scholarly journals Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation

2021 ◽  
Author(s):  
Xin Yuan ◽  
Weihao Yuan ◽  
Lu Ding ◽  
Ming Shi ◽  
Liang Luo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Dynamic Network ◽  
Motor Evoked Potential ◽  
Delivery Vehicle ◽  
Inflammatory Microenvironment ◽  
Cord Injury ◽  
A Cell ◽  
Promising Source

ABSTRACTSpinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel‒mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases.

scholarly journals Clinical Study of NeuroRegen Scaffold Combined with Human Mesenchymal Stem Cells for the Repair of Chronic Complete Spinal Cord Injury

2017 ◽  
Vol 26 (5) ◽  
pp. 891-900 ◽  
Author(s):  
Yannan Zhao ◽  
Fengwu Tang ◽  
Zhifeng Xiao ◽  
Guang Han ◽  
Nuo Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Perioperative Complications ◽  
Motor Evoked Potential ◽  
Neurophysiological Monitoring ◽  
Human Umbilical Cord ◽  
Cord Injury ◽  
Complete Spinal Cord Injury

Regeneration of damaged neurons and recovery of sensation and motor function after complete spinal cord injury (SCI) are challenging. We previously developed a collagen scaffold, NeuroRegen, to promote axonal growth along collagen fibers and inhibit glial scar formation after SCI. When functionalized with multiple biomolecules, this scaffold promoted neurological regeneration and functional recovery in animals with SCI. In this study, eight patients with chronic complete SCI were enrolled to examine the safety and efficacy of implanting NeuroRegen scaffold with human umbilical cord mesenchymal stem cells (hUCB-MSCs). Using intraoperative neurophysiological monitoring, we identified and surgically resected scar tissues to eliminate the inhibitory effect of glial scarring on nerve regeneration. We then implanted NeuroRegen scaffold loaded with hUCB-MSCs into the resection sites. No adverse events (infection, fever, headache, allergic reaction, shock, perioperative complications, aggravation of neurological status, or cancer) were observed during 1 year of follow-up. Primary efficacy outcomes, including expansion of sensation level and motor-evoked potential (MEP)-responsive area, increased finger activity, enhanced trunk stability, defecation sensation, and autonomic neural function recovery, were observed in some patients. Our findings suggest that combined application of NeuroRegen scaffold and hUCB-MSCs is safe and feasible for clinical therapy in patients with chronic SCI. Our study suggests that construction of a regenerative microenvironment using a scaffold-based strategy may be a possible future approach to SCI repair.

scholarly journals Transplantation of Wnt4-modified Neural Stem Cells Mediate M2 Polarization to Promote Spinal Cord Injury Repair

2021 ◽  
Author(s):  
Xiang Li ◽  
Lingli Long ◽  
Yue Hu ◽  
Wenwu Zhang ◽  
Fangling Zhong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Neural Stem Cells ◽  
Therapeutic Effect ◽  
Signal Pathway ◽  
Inflammatory Microenvironment ◽  
M2 Polarization ◽  
M1 Polarization ◽  
Cord Injury

Abstract Background: Neural stem cells (NSCs) transplantation has been considered as a potential strategy to reconnect the neural circuit after spinal cord injury (SCI) but the therapeutic effect was still unsatisfied because of the poor inflammatory microenvironment. Wnt4 has been considered to be neurogenesis and anti-inflammatory so that it would be an essential assistant agent for NSCs transplantation. To explore interaction between Wnt4-modified NSCs and macrophages; and the effect of Wnt4-modified NSCs on the inflammatory microenvironment of SCI is relevant for targeted and effective treatments that promote injured spinal cord repair. Methods: In vitro NSCs-macrophages co-cultured system was established to unravel the interaction and involved mechanism between Wnt4-modified NSCs and macrophages. Wnt4-modified NSCs were transplanted into SCI model to confirm the effect of Wnt4-modified NSCs on modulation of inflammatory microenvironment of SCI and the therapeutic effect of Wnt4-modified NSCs on SCI. Results: Wnt4-modified NSCs induce M2 polarization and inhibit M1 polarization of macrophages through suppress TLR4/NF-κB signal pathway; furthermore, M2 cells promote neuronal differentiation of NSCs through MAPK/JNK signal pathway. In vivo, transplantation of Wnt4-modified NSCs improve inflammatory microenvironment through induce M2 polarization and inhibit M1 polarization of macrophages to promote axonal regeneration and tissue repair.Conclusions: Transplantation of Wnt4-modified NSCs effectively improve the inflammatory microenvironment through inducing M2 polarization and suppressing M1 polarization of macrophages after SCI. Considering these positive therapeutic effects, Wnt4 may have remarkable potential to be optimal assistant agent in NSCs transplantation for SCI.

scholarly journals Olfactory Stem Cells for the Treatment of Spinal Cord Injury: Isolation, Purification and Behaviour in a Plasma Clot Matrix

2020 ◽  
pp. 1-12
Author(s):  
Christina Sengstock ◽  
Markus Rövekamp ◽  
Stefan Volkenstein ◽  
Amir Minovi ◽  
Aliana Neubaur ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Case Reports ◽  
Autologous Transplantation ◽  
Isolated Cells ◽  
Plasma Clot ◽  
Cell Therapies ◽  
Cord Injury ◽  
A Cell

Cell therapies represent promising strategies to improve neurological functions after spinal cord injury (SCI). Olfactory mucosa (OM) might be an attractive source of multipotent cells for neuroregeneration because olfactory stem cells (OSCs) are resident. The regenerative capacity of OSCs has been demonstrated in animal models and some clinical case reports. Up to now, there are no standard methods for purification, characterization, and delivery of OSCs to the injury site. However, purification and characterization of the grafted cells are prerequisites for clinical use to ensure maximum safety for the patients. In this study, we isolated and purified OSCs from human OM using the neurosphere assay. Subsequently, the cells were characterized, and the behavior of purified OSCs in a plasma clot was investigated. Our study demonstrated that isolated cells from OM form neurospheres, which cells are positive for CD105 (98%) and CD90 (99%) and negative for Epcam (<1%) and MUC5AC (<1%). Purified OSCs were positive for Nestin, CD44 as well as GFAP and showed a lack of CD34 and CD45 expression. OSCs differentiated into neuron-like cells expressing ß-III tubulin. However, differentiation into adipocytes, chondrocytes or osteoblast could not be observed. In addition, OSCs stayed viable and were able to proliferate within the plasma clot. These results highlight OSC as a candidate for autologous transplantation in combination with the plasma clot as a cell carrier in SCI and neurodegenerative disease.

scholarly journals Transplantation of Wnt4-Modified Neural Stem Cells Mediate M2 Polarization to Promote Spinal Cord Injury Repair

2021 ◽  
Author(s):  
Xiang Li ◽  
Lingli Long ◽  
Yue Hu ◽  
Wenwu Zhang ◽  
Fangling Zhong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Neural Stem Cells ◽  
Signal Pathway ◽  
Inflammatory Microenvironment ◽  
Injury Repair ◽  
M2 Polarization ◽  
M1 Polarization ◽  
Cord Injury

Abstract Background: Neural stem cells (NSCs) transplantation has been considered as a potential strategy to reconnect the neural circuit after spinal cord injury (SCI) but the therapeutic effect was still unsatisfied because of the poor inflammatory microenvironment. Previous study reported that neuroprotection and inflammatory immunomodulation were considered to be most important mechanism of NSCs transplantation. In addition, Wnt4 has been considered to be neurogenesis and anti-inflammatory so that it would be an essential assistant agent for NSCs transplantation.Results: We report the first piece of evidence to confirm the interaction between Wnt4-modified NSCs and macrophages using NSCs- macrophages co-cultured system. Wnt4-modified NSCs induce M2 polarization and inhibit M1 polarization of macrophages through suppress TLR4/NF-κB signal pathway; furthermore, M2 cells promote neuronal differentiation of NSCs through MAPK/JNK signal pathway. In vivo, transplantation of Wnt4-modified NSCs improve inflammatory microenvironment through induce M2 polarization and inhibit M1 polarization of macrophages to promote axonal regeneration and tissue repair.Conclusion: The current study indicated that transplantation of Wnt4-modified NSCs mediate M2 polarization of macrophages to promote spinal cord injury repair. Our novel findings would provide more insight of SCI and help with identification of novel treatment strategy.

Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

2020 ◽  
Vol 15 (4) ◽  
pp. 321-331 ◽  
Author(s):  
Zhe Gong ◽  
Kaishun Xia ◽  
Ankai Xu ◽  
Chao Yu ◽  
Chenggui Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Current Status ◽  
Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

Bone marrow mesenchymal stem cells-derived exosomes reduce apoptosis and inflammatory response during spinal cord injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway

2021 ◽  
pp. 096032712110033
Author(s):  
Liying Fan ◽  
Jun Dong ◽  
Xijing He ◽  
Chun Zhang ◽  
Ting Zhang
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Motor Function ◽  
Inflammatory Factors ◽  
Cord Injury ◽  
Marrow Mesenchymal Stem Cells ◽  
Apoptosis And Inflammation

Spinal cord injury (SCI) is one of the most common destructive injuries, which may lead to permanent neurological dysfunction. Currently, transplantation of bone marrow mesenchymal stem cells (BMSCs) in experimental models of SCI shows promise as effective therapies. BMSCs secrete various factors that can regulate the microenvironment, which is called paracrine effect. Among these paracrine substances, exosomes are considered to be the most valuable therapeutic factors. Our study found that BMSCs-derived exosomes therapy attenuated cell apoptosis and inflammation response in the injured spinal cord tissues. In in vitro studies, BMSCs-derived exosomes significantly inhibited lipopolysaccharide (LPS)-induced PC12 cell apoptosis, reduced the secretion of pro-inflammatory factors including tumor necrosis factor (TNF)-α and IL (interleukin)-1β and promoted the secretion of anti-inflammatory factors including IL-10 and IL-4. Moreover, we found that LPS-induced protein expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear transcription factor-κB (NF-κB) was significantly downregulated after treatment with BMSCs-derived exosomes. In in vivo studies, we found that hindlimb motor function was significantly improved in SCI rats with systemic administration of BMSCs-derived exosomes. We also observed that the expression of pro-apoptotic proteins and pro-inflammatory factors was significantly decreased, while the expression of anti-apoptotic proteins and anti-inflammatory factors were upregulated in SCI rats after exosome treatment. In conclusion, BMSCs-derived exosomes can inhibit apoptosis and inflammation response induced by injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which suggests that BMSCs-derived exosomes are expected to become a new therapeutic strategy for SCI.

Efficacy of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in spinal cord injury in rats: Stereological evidence

2021 ◽  
Vol 116 ◽  
pp. 101978
Author(s):  
Reza Asadi-Golshan ◽  
Vahid Razban ◽  
Esmaeil Mirzaei ◽  
Abdolkarim Rahmanian ◽  
Sahar Khajeh ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Conditioned Medium ◽  
Dental Pulp ◽  
Collagen Hydrogel ◽  
Cord Injury

scholarly journals CD157 in bone marrow mesenchymal stem cells mediates mitochondrial production and transfer to improve neuronal apoptosis and functional recovery after spinal cord injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Li ◽  
Heyangzi Li ◽  
Simin Cai ◽  
Shi Bai ◽  
Huabo Cai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Spinal Cord Injury ◽  
Mesenchymal Stem Cells ◽  
Motor Neurons ◽  
Functional Recovery ◽  
Mitochondrial Transfer ◽  
Cord Injury ◽  
Marrow Mesenchymal Stem Cells

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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