Mesenchymal Stem Cell Transplantation Promotes Functional Recovery through MMP2/STAT3 Related Astrogliosis after Spinal Cord Injury

Kim, Choonghyo; Kim, Hee Jung; Lee, Hyun; Lee, Hanbyeol; Lee, Seung Jin; Lee, Seung Tae; Yang, Se‐Ran; Chung, Chun Kee

doi:10.15283/ijsc18133

Cited by 20 publications

(13 citation statements)

References 34 publications

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“…It should be noted that MFs can be coated with very different combinations of proteins and thus offer an extensive therapeutic flexibility. Besides proteins associated to cell adhesion and growth factors, the MF coating could also provide modulators of molecular pathways involved in intrinsic growth, thereby extending the range of manipulation of the local environment, especially at early time points [ 33 , 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury

Waly

Escarrat

Pérez-Sánchez

et al. 2021

Cells

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The extension of the lesion following spinal cord injury (SCI) poses a major challenge for regenerating axons, which must grow across several centimetres of damaged tissue in the absence of ordered guidance cues. Biofunctionalized electroconducting microfibres (MFs) that provide biochemical signals, as well as electrical and mechanical cues, offer a promising therapeutic approach to help axons overcome this blind journey. We used poly(3,4-ethylenedioxythiophene)-coated carbon MFs functionalized with cell adhesion molecules and growth factors to bridge the spinal cord after a partial unilateral dorsal quadrant lesion (PUDQL) in mice and followed cellular responses by intravital two-photon (2P) imaging through a spinal glass window. Thy1-CFP//LysM-EGFP//CD11c-EYFP triple transgenic reporter animals allowed real time simultaneous monitoring of axons, myeloid cells and microglial cells in the vicinity of the implanted MFs. MF biocompatibility was confirmed by the absence of inflammatory storm after implantation. We found that the sprouting of sensory axons was significantly accelerated by the implantation of functionalized MFs after PUDQL. Their implantation produced better axon alignment compared to random and misrouted axon regeneration that occurred in the absence of MF, with a most striking effect occurring two months after injury. Importantly, we observed differences in the intensity and composition of the innate immune response in comparison to PUDQL-only animals. A significant decrease of immune cell density was found in MF-implanted mice one month after lesion along with a higher ratio of monocyte-derived dendritic cells whose differentiation was accelerated. Therefore, functionalized carbon MFs promote the beneficial immune responses required for neural tissue repair, providing an encouraging strategy for SCI management.

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Section: Discussionmentioning

confidence: 99%

Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury

Waly

Escarrat

Pérez-Sánchez

et al. 2021

Cells

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“…STAT3 is activated following SCI and plays a vital role in the differentiation and organization of astrocytes (43), which contribute to glial scar formation (22,38,39). In addition, according to previous studies, the microenvironment surrounding the spinal cord lesion site following SCI result in the differentiation of exogenous NSCs into astrocytes (28,44,45). This leads to the formation of glial scars in the lesion site that are widely regarded to inhibit axon regeneration and functional recovery during the chronic phase of SCI (17,46,47).…”

Section: Discussionmentioning

confidence: 96%

Targeted inhibition of STAT3 in neural stem cells promotes neuronal differentiation and functional recovery in rats with spinal cord injury

Zhao

Duan

et al. 2021

Exp Ther Med

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STAT3 is expressed in neural stem cells (NSCs), where a number of studies have previously shown that STAT3 is involved in regulating NSC differentiation. However, the possible molecular mechanism and role of STAT3 in spinal cord injury (SCI) remain unclear. In the present study, the potential effect of STAT3 in NSCs was first investigated by using short hairpin RNA (shRNA)-mediated STAT3 knockdown in rat NSCs in vitro . Immunofluorescence of β3-tubulin and glial fibrillary acidic protein staining and western blotting showed that knocking down STAT3 expression promoted NSC neuronal differentiation, where the activity of mTOR was upregulated. Subsequently, rats underwent laminectomy and complete spinal cord transection followed by transplantation of NSCs transfected with control-shRNA or STAT3-shRNA at the injured site in vivo . Spinal cord-evoked potentials and the Basso-Beattie-Bresnahan scores were used to examine functional recovery. In addition, axonal regeneration and tissue repair were assessed using retrograde tracing with FluoroGold, hematoxylin and eosin, Nissl and immunofluorescence staining of β3-tubulin, glial fibrillary acidic protein and microtubule-associated protein 2 following SCI. The results showed that transplantation with NSCs transfected with STAT3-RNA enhanced functional recovery following SCI and promoted tissue repair in rats, in addition to improving neuronal differentiation of the transplanted NSCs in the injury site. Taken together, in vitro and in vivo evidence that inhibiting STAT3 could promote NSC neuronal differentiation was demonstrated in the present study. Therefore, transplantation with NSCs with STAT3 expression knocked down appears to hold promising potential for enhancing the benefit of NSC-mediated regenerative cell therapy for SCI.

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“…STAT3 is a member of the JAK-STAT signaling family that transduces signals for many cytokines, and growth factors, including IL-6, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), EGF, and transforming growth factor α (TGFα), have been implicated as triggers of reactive astrogliosis [22]. STAT3 is active after SCI and plays a vital role in the differentiation of astrocytes, which contributes to glial scar formation [19,23]. STAT3 inhibitors have been shown to reverse the inhibitory effect of STAT3 on neuronal recovery [24].…”

Section: Discussionmentioning

confidence: 99%

Targeted Inhibition of STAT3 in Neural Stem Cells Promotes Neuronal Differentiation and Functional Recovery in Rats with Spinal Cord Injury

Zhao

Duan

et al. 2020

Preprint

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BackgroundSignal transducer and activator of transcription protein 3 (STAT3) is expressed in neural stem cells (NSCs), and some studies have shown that STAT3 is involved in regulating NSC differentiation. However, the possible molecular mechanism and the role of STAT3 in spinal cord injury (SCI) are unknown. Thus, in the present study, we identified possible molecular mechanisms by which STAT3 regulates NSC differentiation in vitro and investigated the potential therapeutic effect of transplanting STAT3-silenced NSCs in rat SCI models in vivo.MethodsIn vitro, NSCs were divided into the following three groups: control, control shRNA, and STAT3-shRNA lentivirus groups. NSCs in each treatment group were examined for neuronal differentiation via immunofluorescence, and Western blot analysis was used to investigate the possible molecular mechanisms. In vivo, the rats were divided into four groups that underwent laminectomy and complete spinal cord transection accompanied by transplantation of control-shRNA-treated or STAT3-shRNA-treated NSCs at the injured site. Spinal cord-evoked potentials and the Basso-Beattie-Bresnahan score were used to examine functional recovery after SCI. Axonal regeneration and tissue repair were assessed via retrograde tracing using Fluorogold, hematoxylin-eosin staining and immunofluorescence.ResultsKnockdown of STAT3 promoted neuronal differentiation in NSCs and mechanistic target of mammal rapamycin (mTOR) activation in vitro, and transplantation of STAT3-RNAi-treated NSCs enhanced rat functional recovery and tissue repair, as well as neuronal differentiation of the transplanted NSCs in vivo.ConclusionsWe have provided in vitro and in vivo evidence that STAT3 is a negative regulator of NSC neuronal differentiation. Transplantation of STAT3-inhibited NSCs appears to be a promising potential strategy for enhancing the benefit of NSC-mediated regenerative cell therapy for SCI.

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Mesenchymal Stem Cell Transplantation Promotes Functional Recovery through MMP2/STAT3 Related Astrogliosis after Spinal Cord Injury

Cited by 20 publications

References 34 publications

Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury

Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury

Targeted inhibition of STAT3 in neural stem cells promotes neuronal differentiation and functional recovery in rats with spinal cord injury

Targeted Inhibition of STAT3 in Neural Stem Cells Promotes Neuronal Differentiation and Functional Recovery in Rats with Spinal Cord Injury

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