of GABA-releasing cells is an effective way to reduce neuropathic pain symptoms in experimental models of pain (7,22,23,38,43,54,71,74). The findings in our lab suggest that the positive effects of neural progenitor grafts are likely mediated, at least in part, by releasing GABA in the dorsal horn, as both antinociceptive effects and attenuated dorsal horn hyperexcitability by NPC grafts were reduced by GABAergic antagonists (42,43).…”

“…Dysfunctional GABA signaling is thought to contribute to chronic pain, and GABAergic neural progenitor cells (NPCs) have shown promise in reducing neuropathic pain behavior following transplantation in rat and mouse pain models (7,38,46,52,54). Previous studies in our laboratory showed amelioration of neuropathic pain in rats induced by either peripheral nerve injury or spinal cord injury by intraspinal GABAergic NPC grafts (42,43,48,49).…”

Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice

“…Indeed, intravenous administration of MSCs was able to increase the expression of some growth factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in the rat brain after traumatic brain injury [41]. Similarly, it has been shown that transplantation of pre-differentiated embryonic stem (ES) cells into neuronal progenitors is able to prevent the appearance of chronic pain in an experimental model of spinal cord injury in mice [42]. These pre-differentiated ES cells activate both BDNF and IL-6 signaling pathways in the host tissue leading to activation of cAMP/PKA, phosporylation of cofilin and synapsin I, and promotion of regenerative growth and neuronal survival [43].…”

Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: A pharmacologic and neurophysiological evaluation

“…The injection of saline vehicle was chosen as control to avoid any potential confounding effects that may result from release of trophic factors or other active agents by control cellular transplants. The use of vehicle or cell culture media as control has been previously employed in other transplantation studies (Hendricks, et al, 2006, McDonald, et al, 1999, Mitsui, et al, 2003, Park, et al, 2010, Zhao, et al, 2004). After injection, the pipette was kept in place for additional 1 min.…”