Transplantation of Neuronal and Glial Restricted Precursors into Contused Spinal Cord Improves Bladder and Motor Functions, Decreases Thermal Hypersensitivity, and Modifies Intraspinal Circuitry

Abstract

Transplanting neuronal and glial restricted precursors (NRP/GRP) into a midthoracic injury 9 d after contusion improved bladder and motor function, diminished thermal hypersensitivity, and modified lumbosacral circuitry compared with operated controls (OPcontrols). Histological analysis showed that NRP/GRP survived, filled the lesion site, differentiated into neurons and glia, and migrated selectively. Volume of spinal cord spared was increased in NRP/GRP recipients, suggesting local protection. Bladder areflexia developed in both operated groups, but NRP/GRP recipients exhibited an accelerated recovery, with decreased micturition pressure and fewer episodes of detrusor hyperreflexia. Because noradrenergic receptors proliferate after spinal injury and descending noradrenergic pathways contribute to regulation of bladder control, we examined the effects of administering an ␣-1A-adrenergic antagonist, Tamsulosin, on urodynamics. This improved all cystometric parameters in both operated groups, and micturition pressure in NRP/GRP rats recovered to normal levels. Both operated groups initially showed increased sensitivity to a thermal stimulus applied to the tail; the NRP/GRP rats showed significant improvement over time. NRP/GRP grafts also produced greater recovery of hindlimb function in several tests, although both groups showed persistent and similar deficits in locomotion on a grid.Because bladder, hindlimb, and tail sensory and motor functions are organized through lumbosacral cord, we examined descending and primary afferent projections at L6 -S1. The density of serotonergic, noradrenergic, and corticotrophin releasing factor-positive fibers increased in the NRP/GRP group compared with OP-controls, suggesting some sparing and/or sprouting of these modulatory pathways. Immunocytochemical staining density of dorsal root axons in the dorsal horn increased in the OP-controls but appeared normal in the NRP/GRP group. Synaptophysin immunoreactivity in the lumbosacral dorsal horn was similar among groups, consistent with restoration of synaptic density in both groups of operated animals but by different pathways. We suggest that local protection provided by NRP/GRP resulted in increased sparing/sprouting of descending pathways, which prevented sprouting by dorsal root axons, and that this modification in lumbosacral circuitry contributes to the recovery of function.

Functional Reinnervation of the Rat Lower Urinary Tract after Cauda Equina Injury and Repair

“…After VRA injury, unlike the denervated EUS muscle that becomes flaccid, the bladder maintains innervation by the postganglionic parasympathetic neurons. Thus, in avulsed rats, the bladders were hypertrophied rather than atrophied, similar to the findings in rats after a midthoracic injury (Kruse et al, 1993;Pikov and Wrathall, 2001;Mitsui et al, 2005). However, after implantation, the bladder size was normalized and was associated with the re-establishment of reflexive micturition.…”

Intravenously transplanted bone marrow stromal cells promote recovery of lower urinary tract function in rats with complete spinal cord injury

“…It was a new view of the recovery of the urethral function, comparing with the similar studies. 5,7,8 This could clearly prove the recovery of bladdersphincter synergia in rats after BMSC transplantation. We analyzed the EUS EMG pattern to show that the EUS exhibited bursting activity which appeared to facilitate voiding in sham rats; whereas the EUS exhibited tonic activity which inhibited voiding in SCI rats.…”

“…These BrdU-labeled BMSCs cannot promote partial sparing of descending modulatory pathways that course through the lateral and ventral funiculi to the lumbosacral cord in SCT rats, which is a reasonable hypothesis responsible for the bladder function improvement in rats with spinal cord contusion. 6,7 So what is the actual mechanism for the LUT function recovery in BMSC rats? The discovery of BrdU-labeled BMSCs in the dorsal gray commissure of L [3][4] indicates that the reorganization of synaptic connections may be taken place, which is responsible for the formation of the new pathways of voiding reflex in BMSC rats.…”

“…However, recent studies suggest that transplanted neural progenitor cells promote recovery of the bladder function through regeneration of the injury site. [5][6][7][8] In most of these studies, stem cells have been injected into the lesion directly with a needle, 5,7,8 carrying the risk of further injury to the spinal cord. Otherwise, these studies did not examine the changes of EUS activity in the spinal injured rats after cells transplantation.…”

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

“…Both cases reported moderate but significant improvements on the BBB scale from *7 to *9; in addition, bladder control was improved and the hypersensitivity to thermal stimuli ameliorated (Mitsui et al, 2005;Neuhuber et al, 2008). The cells were neuroprotective, and many differentiated into astrocytes, some into oligodendrocytes.…”