Effect of spinal cord extracts after spinal cord injury on proliferation of rat embryonic neural stem cells and Notch signal pathway in vitro

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.

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Rosiglitazone Ameliorates Spinal Cord Injury via Inhibiting Mitophagy and Inflammation of Neural Stem Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/5583512 ◽

2022 ◽

Vol 2022 ◽

pp. 1-22

Author(s):

Qingqi Meng ◽

Zhiteng Chen ◽

Qingyuan Gao ◽

Liqiong Hu ◽

Qilong Li ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Atp Production ◽

Beneficial Effects ◽

Cord Injury ◽

Underlying Mechanisms

Background. Neurodegenerative diseases, such as Alzheimer’s disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. Methods. SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. Results. We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. Conclusions. Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.

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GP.04 Smart human neural stem cells to degrade scar and optimize regeneration after traumatic cervical spinal cord injury

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.81 ◽

2018 ◽

Vol 45 (s2) ◽

pp. S9-S9

Author(s):

CS Ahuja ◽

M Khazaei ◽

P Chan ◽

J Bhavsar ◽

Y Yao ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Chronic Injury ◽

Long Distance ◽

Degrading Enzyme ◽

Genetically Engineer ◽

Cord Injury

Background: Human induced pluripotent stem cell-derived neural stem cells (hiPS-NSCs) represent an exciting therapeutic approach for traumatically spinal cord injury (SCI). Unfortunately, most patients are the in chronic injury phase where a dense perilesional chondroitin sulfate proteoglycan (CSPG) scar significantly hinders regeneration. CSPG-degrading enzymes can enhance NSC-mediated recovery, however, nonspecific intrathecal administration causes off-target effects. We aimed to genetically engineer hiPS-NSCs to express a scar-degrading ENZYME into their local environment to enhance functional recovery. Methods: A bicistronic scar-degrading ENZYME and RFP reporter vector was non-virally integrated into hiPS-NSCs and monoclonalized. ENZYME activity was assessed by WST-1 and DMMB biochemical assays and an in vitro CSPG spot assay with hiPS-NSC-derived neurons. To assess in vivo efficacy, T-cell deficient rats (N=60) with chronic (8wk) C6-7 SCIs were randomized to receive (1)SMaRT cells, (2)hiPS-NSCs, (3)vehicle, or (4)sham surgery. Results: SMaRT cells retained key hiPS-NSC characteristics while stably expressing ENZYME. The expressed ENZYME could appropriately degrade in vitro and ex vivo CSPGs. While blinded neurobehavioural and immunohistochemical assessments are ongoing at 40wks post-injury, an interim analysis demonstrated human cells extending remarkably long (≥20,000µm) axons along host white matter tracts. Conclusions: This work provides exciting proof-of-concept data that genetically-engineered SMaRT cells can degrade CSPGs and human NSCs can extend long-distance processes in chronic SCI.

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Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury

Cell Cycle ◽

10.1080/15384101.2019.1667189 ◽

2019 ◽

Vol 18 (21) ◽

pp. 3010-3029 ◽

Cited By ~ 9

Author(s):

Dingfei Qian ◽

Linwei Li ◽

Yuluo Rong ◽

Wei Liu ◽

Qian Wang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signal Pathway ◽

Notch Signal ◽

Cord Injury ◽

Notch Signal Pathway

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

10.21203/rs.3.rs-779187/v2 ◽

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.

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