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Browsing by Author "Deng, Lingxiao"
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Item Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury(Elsevier, 2015-02) Walker, Chandler L.; Wang, Xiaofei; Bullis, Carli; Liu, Nai-Kui; Lu, Qingbo; Fry, Colin; Deng, Lingxiao; Xu, Xiao-Ming; Department of Neurological Surgery, IU School of MedicineSchwann cells (SCs) hold promise for spinal cord injury (SCI) repair; however, there are limitations for its use as a lone treatment. We showed that acute inhibition of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) by bisperoxovanadium (bpV) was neuroprotective and enhanced function following cervical hemicontusion SCI. We hypothesized that combining acute bpV therapy and delayed SC engraftment would further improve neuroprotection and recovery after cervical SCI. Adult female Sprague-Dawley (SD) rats were randomly sorted into 5 groups: sham, vehicle, bpV, SC transplantation, and bpV+SC transplantation. SCs were isolated from adult green fluorescent protein (GFP)-expressing SD rats (GFP-SCs). 200 μg/kg bpV(pic) was administered intraperitoneally (IP) twice daily for 7 days post-SCI in bpV-treated groups. GFP-SCs (1×10(6) in 5 μl medium) were transplanted into the lesion epicenter at the 8th day post-SCI. Forelimb function was tested for 10 weeks and histology was assessed. bpV alone significantly reduced lesion (by 40%, p<0.05) and cavitation (by 65%, p<0.05) and improved functional recovery (p<0.05) compared to injury alone. The combination promoted similar neuroprotection (p<0.01 vs. injury); however, GFP-SCs alone did not. Both SC-transplanted groups exhibited remarkable long-term SC survival, SMI-31(+) axon ingrowth and RECA-1(+) vasculature presence in the SC graft; however, bpV+SCs promoted an 89% greater axon-to-lesion ratio than SCs only. We concluded that bpV likely contributed largely to the neuroprotective and functional benefits while SCs facilitated considerable host-tissue interaction and modification. The combination of the two shows promise as an attractive strategy to enhance recovery after SCI.Item Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment(Elsevier, 2016-03) Deng, Lingxiao; Ruan, Yiwen; Chen, Chen; Frye, Christian Corbin; Xiong, Wenhui; Jin, Xiaoming; Jones, Kathryn; Sengelaub, Dale; Xu, Xiao-Ming; Department of Anatomy & Cell Biology, IU School of MedicineAfter spinal cord injury (SCI), poor regeneration of damaged axons of the central nervous system (CNS) causes limited functional recovery. This limited spontaneous functional recovery has been attributed, to a large extent, to the plasticity of propriospinal neurons, especially the descending propriospinal neurons (dPSNs). Compared with the supraspinal counterparts, dPSNs have displayed significantly greater regenerative capacity, which can be further enhanced by glial cell line-derived neurotrophic factor (GDNF). In the present study, we applied a G-mutated rabies virus (G-Rabies) co-expressing green fluorescence protein (GFP) to reveal Golgi-like dendritic morphology of dPSNs. We also investigated the neurotransmitters expressed by dPSNs after labeling with a retrograde tracer Fluoro-Gold (FG). dPSNs were examined in animals with sham injuries or complete spinal transections with or without GDNF treatment. Bilateral injections of G-Rabies and FG were made into the 2nd lumbar (L2) spinal cord at 3 days prior to a spinal cord transection performed at the 11th thoracic level (T11). The lesion gap was filled with Gelfoam containing either saline or GDNF in the injury groups. Four days post-injury, the rats were sacrificed for analysis. For those animals receiving G-rabies injection, the GFP signal in the T7-9 spinal cord was visualized via 2-photon microscopy. Dendritic morphology from stack images was traced and analyzed using a Neurolucida software. We found that dPSNs in sham injured animals had a predominantly dorsal-ventral distribution of dendrites. Transection injury resulted in alterations in the dendritic distribution with dorsal-ventral retraction and lateral-medial extension. Treatment with GDNF significantly increased the terminal dendritic length of dPSNs. The density of spine-like structures was increased after injury, and treatment with GDNF enhanced this effect. For the group receiving FG injections, immunohistochemistry for glutamate, choline acetyltransferase (ChAT), glycine, and GABA was performed in the T7-9 spinal cord. We show that the majority of FG retrogradely-labeled dPSNs were located in the Rexed Lamina VII. Over 90% of FG-labeled neurons were glutamatergic, with the other three neurotransmitters contributing less than 10% of the total. To our knowledge this is the first report describing the morphologic characteristics of dPSNs and their neurotransmitter expressions, as well as the dendritic response of dPSNs after transection injury and GDNF treatment.Item Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death(Wiley, 2009-11) Titsworth, W. Lee; Cheng, Xiaoxin; Ke, Yan; Deng, Lingxiao; Burckardt, Kenneth A.; Pendleton, Chris; Liu, Nai-Kui; Shao, Hui; Cao, Qi-Lin; Xu, Xiao-Ming; Department of Medicine, IU School of MedicineAfter the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipase activity and cytosolic PLA(2)-IV alpha protein expression increased. However, the expression of secreted isoforms of PLA(2) (sPLA(2)) and their possible roles in oligodendrocyte death following SCI remained unclear. Here we report that mRNAs extracted 15 min, 4 h, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA(2)-IIA and IIE at 4 h after injury. In contrast, SCI induced down regulation of sPLA(2)-X, and no change in sPLA(2)-IB, IIC, V, and XIIA expression. At the lesion site, sPLA(2)-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA(2)-IIA (0.01, 0.1, or 2 microM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA(2)-IIA inhibitor, before a 30 min H(2)O(2) injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 h. Similarly, pretreatment with S3319 before injury with IL-1 beta and TNFalpha prevented cell death and loss of oligodendrocyte processes at 72 h. Collectively, these findings suggest that sPLA(2)-IIA and IIE are increased following SCI, that increased sPLA(2)-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA(2) can create sparing of oligodendrocytes in two distinct injury models. Therefore, sPLA(2)-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI.Item Human Schwann Cell Transplantation for Spinal Cord Injury: Prospects and Challenges in Translational Medicine(Frontiers Media, 2021-06-18) Monje, Paula V.; Deng, Lingxiao; Xu, Xiao-Ming; Neurological Surgery, School of MedicineThe benefits of transplanting cultured Schwann cells (SCs) for the treatment of spinal cord injury (SCI) have been systematically investigated in experimental animals since the early 1990s. Importantly, human SC (hSC) transplantation for SCI has advanced to clinical testing and safety has been established via clinical trials conducted in the USA and abroad. However, multiple barriers must be overcome to enable accessible and effective treatments for SCI patients. This review presents available information on hSC transplantation for SCI with the intention to uncover gaps in our knowledge and discuss areas for future development. To this end, we introduce the historical progression of the work that supports existing and prospective clinical initiatives and explain the reasons for the choice of hSCs while also addressing their limitations as cell therapy products. A search of the relevant literature revealed that rat SCs have served as a preclinical model of reference since the onset of investigations, and that hSC transplants are relatively understudied, possibly due to the sophisticated resources and expertise needed for the traditional processing of hSC cultures from human nerves. In turn, we reason that additional experimentation and a reexamination of the available data are needed to understand the therapeutic value of hSC transplants taking into consideration that the manufacturing of the hSCs themselves may require further development for extended uses in basic research and clinical settings.Item Locomotor Exercise Enhances Supraspinal Control of Lower-Urinary-Tract Activity to Improve Micturition Function after Contusive Spinal-Cord Injury(MDPI, 2022-04-20) Deng, Lingxiao; Sui, Tao; Wang, Dong V.; Hou, Shaoping; Cao, Xiaojian; Peng, Kaiwen; Xu, Zaocheng; Xu, Xiaoming; Neurological Surgery, School of MedicineThe recovery of lower-urinary-tract activity is a top priority for patients with spinal-cord injury. Historically, locomotor training improved micturition function in both patients with spinal cord injury and animal models. We explore whether training augments such as the supraspinal control of the external urethral sphincter results in enhanced coordination in detrusor-sphincter activity. We implemented a clinically relevant contusive spinal-cord injury at the 12th thoracic level in rats and administered forced wheel running exercise for 11 weeks. Awake rats then underwent bladder cystometrogram and sphincter electromyography recordings to examine the micturition reflex. Subsequently, pseudorabies-virus-encoding red fluorescent protein was injected into the sphincter to trans-synaptically trace the supraspinal innervation of Onuf's motoneurons. Training in the injury group reduced the occurrence of bladder nonvoiding contractions, decreased the voiding threshold and peak intravesical pressure, and shortened the latency of sphincter bursting during voiding, leading to enhanced voiding efficiency. Histological analysis demonstrated that the training increased the extent of spared spinal-cord tissue around the epicenter of lesions. Compared to the group of injury without exercise, training elicited denser 5-hydroxytryptamine-positive axon terminals in the vicinity of Onuf's motoneurons in the cord; more pseudorabies virus-labeled or c-fos expressing neurons were detected in the brainstem, suggesting the enhanced supraspinal control of sphincter activity. Thus, locomotor training promotes tissue sparing and axon innervation of spinal motoneurons to improve voiding function following contusive spinal-cord injury.Item Molecular examination of bone marrow stromal cells and chondroitinase ABC-assisted acellular nerve allograft for peripheral nerve regeneration(Spandidos, 2016-10) Wang, Ying; Jia, Hua; Li, Wen-Yuan; Guan, Li-Xin; Deng, Lingxiao; Liu, Yan-Cui; Liu, Gui-Bo; Department of Anatomy and Cell Biology, IU School of MedicineThe present study aimed to evaluate the molecular mechanisms underlying combinatorial bone marrow stromal cell (BMSC) transplantation and chondroitinase ABC (Ch-ABC) therapy in a model of acellular nerve allograft (ANA) repair of the sciatic nerve gap in rats. Sprague Dawley rats (n=24) were used as nerve donors and Wistar rats (n=48) were randomly divided into the following groups: Group I, Dulbecco's modified Eagle's medium (DMEM) control group (ANA treated with DMEM only); Group II, Ch-ABC group (ANA treated with Ch-ABC only); Group III, BMSC group (ANA seeded with BMSCs only); Group IV, Ch-ABC + BMSCs group (Ch-ABC treated ANA then seeded with BMSCs). After 8 weeks, the expression of nerve growth factor, brain-derived neurotrophic factor and vascular endothelial growth factor in the regenerated tissues were detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Axonal regeneration, motor neuron protection and functional recovery were examined by immunohistochemistry, horseradish peroxidase retrograde neural tracing and electrophysiological and tibialis anterior muscle recovery analyses. It was observed that combination therapy enhances the growth response of the donor nerve locally as well as distally, at the level of the spinal cord motoneuron and the target muscle organ. This phenomenon is likely due to the propagation of retrograde and anterograde transport of growth signals sourced from the graft site. Collectively, growth improvement on the donor nerve, target muscle and motoneuron ultimately contribute to efficacious axonal regeneration and functional recovery. Thorough investigation of molecular peripheral nerve injury combinatorial strategies are required for the optimization of efficacious therapy and full functional recovery following ANA.Item Neuroprotective effects of interleukin 10 in spinal cord injury(Frontiers Media, 2023-07-10) Li, Juan; Wang, Pei; Zhou, Ting; Jiang, Wenwen; Wu, Hang; Zhang, Shengqi; Deng, Lingxiao; Wang, Hongxing; Neurological Surgery, School of MedicineSpinal cord injury (SCI) starts with a mechanical and/or bio-chemical insult, followed by a secondary phase, leading progressively to severe collapse of the nerve tissue. Compared to the peripheral nervous system, injured spinal cord is characterized by weak axonal regeneration, which leaves most patients impaired or paralyzed throughout lifetime. Therefore, confining, alleviating, or reducing the expansion of secondary injuries and promoting functional connections between rostral and caudal regions of lesion are the main goals of SCI therapy. Interleukin 10 (IL-10), as a pivotal anti-inflammatory and immunomodulatory cytokine, exerts a wide spectrum of positive effects in the treatment of SCI. The mechanisms underlying therapeutic effects mainly include anti-oxidative stress, limiting excessive inflammation, anti-apoptosis, antinociceptive effects, etc. Furthermore, IL-10 displays synergistic effects when combined with cell transplantation or neurotrophic factor, enhancing treatment outcomes. This review lists pleiotropic mechanisms underlying IL-10-mediated neuroprotection after SCI, which may offer fresh perspectives for clinical translation.Item Regeneration and plasticity of descending propriospinal neurons after transplantation of Schwann cells overexpressing glial cell line-derived neurotrophic factor following thoracic spinal cord injury in adult rats(2015-07) Deng, Lingxiao; Xu, Xiao-Ming; Sengelaub, Dale R.; Jin, Xiao-Ming; Khanna, Rajesh; Chen, JinhuiAfter spinal cord injury (SCI), poor axonal regeneration of the central nervous system, which mainly attributed to glial scar and low intrinsic regenerating capacity of severely injured neurons, causes limited functional recovery. Combinatory strategy has been applied to target multiple mechanisms. Schwann cells (SCs) have been explored as promising donors for transplantation to promote axonal regeneration. Among the central neurons, descending propriospinal neurons (DPSN) displayed the impressive regeneration response to SCs graft. Glial cell line-derived neurotrophic factor (GDNF), which receptor is widely expressed in nervous system, possesses the ability to promote neuronal survival, axonal regeneration/sprouting, remyelination, synaptic formation and modulate the glial response. We constructed a novel axonal permissive pathway in rat model of thoracic complete transection injury by grafting SCs over-expressing GDNF (SCs-GDNF) both inside and caudal to the lesion gap. Behavior evaluation and histological analyses have been applied to this study. Our results indicated that tremendous DPSN axons as well as brain stem axons regenerated across the lesion gap back to the caudal spinal cord. In addition to direct promotion on axonal regeneration, GDNF also significantly improved the astroglial environment around the lesion. These regenerations caused motor functional recovery. The dendritic plasticity of axotomized DPSN also contributed to the functional recovery. We applied a G-mutated rabies virus (G-Rabies) co-expressing green fluorescence protein (GFP) to reveal Golgi-like dendritic morphology of DPSNs and its response to axotomy injury and GDNF treatment. We also investigated the neurotransmitters phenotype of FluoroGold (FG) labeled DPSNs. Our results indicated that over 90 percent of FG-labeled DPSNs were glutamatergic neurons. DPSNs in sham animals had a predominantly dorsal-ventral distribution of dendrites. Transection injury resulted in alterations in the dendritic distribution, with dorsal-ventral retraction and lateral-medial extension of dendrites. Treatment with GDNF significantly increased the terminal dendritic length of DPSNs. The density of spine-like structures was increased after injury and treatment with GDNF enhanced this effect.Item Transplantation of a Peripheral Nerve with Neural Stem Cells Plus Lithium Chloride Injection Promote the Recovery of Rat Spinal Cord Injury(SAGE, 2018-03) Zhang, Li-Qun; Zhang, Wen-Ming; Deng, Lingxiao; Xu, Zi-Xing; Lan, Wen-Bin; Lin, Jian-Hua; Neurological Surgery, School of MedicineTransplantation of neural stem cells (NSCs) holds great potential for the treatment of spinal cord injury (SCI). However, transplanted NSCs poorly survive in the SCI environment. We injected NSCs into tibial nerve and transplanted tibial nerve into a hemisected spinal cord and investigated the effects of lithium chloride (LiCl) on the survival of spinal neurons, axonal regeneration, and functional recovery. Our results show that most of the transplanted NSCs expressed glial fibrillary acidic protein, while there was no obvious expression of nestin, neuronal nuclei, or acetyltransferase found in NSCs. LiCl treatment produced less macrosialin (ED1) expression and axonal degeneration in tibial nerve after NSC injection. Our results also show that a regimen of LiCl treatment promoted NSC differentiation into NF200-positive neurons with neurite extension into the host spinal cord. The combination of tibial nerve transplantation with NSCs and LiCl injection resulted in more host motoneurons surviving in the spinal cord, more regenerated axons in tibial nerve, less glial scar area, and decreased ED1 expression. We conclude that lithium may have therapeutic potential in cell replacement strategies for central nervous system injury due to its ability to promote survival and neuronal generation of grafted NSCs and reduced host immune reaction.