Tissue engineering with peripheral blood-derived mesenchymal stem cells promotes the regeneration of injured peripheral nerves

Pan, Mengjie; Wang, Xianghai; Chen, Yijing; Cao, Shuiyan; Wen, Jinkun; Wu, Guofeng; Li, Yuanyuan; Li, Lixia; Qian, Changhui; Qin, Zhenqi; Li, Zhenlin; Tan, Dandan; Fan, Zhihao; Wu, Wutian; Guo, Jiasong

doi:10.1016/j.expneurol.2017.03.005

Cited by 30 publications

(18 citation statements)

References 45 publications

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“…According to our previous studies and related literatures [ 35 , 37 , 42 ], mice survived for 28 days after crush and then the wet weight and myofiber area of gastrocnemius muscle as well as the amplitude and CMAP were detected to assess the functional outcomes of nerve regeneration. First of all, the size of the gastrocnemius muscles in the cKO group was obviously smaller than that in the Cre group, and the statistics showed the wet weight of the muscles was lighter in the cKO group than that in the Cre group ( p = 0.002, Fig.…”

Section: Resultsmentioning

confidence: 99%

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Wen

et al. 2021

J Neuroinflammation

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Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the LyzCre+/−; RhoAflox/flox (cKO) mice or Lyz2Cre+/− (Cre) mice, regardless of sex. Macrophages’ migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

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Section: Resultsmentioning

confidence: 99%

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Wen

et al. 2021

J Neuroinflammation

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“…Subsequently, the muscles were embedded with Tissue OCT-Freeze Medium and transversally cut into 10-μm sections. The sections were stained with 0.5% hemeatoxylin to show the outline of the myofibers, and the areas of the myofibers were calculated as described in our previous publications (Wang et al, 2014; Pan et al, 2017). Briefly, six random non-overlapping fields from five sections from each animal were captured, and the image analysis was performed using Image-Pro Plus 6.0 software to quantify the areas of the myofibers.…”

Section: Methodsmentioning

confidence: 99%

Ascorbic Acid Facilitates Neural Regeneration After Sciatic Nerve Crush Injury

Fan

et al. 2019

Front. Cell. Neurosci.

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Ascorbic acid (AA) is an essential micronutrient that has been safely used in the clinic for many years. The present study indicates that AA has an unexpected function in facilitating nerve regeneration. Using a mouse model of sciatic nerve crush injury, we found that AA can significantly accelerate axonal regrowth in the early stage [3 days post-injury (dpi)], a finding that was revealed by immunostaining and Western blotting for antibodies against GAP-43 and SCG10. On day 28 post-injury, histomorphometric assessments demonstrated that AA treatment increased the density, size, and remyelination of regenerated axons in the injured nerve and alleviated myoatrophy in the gastrocnemius. Moreover, the results from various behavioral tests and electrophysiological assays revealed that nerve injury-derived functional defects in motor and sensory behavior as well as in nerve conduction were significantly attenuated by treatment with AA. The potential mechanisms of AA in nerve regeneration were further explored by investigating the effects of AA on three types of cells involved in this process [neurons, Schwann cells (SCs) and macrophages] through a series of experiments. Overall, the data illustrated that AA treatment in cultured dorsal root ganglionic neurons resulted in increased neurite growth and lower expression of RhoA, which is an important inhibitory factor in neural regeneration. In SCs, proliferation, phagocytosis, and neurotrophin expression were all enhanced by AA. Meanwhile, AA treatment also improved proliferation, migration, phagocytosis, and anti-inflammatory polarization in macrophages. In conclusion, this study demonstrated that treatment with AA can promote the morphological and functional recovery of injured peripheral nerves and that this effect is potentially due to AA’s bioeffects on neurons, SCs and macrophages, three of most important types of cells involved in nerve injury and regeneration.

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“…repair/regeneration, which include their multipotent differentiation potentials into neuronal and Schwann cells, 14,48,49 their capability to produce a variety of neurotrophic and proangiogenic factors, 13,16,50,51 and their profound immunosuppressive and anti-inflammatory functions to harness the local inflammatory responses at the injured site. [52][53][54] However, the exact mechanisms by which MSCs promote peripheral nerve repair/ regeneration are still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration

Mao

Nguyen

Shanti

et al. 2019

Tissue Engineering Part A

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A fully functional recovery of peripheral nerve injury remains a major challenge and an unmet clinical need. Recent evidence has reported promising therapeutic effects of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in experimental models of tissue injuries and inflammatory diseases, but less is known about their effects on peripheral nerve regeneration. In this study, we investigated the effects of gingiva-derived mesenchymal stem cell (GMSC)-derived EVs on peripheral nerve regeneration of crush-injured mice sciatic nerves. In vivo studies mimicking clinical nerve repair showed that locally wrapping Gelfoam embedded with GMSC-derived EVs at the crush injury site promoted functional recovery and axonal regeneration, which were comparable with effects conferred by direct transplantation of GMSCs. Mechanistically, we showed that GMSC-derived EVs promoted proliferation and migration of Schwann cells, upregulated the protein expressions of c-JUN, Notch1, GFAP (glial fibrillary acidic protein), and SRY (sex determining region Y)-box 2 (SOX2), characteristic genes of dedifferentiation or repair phenotype of Schwann cells, through which pharmacologically blocking c-JUN/JNK (c-JUN N-terminal kinase) activity significantly abrogated GMSC-derived EV-induced upregulation of these Schwann cell dedifferentiation/repair phenotype-related genes. These findings suggest that GMSC-derived EVs promote peripheral nerve regeneration possibly by activating c-JUNgoverned repair phenotype of Schwann cells.

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Tissue engineering with peripheral blood-derived mesenchymal stem cells promotes the regeneration of injured peripheral nerves

Cited by 30 publications

References 45 publications

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Ascorbic Acid Facilitates Neural Regeneration After Sciatic Nerve Crush Injury

Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration

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