scholarly journals Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo

2017 ◽  
Vol 6 (4) ◽  
pp. 1207-1216 ◽  
Author(s):  
Yoshihiro Sowa ◽  
Tsunao Kishida ◽  
Koichi Tomita ◽  
Kenta Yamamoto ◽  
Toshiaki Numajiri ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Human Fibroblasts ◽  
Direct Conversion

scholarly journals Fibroblasts Colonizing Nerve Conduits Express High Levels of Soluble Neuregulin1, a Factor Promoting Schwann Cell Dedifferentiation

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1366 ◽  
Author(s):  
Benedetta E. Fornasari ◽  
Marwa El Soury ◽  
Giulia Nato ◽  
Alessia Fucini ◽  
Giacomo Carta ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Peripheral Nerve Regeneration ◽  
Good Alternative ◽  
Cell Dedifferentiation ◽  
Nerve Conduits ◽  
Early Regeneration

Conduits for the repair of peripheral nerve gaps are a good alternative to autografts as they provide a protected environment and a physical guide for axonal re-growth. Conduits require colonization by cells involved in nerve regeneration (Schwann cells, fibroblasts, endothelial cells, macrophages) while in the autograft many cells are resident and just need to be activated. Since it is known that soluble Neuregulin1 (sNRG1) is released after injury and plays an important role activating Schwann cell dedifferentiation, its expression level was investigated in early regeneration steps (7, 14, 28 days) inside a 10 mm chitosan conduit used to repair median nerve gaps in Wistar rats. In vivo data show that sNRG1, mainly the isoform α, is highly expressed in the conduit, together with a fibroblast marker, while Schwann cell markers, including NRG1 receptors, were not. Primary culture analysis shows that nerve fibroblasts, unlike Schwann cells, express high NRG1α levels, while both express NRG1β. These data suggest that sNRG1 might be mainly expressed by fibroblasts colonizing nerve conduit before Schwann cells. Immunohistochemistry analysis confirmed NRG1 and fibroblast marker co-localization. These results suggest that fibroblasts, releasing sNRG1, might promote Schwann cell dedifferentiation to a “repair” phenotype, contributing to peripheral nerve regeneration.

scholarly journals Placenta to cartilage: direct conversion of human placenta to chondrocytes with transformation by defined factors

2012 ◽  
Vol 23 (18) ◽  
pp. 3511-3521 ◽  
Author(s):  
Ryuga Ishii ◽  
Daisuke Kami ◽  
Masashi Toyoda ◽  
Hatsune Makino ◽  
Satoshi Gojo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Human Fibroblasts ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Irreversible Processes ◽  
Cell Based Therapy ◽  
Decidual Cells ◽  
Cell Conversion

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human placental cells into chondrocytes. Starting from a pool of candidate genes, we identified a combination of only five genes (5F pool)—BCL6, T (also called BRACHYURY), c-MYC, MITF, and BAF60C (also called SMARCD3)—that rapidly and efficiently convert postnatal human chorion and decidual cells into chondrocytes. The cells generated expressed multiple cartilage-specific genes, such as Collagen type II α1, LINK PROTEIN-1, and AGGRECAN, and exhibited characteristics of cartilage both in vivo and in vitro. Expression of the endogenous genes for T and MITF was initiated, implying that the cell conversion is due to not only the forced expression of the transgenes, but also to cellular reprogramming by the transgenes. This direct conversion system from noncartilage tissue to cartilaginous tissue is a substantial advance toward understanding cartilage development, cell-based therapy, and oncogenesis of chondrocytes.

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.

A novel approach to 32-channel peripheral nervous system myelin imaging in vivo, with single axon resolution

2018 ◽  
Vol 130 (1) ◽  
pp. 163-171 ◽  
Author(s):  
Joey Grochmal ◽  
Wulin Teo ◽  
Hardeep Gambhir ◽  
Ranjan Kumar ◽  
Jo Anne Stratton ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nerve ◽  
Peripheral Nervous System ◽  
Schwann Cells ◽  
Tibial Nerve ◽  
Nile Red ◽  
Spectral Imaging ◽  
High Definition ◽  
Myelin Imaging

OBJECTIVEIntravital spectral imaging of the large, deeply situated nerves in the rat peripheral nervous system (PNS) has not been well described. Here, the authors have developed a highly stable platform for performing imaging of the tibial nerve in live rodents, thus allowing the capture of high-resolution, high-magnification spectral images requiring long acquisition times. By further exploiting the qualities of the topically applied myelin dye Nile red, this technique is capable of visualizing the detailed microenvironment of peripheral nerve demyelination injury and recovery, while allowing us to obtain images of exogenous Schwann cell myelination in a living animal.METHODSThe authors caused doxorubicin-induced focal demyelination in the tibial nerves of 25 Thy-1 GFP rats, of which 2 subsets (n = 10 each) received either BFP-labeled SKP-SCs or SCs to the zone of injury. Prior to acquiring images of myelin recovery in these nerves, a tibial nerve window was constructed using a silicone hemitube, a fast drying silicone polymer, and a small coverslip. This construct was then affixed to a 3D-printed nerve stage, which in turn was affixed to an external fixation/microscope stage device. Myelin visualization was facilitated by the topical application of Nile red.RESULTSThe authors reliably demonstrated intravital peripheral nerve myelin imaging with micron-level resolution and magnification, and minimal movement artifact. The detailed microenvironment of nerve remyelination can be vividly observed, while exogenously applied Schwann cells and skin-derived precursor Schwann cells can be seen myelinating axons.CONCLUSIONSTopically applied Nile red enables intravital study of myelin in the living rat PNS. Furthermore, the use of a tibial nerve window facilitates stable intravital peripheral nerve imaging, making possible high-definition spectral imaging with long acquisition times.

scholarly journals Betacellulin Regulates Peripheral Nerve Regeneration by Affecting Schwann Cell Migration and Axon Elongation

2021 ◽  
Author(s):  
Yaxian Wang ◽  
Fuchao Zhang ◽  
Yunsong Zhang ◽  
Qi Shan ◽  
Wei Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Cultured Cells ◽  
Axon Elongation ◽  
Schwann Cell Migration

Abstract Background Growth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve injury and regeneration. Our previous sequencing analysis found that betacellulin (Btc), an epidermal growth factor protein family member, showed elevated mRNA expressions in the nerve segment after rat peripheral nerve injury, implying the potential involvement of Btc during peripheral nerve repair. Methods Expression of Btc was examined in Schwann cells. The role of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or exposed cultured cells with Btc recombinant protein, respectively. The biological functions of Schwann cell-secreted Btc on neurons were also determined. Moreover, the in vivo effect of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated.Results Immunostaining images and ELISA readings showed Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that siRNA against Btc impeded Schwann cell migration while exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells might influence neuron behavior and affect axon length. In vivo evidence showed that Btc enhanced axonal regrowth and nerve regeneration after both rat sciatic nerve crush injury and transection injury. Conclusion Our findings demonstrated Btc-mediated Schwann cell-axon interactions, revealed the essential roles of Btc on Schwann cell migration and axon elongation, and implied the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

Syringic acid promotes proliferation and migration of Schwann cells via down-regulating miR-451-5p

2019 ◽  
Author(s):  
Yaofa Lin ◽  
Xin Jiang ◽  
Gang Yin ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Cellular Response ◽  
Target Genes ◽  
Syringic Acid ◽  
Neuroprotective Activity ◽  
Chemical Stimulus ◽  
And Migration ◽  
Proliferation And Migration

Abstract Schwann cells are the main force in spontaneous regeneration after peripheral nerve injury. The neurotrophic factors could promote the regeneration, but clinical applications of these factors are limited by some constraints. Hence, searching for new substances to elevate the function of Schwann cells and facilitate the regeneration of nerve is urgently needed. Syringic acid (SA) is a natural product with neuroprotective activity in vivo, but the role of SA on Schwann cells remains unclear. In this study, we for the first time found that SA was able to promote the proliferation and migration of Schwann cells, two important abilities in the process of regeneration. Then, microRNA (miRNA) microarray analysis was performed and 26 differentially expressed miRNAs (22 down-regulated and 4 up-regulated) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses found that the target genes of these miRNAs were mainly enriched in cellular response to chemical stimulus and cancer-related pathways, respectively. Subsequently, the levels of top 6 down-regulated miRNAs were validated by RT-qPCR and miR-451-5p was shown to be the most down-regulated one. Further experiments demonstrated that inhibition of miR-451-5p significantly promoted the proliferation and migration of Schwann cells. These results suggested that SA promoted the proliferation and migration of Schwann cells via down-regulation of miR-451-5p, and SA could be developed into a promising nutritional supplement to assist peripheral nerve regeneration.

scholarly journals Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

2015 ◽  
Vol 112 (5) ◽  
pp. E497-E505 ◽  
Author(s):  
Elisa Duregotti ◽  
Samuele Negro ◽  
Michele Scorzeto ◽  
Irene Zornetta ◽  
Bryan C. Dickinson ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Motor Axon ◽  
Nerve Terminals ◽  
Axon Terminals ◽  
Terminal Degeneration

An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin-treated primary neurons release signaling molecules derived from mitochondria: hydrogen peroxide, mitochondrial DNA, and cytochrome c. These molecules activate isolated primary Schwann cells, Schwann cells cocultured with neurons and at neuromuscular junction in vivo through the MAPK pathway. We propose that this inter- and intracellular signaling is involved in triggering the regeneration of peripheral nerve terminals affected by other forms of neurodegenerative diseases.

scholarly journals Directly Converted Human Fibroblasts Mature to Neurons and Show Long-Term Survival in Adult Rodent Hippocampus

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Natalia Avaliani ◽  
Ulrich Pfisterer ◽  
Andreas Heuer ◽  
Malin Parmar ◽  
Merab Kokaia ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Human Fibroblasts ◽  
Morphological Differentiation ◽  
High Amplitude ◽  
Direct Conversion ◽  
Term Survival ◽  
Electrophysiological Properties ◽  
Adult Rat ◽  
Induced Neurons

Direct conversion of human somatic cells to induced neurons (iNs), using lineage-specific transcription factors has opened new opportunities for cell therapy in a number of neurological diseases, including epilepsy. In most severe cases of epilepsy, seizures often originate in the hippocampus, where populations of inhibitory interneurons degenerate. Thus, iNs could be of potential use to replace these lost interneurons. It is not known, however, if iNs survive and maintain functional neuronal properties for prolonged time periods in in vivo. We transplanted human fibroblast-derived iNs into the adult rat hippocampus and observed a progressive morphological differentiation, with more developed dendritic arborisation at six months as compared to one month. This was accompanied by mature electrophysiological properties and fast high amplitude action potentials at six months after transplantation. This proof-of-principle study suggests that human iNs can be developed as a candidate source for cell replacement therapy in temporal lobe epilepsy.

scholarly journals Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy using Schwann cells and PLGA: in vitro and in vivo

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hui Liu ◽  
Peizhen Lv ◽  
Yongjia Zhu ◽  
Huayu Wu ◽  
Kun Zhang ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Schwann Cells ◽  
Nerve Injury ◽  
Peripheral Nerve Regeneration ◽  
Immunohistochemical Analysis ◽  
Neuroprotective Effects

Abstract Salidriside (SDS), a phenylpropanoid glycoside derived from Rhodiola rosea L, has been shown to be neuroprotective in many studies, which may be promising in nerve recovery. In this study, the neuroprotective effects of SDS on engineered nerve constructed by Schwann cells (SCs) and Poly (lactic-co-glycolic acid) (PLGA) were studied in vitro. We further investigated the effect of combinational therapy of SDS and PLGA/SCs based tissue engineering on peripheral nerve regeneration based on the rat model of nerve injury by sciatic transection. The results showed that SDS dramatically enhanced the proliferation and function of SCs. The underlying mechanism may be that SDS affects SCs growth through the modulation of neurotrophic factors (BDNF, GDNF and CNTF). 12 weeks after implantation with a 12 mm gap of sciatic nerve injury, SDS-PLGA/SCs achieved satisfying outcomes of nerve regeneration, as evidenced by morphological and functional improvements upon therapy by SDS, PLGA/SCs or direct suture group assessed by sciatic function index, nerve conduction assay, HE staining and immunohistochemical analysis. Our results demonstrated the significant role of introducing SDS into neural tissue engineering to promote nerve regeneration.

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