scholarly journals Upregulated lncARAT in Schwann cells promotes axonal regeneration through recruiting macrophages and inducing macrophages M2 polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract BackgroundAxonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear.MethodsThe total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.ResultsHere we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration.ConclusionsLncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

scholarly journals Upregulated lncARAT in Schwann Cells Promotes Axonal Regeneration through Recruiting Macrophages and Inducing Macrophages M2 Polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract Background: Axonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear. Methods: The total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.Results: Here we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration. Conclusions: LncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

Bioresorbable Glass Fibres Facilitate Peripheral Nerve Regeneration

2005 ◽  
Vol 30 (3) ◽  
pp. 242-247 ◽  
Author(s):  
S. BUNTING ◽  
L. DI SILVIO ◽  
S. DEB ◽  
S. HALL
Keyword(s):  
Axonal Regeneration ◽  
Peripheral Nerve Regeneration ◽  
Adult Rats ◽  
Quantitative Evidence ◽  
Qualitative And Quantitative ◽  
Axonal Regrowth ◽  
Sciatic Nerves ◽  
Proof Of Principle

This is a proof of principle report showing that fibres of Bioglass® 45S5 can form a biocompatible scaffold to guide regrowing peripheral axons in vivo. We demonstrate that cultured rat Schwann cells and fibroblasts grow on Bioglass® fibres in vitro using SEM and immunohistochemistry, and provide qualitative and quantitative evidence of axonal regeneration through a Silastic conduit filled with Bioglass® fibres in vivo (across a 0.5 cm interstump gap in the sciatic nerves of adult rats). Axonal regrowth at 4 weeks is indistinguishable from that which occurs across an autograft. Bioglass® fibres are not only biocompatible and bioresorbable, which are absolute requirements of successful devices, but are also amenable to bioengineering, and therefore have the potential for use in the most challenging clinical cases, where there are long inter-stump gaps to be bridged.

scholarly journals SIRT6 inhibition delays peripheral nerve recovery by suppressing migration, phagocytosis and M2-polarization of macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Zou ◽  
Jiaqi Zhang ◽  
Jiawei Xu ◽  
Lanya Fu ◽  
Yizhou Xu ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Macrophage Polarization ◽  
Nerve Degeneration ◽  
M2 Polarization ◽  
M1 Macrophage ◽  
Nerve Recovery

Abstract Background Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Prior evidences suggested that the anti-inflammatory function of SIRT6 after spinal cord and brain injury, and it plays a crucial role in macrophages polarization of adipose tissue and skin. However, the role of SIRT6 in macrophages involved peripheral nerve injury is still unknown. Given the prominent role of macrophages in peripheral nerve recovery, we aim to investigate the role of SIRT6 in the regulation of phenotypes shift and functions in macrophages after peripheral nerve injury. Results In the present study, we first identified a significant increase of SIRT6 expression during nerve degeneration and macrophages phagocytosis. Next, we found nerve recovery was delayed after SIRT6 silencing by injected shRNA lentivirus into the crushed sciatic nerve, which exhibited a reduced expression of myelin-related proteins (e.g., MAG and MBP), severer myoatrophy of target muscles, and inferior nerve conduction compared to the shRNA control injected mice. In vitro, we found that SIRT6 inhibition by being treated with a selective inhibitor OSS_128167 or lentivirus transfection impairs migration and phagocytosis capacity of bone marrow-derived macrophages (BMDM). In addition, SIRT6 expression was discovered to be reduced after M1 polarization, but SIRT6 was enhanced after M2 polarization in the monocyte-macrophage cell line RAW264.7 and BMDM. Moreover, SIRT6 inhibition increased M1 macrophage polarization with a concomitant decrease in M2 polarization both in RAW264.7 and BMDM via activating NF-κB and TNF-α expression, and SIRT6 activation by UBCS039 treatment could shift the macrophages from M1 to M2 phenotype. Conclusion Our findings indicate that SIRT6 inhibition impairs peripheral nerve repair through suppressing the migration, phagocytosis, and M2 polarization of macrophages. Therefore, SIRT6 may become a favorable therapeutic target for peripheral nerve injury.

scholarly journals BMP-7/Smad expression in dedifferentiated Schwann cells during axonal regeneration and upregulation of endogenous BMP-7 following administration of PTH (1-34)

2018 ◽  
Vol 26 (3) ◽  
pp. 230949901881295 ◽  
Author(s):  
Naoki Kokubu ◽  
Masaya Tsujii ◽  
Koji Akeda ◽  
Takahiro Iino ◽  
Akihiro Sudo
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Axonal Regeneration ◽  
Double Immunostaining ◽  
Aneurysm Clip ◽  
Smad Signaling ◽  
Bmp Receptors ◽  
Smad Protein

Purpose: To determine the expression and distribution of bone morphogenetic protein (BMP)-7 and related molecules during peripheral nerve regeneration and to assess whether administration of parathyroid hormone (PTH) drug (1-34) potentiates the intrinsic upregulation of BMP-7/Smad signaling. Methods: The rat sciatic nerves were crushed with an aneurysm clip resulting in axonal degeneration. In the normal nerve, and at 1, 2, 4, and 8 weeks after injury, BMP-7, BMP receptors, p-Smad 1/5/8, and Noggin, the endogenous BMP antagonist, were evaluated. Additionally, the distribution of BMP-7 was assessed by fluorescent double immunostaining. In vitro studies were also performed to examine the effect of BMP-7 and PTH (1-34) administration on rat Schwann cells (SCs). Results: Aneurysm clip made reliable animal model of the nerve injury with recovery at 8 weeks after the injury. BMP-7/Smad protein and mRNA were significantly upregulated on axon-SCs units at 1 week after injury, and this upregulated expression was maintained for 4 weeks. Besides, significant upregulation of Noggin’s expression was observed on axon-SCs units at 2 weeks after injury. Moreover, fluorescent double immunostaining showed co-localization between expression of BMP-7 and p75NTR during axonal regeneration. In the in vitro study, administration of BMP-7 induced significant proliferation of SCs. Application of PTH (1-34) upregulated BMP-7 on SCs. Discussion/conclusion: BMPs were reported to be involved in protection and recovery after injury as well as in neurogenesis. Our current study showed that BMP/Smad signaling molecules were upregulated on dedifferentiated SCs after peripheral nerve injury and that administration of BMP-7 increased SC viability in vitro. These results suggested that axonal regeneration could be induced via upregulation of endogenous BMP-7 on SCs by PTH (1-34) administration.

scholarly journals Electrospun Hyaluronan-Gelatin Nanofibrous Matrix for Nerve Tissue Engineering

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Hau-Min Liou ◽  
Lih-Rou Rau ◽  
Chun-Chiang Huang ◽  
Meng-Ru Lu ◽  
Fu-Yin Hsu
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Cell Attachment ◽  
Nerve Repair ◽  
Critical Role ◽  
Nerve Tissue ◽  
Growth Environment ◽  
Biological Performance ◽  
Electrospun Gelatin

Schwann cells play a critical role in the repair of the peripheral nerve. The goal of this study was to fabricate electrospun gelatin (Gel) and hyaluronan-gelatin (HA-Gel) composite nanofibers to provide a suitable growth environment for Schwann cells. The fiber diameters of Gel, 0.5 HA-Gel, 1 HA-Gel, and 1.5 HA-Gel were 130 ± 30 nm, 294 ± 87 nm, 362 ± 129 nm, and 224 ± 54 nm, respectively. The biological performance of Gel and HA-Gel was evaluated using anin vitroculture of RT4-D6P2T rat Schwann cells. We found that the cell attachment and proliferation rates were not significantly different on these matrices. However, the Schwann cells displayed better organized F-actin on HA-Gel than on Gel. Moreover, the expression levels of several genes, including Nrg1, GFAP, and P0, were significantly higher on HA-Gel than on Gel. In addition, the levels of Nrg1 and P0 protein expression were also higher on the HA-Gel than on Gel. These results indicate that the hyaluronan-gelatin composite nanofibrous matrix could potentially be used in peripheral nerve repair.

scholarly journals Peripheral Nerve Repair with Cultured Schwann Cells: Getting Closer to the Clinics

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Maria Carolina O. Rodrigues ◽  
Antonio Antunes Rodrigues ◽  
Loren E. Glover ◽  
Julio Voltarelli ◽  
Cesario V. Borlongan
Keyword(s):  
Bone Marrow ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Repair ◽  
Experimental Studies ◽  
Experimental Treatment ◽  
Mesenchymal Cells ◽  
Nerve Conduits ◽  
Cultured Schwann Cells

Peripheral nerve injuries are a frequent and disabling condition, which affects 13 to 23 per 100.000 persons each year. Severe cases, with structural disruption of the nerve, are associated with poor functional recovery. The experimental treatment using nerve grafts to replace damaged or shortened axons is limited by technical difficulties, invasiveness, and mediocre results. Other therapeutic choices include the adjunctive application of cultured Schwann cells and nerve conduits to guide axonal growth. The bone marrow is a rich source of mesenchymal cells, which can be differentiatedin vitrointo Schwann cells and subsequently engrafted into the damaged nerve. Alternatively, undifferentiated bone marrow mesenchymal cells can be associated with nerve conduits and afterward transplanted. Experimental studies provide evidence of functional, histological, and electromyographical improvement following transplantation of bone-marrow-derived cells in animal models of peripheral nerve injury. This paper focuses on this new therapeutic approach highlighting its direct translational and clinical utility in promoting regeneration of not only acute but perhaps also chronic cases of peripheral nerve damage.

scholarly journals Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury

2002 ◽  
Vol 159 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Caroline Pot ◽  
Marjo Simonen ◽  
Oliver Weinmann ◽  
Lisa Schnell ◽  
Franziska Christ ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Neurite Growth ◽  
Sciatic Nerve Crush ◽  
Nerve Crush ◽  
Transgenic Expression ◽  
Growth Inhibitory ◽  
Brain And Spinal Cord

Înjured axons in mammalian peripheral nerves often regenerate successfully over long distances, in contrast to axons in the brain and spinal cord (CNS). Neurite growth-inhibitory proteins, including the recently cloned membrane protein Nogo-A, are enriched in the CNS, in particular in myelin. Nogo-A is not detectable in peripheral nerve myelin. Using regulated transgenic expression of Nogo-A in peripheral nerve Schwann cells, we show that axonal regeneration and functional recovery are impaired after a sciatic nerve crush. Nogo-A thus overrides the growth-permissive and -promoting effects of the lesioned peripheral nerve, demonstrating its in vivo potency as an inhibitor of axonal regeneration.

scholarly journals MSC-derived miR-181b Overexpressing Exosomes Enhanced Osteointegration by Enhancing M2 Polarization of Macrophages via Targeting the PRKCD/AKT Pathway

2020 ◽  
Author(s):  
Wei Liu ◽  
Muyu Yu ◽  
Feng Chen ◽  
Dong Xie ◽  
Longqing Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
Fluorescent Labeling ◽  
M2 Macrophage ◽  
Implant Loosening ◽  
M2 Polarization ◽  
Tnf Α

Abstract Background: Many patients suffer from implant loosening after the implantation of titanium alloy caused by immune response to the foreign bodies and this could inhibit osteogenesis, which could possibly give rise to poor osteointegration and there is currently no appropriate solution in clinical practice. Exosomes overexpressing miRNA has been proven to be a suitable candidate for solving this problem. In this study, we explored whether miR-181b could exert beneficial effect on promoting M2 macrophage polarization, thus inhibiting inflammation as well as promoting osteogenesis and elaborated the underlying mechanism in vitro. Furthermore, we aimed to find whether exosomes overexpressing miR-181b (Exo-181b) could enhance osteointegration in vivo.Methods: In vitro and in vivo studies were carried out for assessing the anti-inflammatory and pro-osteogenesis effect of miR-181b. In vitro, ELISA was applied for the detection of the inflammation factors levels including IL-6, TNF-α, as well as IL-10 and the percentage of M1 or M2 polarization was determined by flow cytometry. Also, qRT-PCR was used for the detection of the relative gene expression of the CCR7, CD206, Arg-1, iNOS, VEGF and BMP-2 genes. Western blotting was applied for detecting the protein expression of PRKCD, AKT and p-AKT. In vivo, we established air pouch model for evaluating the effect of Exo-181b on macrophage polarization and distal femoral bone defect model was established for determining the osteointegration effect of Exo-181b by MicroCT, sequential fluorescent labeling and histological analysis. Results: In vitro, we firstly verified that miR-181b significantly enhanced M2 polarization and inhibited inflammation by suppressing PRKCD and activating p-AKT. Then, in vivo, we verified that Exo-181b enhanced M2 polarization, reduced the inflammatory response and enhanced osteointegration. Conclusions: MiR-181b could suppress inflammatory response by regulating the PRKCD/AKT signaling pathway and promoting M2 polarization, which further promoting osteogenesis of hBMSC in vitro and Exo-181b could promote osteointegration in vivo.

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