• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration

    2020-05-07 12:01:16ChristineBojanicKendrickToBridgetZhangChristopherMakWasimKhan
    World Journal of Stem Cells 2020年4期
    關(guān)鍵詞:所帶科學(xué)合理閱讀課

    Christine Bojanic, Kendrick To, Bridget Zhang, Christopher Mak, Wasim S Khan

    Christine Bojanic, Department of Plastic and Reconstructive Surgery, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom

    Kendrick To, Wasim S Khan, Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom

    Bridget Zhang, Christopher Mak, School of Clinical Medicine, University of Cambridge,Cambridge CB2 0QQ, United Kingdom

    Abstract

    Key words: Umbilical cord; Mesenchymal stem cells; Transplantation; Peripheral nerve regeneration

    INTRODUCTION

    Peripheral nerve injuries can occur as a result of trauma or disease and can lead to significant morbidity including sensory loss, motor loss and chronic pain[1]. These injuries cause life-long disability in up to 2.8% of all trauma patients[2]. Damage to peripheral nerves most commonly occurs as a result of laceration, compression,ischaemia or traction[1]. As classified by Seddon in 1943, nerve injury can range from focal demyelination termed neurapraxia, to total nerve transection termed neurotmesis[3,4]. The mechanism of recovery post-injury occurs by either branching of collateral axons or by regeneration of the damaged neuron[4,5]. In order for full neuronal recovery to occur, Wallerian degeneration, axonal regeneration and endorgan reinnervation must take place. This is driven by an array of neurotropic factors[4]. However, recovery in function following peripheral nerve injury is hindered by complex pathological mechanisms such as poor nerve regeneration,neuromuscular atrophy, and end-plate degeneration which can lead to suboptimal neuron function[6-9].

    Traditionally, peripheral nerve injury can be managed conservatively or surgically with neurolysis, neural suturing, end-to-side neurorrhaphy and nerve autograft[10-12].Even with optimum surgical repair, most methods will attain partial but not full return of nerve function[10]. Certain peripheral nerve injuries, such as severe brachial plexus or long traction injuries remain inoperable[10]. Autografts have several disadvantages, including donor site morbidity, mismatch in nerve and graft size resulting in poor engraftment, and the potential for development of painful neuromas[11,13,14]. Alternative methods of treating peripheral nerve injuries may be through cell-based regenerative therapies[15].

    Transplantation of mesenchymal stem cells (MSCs), given their regenerative properties and highly proliferative capacity, has been proposed as a promising therapeutic option for peripheral nerve regeneration[16,17]. MSCs are plastic-adherent,undifferentiated, multipotent cells that can be harvested from numerous sites of the body including bone marrow, adipose tissue, dental pulp, amniotic fluid and umbilical cord[17-19]. MSCs from different tissue origins can have distinct cytokine expression profiles, and thus may enable different MSCs to be particularly suited to certain clinical applications[20,21]. Owing to low immunogenicity, MSCs may be transplanted allogenically with minimal consequence[22]. The particular mechanisms through which MSCs aid nerve repair have not yet been fully characterised. MSCs from various sources such as adipose tissue and bone marrow are able to differentiate into Schwann cells[23,24]. While somein vitroexperiments suggest that transplanted MSCs may be stimulated by peripheral nerves to differentiate into Schwann cells[25],alternative findings have instead shown that transplanted MSCs encourage endogenous cells to express regenerative phenotypes[26]. Increasingly, MCSs are believed to mediate their regenerative properties predominantly through paracrine effects[27,28]. Aside from acting through soluble factors[29], MSCs have also demonstrated the ability to secrete extracellular vesicles that contain bioactive components such as miRNA and cytokines[30]. Indeed, native Schwann cells have been shown to facilitate axonal regeneration following injury through secretion of exosomes that decrease GTPase RhoA activity[31]. Similarly, human MSCs may act to achieve the same result through exosomes by upregulation of the PI3 kinase and Akt signalling cascades[32].

    MSCs from umbilical cord are convenient to harvest from post-natal tissue in a non-invasive manner and possess a high capacity to expandex vivo[33]. They express low levels of HLA-DR compared to MSCs from other cell sources and therefore pose low risk of immunogenic complications following allogenic transplantation[34].Through sequential treatment with β-mercaptoethanol and various cytokines,umbilical cord derived MSCs (UCMSCs) can adopt a Schwann-like phenotype[35]. In addition, UCMSCs have been shown to possess greater paracrine effects than those of bone marrow-derived MSCs (BMMSC) and adipose-derived MSCs[17,29], and are able to potentiate axonal regeneration and peripheral nerve functional regeneration through these effects[11,17,29,36]. UCMSCs have been proposed to exert neuroprotective effects through secretion of Brain Derived Neurotrophic Factor (BDNF)[37], angiopoietin-2 and CXCL-16[38,39]. Other studies have suggested that they indirectly promote neurogenesis[40,41]. UCMSCs are also able to indirectly enhance expression of neurotransmitters such as BDNF and neurotrophin-3 (NTF3) which are postulated to aid neuro-regeneration[42,43].

    To date, there have been over 400 clinical trials that explore the use of MSCs in transplantation; UCMSCs follow BMMSCs as the second most commonly used cell source[44]. In this PRISMA systematic review, we analyse the evidence for the use of human UCMSCs in peripheral nerve regeneration by examiningin vivostudies.

    MATERIALS AND METHODS

    A literature search was performed from conception to September 2019 using PubMed,EMBASE and Web of Science. The following search terms were used:((((((((Mesenchymal stem cells) OR mesenchymal stem cell) OR MSC) OR MSCs) OR Mesenchymal stromal cell) OR Mesenchymal cell)) AND (((((Nerve) OR Peripheral nerve) OR Peripheral nerve injury) OR damaged nerve) OR nerve injury)) AND((((((repair) OR regeneration) OR regrowth) OR regenerate) OR renew) OR restore).We adhered to the recommendations as stipulated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[45].

    We included case series, case control, cohort studies and randomised controlled trials. We enrolled studies that examined peripheral nerve lesions treated with human UCMSCs inin vivohuman and animal subjects. Studies that only conductedin vitroexperiments were excluded. Studies that investigated central nervous system regeneration using UCMSCs were excluded. All included studies were published in the English language. We excluded all unpublished and retracted literature.

    CB and KT carried out the search independently. RoB2 tool was used by CM and BZ to assess the risk of bias in the studies, all discrepancy in results were resolved by discussion.

    RESULTS

    A total of 210 studies were screened for title, abstract and the inclusion/exclusion criteria were applied (Figure 1). One retracted study was excluded. Fourteen studies were reviewed in full text. The overall bias of studies is shown in Figure 2. The summary of results is shown in Figure 3. All 14 studies were of a case control design(Table 1). Four studies obtained UCMSCs from a third-party source and the remainder were harvested directly from human subjects. Out of the 14 studies, ten involved xenogenic transplantation into sciatic nerve injury specimens that were either crushed or transected. The studies were grouped according to Seddon’s seminal nerve injury classification system, which includes axonotmesis (injury to nerve sheath alone) and neurotmesis (injury to the entire nerve)[3]. A total of 279 subjects were treated with UCMSCs. All studies reported significant improvement in UCMSC treated groups compared with the various different controls and untreated groups.

    The studies did not report any significant complications.

    UCMSCs in peripheral nerve axonotmesis

    Four studies that included a total of 90 treated subjects assessed the use of UCMSCs in peripheral nerve axonotmesis models of sciatic nerve crush injury (Table 1). All four studies harvested UCMSCs from human subjects and transplanted the UCMSCs into murine subjects. The methods of UCMSC delivery to the crush injury varied among studies.

    Studies, by Sunget al[46](2012) and Heiet al[47](2016) examined the effect of direct intralesional UCMSC injections on murine subjects with sciatic nerve crush injuries.Both studies monitored subjects up to 4 wk post-intervention. Sunget al[46](2012)found that expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B mRNA increased at 4 wk following UCMSC injection. Functional recovery was measured in terms of the sciatic function index (SFI), which showed a dramatic improvement at 4 wk in UCMSC treated groups compared to untreated groups. Retrograde axonal transport was estimated through fluoro Gold-labelled neuron counts and the UCMSC group was found to have a significantly higher neuron count. It was found that axon density was significantly greater in the UCMSC group. Heiet al[47](2016) transfected UCMSCs with a BDNF-adenovirus vector. The authors found that both UCMSC and BDNF-UCMSC groups had significant improvements in SFI, axon count and axon density at 4 wk after treatment. The BDNF-UCMSC group displayed increased peripheral nerve regeneration compared with UCMSC alone.

    Gartneret al[48,49]conducted two studies published in the same year. In one study,Chitosan type III membrane was used to aid UCMSC infiltration in murine sciatic crush models[48]. The authors evaluated motor and sensory functional recovery up to 12 wk following transplantation with and without Chitosan type III wrapping. Both treatment groups showed improvement in SFI, extensor postural thrust (EPT) and withdrawal reflex latency (WRL). The control group with Chitosan type III membrane alone showed a significant improvement in post-traumatic axonal regrowth compared to the untreated control group. In a separate study, the same group examined the effect of using poly (DL-lactide-e-caprolactone) (PLC) membranes to deliver UCMSCs into sciatic nerve crush injuries[49]. Peripheral nerve regeneration was assessed in terms of SFI, EPT, and WRL at 12 wk. Undifferentiated and differentiated UCMSCs were used in different groups. Both groups showed an increase in myelin sheath thickness compared to control groups. The SFI was severely affected at week-2 postcrush injury in all experimental groups and improved gradually up to week 12 when values were indistinguishable from controls.

    Studies of UCMSCs in peripheral nerve neurotmesis

    Nine of the fourteen studies assessed the use of UCMSCs in peripheral nerve neurotmesis models (Table 2). All nine were case control studies. Five studies had murine subjects, two had rabbit subjects, one had canine subjects, and one had human subjects. Six studies transplanted UCMSCs into a sciatic nerve gap model. Two studies transplanted UCMSCs into tibial nerve and recurrent laryngeal nerve crush models. One study conducted allogenic transplantation in humans. A total of 151 subjects were treated. Methods of MSC delivery and transplantation varied among studies.

    Several groups sought to improve nerve regeneration with UCMSCs combined with longitudinal scaffolds. Zarbakhshet al[11](2015) loaded UCMSCs on a silicone tube and interposed it into a murine sciatic nerve gap model. The authors attempted to compare the histological outcomes of human UCMSCs and rat BMMSCs in regenerating sciatic nerve gap in rats. While the author showed favourable results in nerve regeneration for both UCMSCs and BMMSC, the latter was found to produce superior results at the end point of 12 wk. The BMMSC group showed greater axon number and thicker myelin sheath diameter than the UCMSC group.

    Maet al[17](2019) injected UCMSC-derived extracellular vesicles (EVs) into the tail veins of rats and sutured a silicone rubber tube into the sciatic nerve gaps of 24 rats.The authors found that UCMSC-EVs promoted motor function recovery and regeneration of axons and attenuated muscle atrophy. SFI analysis was used to assess the functional improvements. At 8 wk, UCMSC-EV group had similar SFI values to normal rats.

    總之,幾種教學(xué)方法,只有根據(jù)小學(xué)語文閱讀課的教材實(shí)際,根據(jù)所帶學(xué)生的認(rèn)知特點(diǎn),進(jìn)行有主有次,科學(xué)合理的組織,綜合的運(yùn)用,才能收到卓越的功效。

    Matsuseet al[35](2010) combined UCMSCs and Matrigel into transpermeable tubes and transplanted it into transected murine sciatic nerve tissue specimens. The authors induced UCMSCs into cells with Schwann cell properties by using βmercaptoethanol, all-trans-retinoic acid and various cytokines. Subsequently, Matsuseet al[35]examined the effect of these induced UCMSCs and used two control groups; a positive control of human Schwann cells and a negative control of Matrigel alone. Thegroup assessed SFI values and compared immunoelectron micrographs. They concluded that the treatment group with Schwann Cell-UCMSCs group was equivalent to treatment with Schwann cells based on histological criteria and functional recovery.

    Table 1 Studies of umbilical cord derived mesenchymal stem cells in peripheral nerve axonotmesis and diabetic neuropathy in vivo

    UCMSCs: Umbilical cord derived mesenchymal stem cells; BDNF: Brain-derived neurotrophic factor; SFI: Sciatic function index; PBS: Phosphate buffered saline; PLC: Poly (DL-lactide-ε-caprolactone); WRL: Withdrawal reflex latency; EPT: Extensor postural thrust.

    Cuiet al[14](2018) and Panet al[50](2017) delivered UCMSCs using a collagen conduit. Cuiet al[14](2018) transplanted human UCMSCs into canine sciatic nerve gap models via a longitudinally orientated collagen conduit embedded with UCMSCs.Compound muscle action potential (CMAP) was found to be statistically greater in the UCMSC treated group compared with the collagen conduit only group. Panet al[50](2017) appraised the use of UCMSCs with a heparinised collagen conduits in transected rabbit recurrent laryngeal nerves. The authors assessed the effectiveness of passage-4 UCMSCs loaded on heparinised scaffold that released Nerve growth factor(NGF). Electromyograms at 8 wk revealed that treated lesions recovered normal nerve function. Biological markers of neurogenesis, including calcium-binding protein S100,neurofilament and AChE, were expressed at a greater level following treatment. Xiaoet al[51](2015) undertook a study exploring the effect of UCMSCs in a chitosan conduit interposed into the tibial nerve of a rabbit model. Xiaoet al[51]found that nerve conduction velocity was significantly higher in the treatment group. The myelin sheath thickness and the growth of axis bud were both increased in the UCMSC group. Pereiraet al[52](2014) used PLC as a conduit for UCMSCs in murine sciatic nerve crush models. The group compared differentiated and undifferentiated UCMSCs. They established no difference in the degree of nerve regeneration between UCMSC that were differentiated into neural-glial-like cells and undifferentiated UCMSC groups. Both UCMSC groups showed increased myelin sheath thickness and enhanced recovery in motor and sensory function.

    Two groups sought to investigate the use of UCMSCs embedded on a human amniotic membrane scaffold[5,53]. Liet al[53](2012) found significant improvements in SFI, CMAP and gastrocnemius muscle diameter in UCMSC-loaded scaffolds group compared to cell-free scaffolds. Liet al[6](2013) analysed how UCMSCs loaded on a human amniotic membrane scaffold affected the repair of a transected radial nerve in human subjects. Thirty-two patients with radial nerve injuries from radial shaft fractures were included in the study; twelve patients received neurolysis to remove neural scar tissue, and transplantation of UCMSCs on an amniotic membrane. The remainder 18 patients received neurolysis only. At 12 wk, the electrophysiological function of the UCMSC-treated group had improved electromyography readings. The muscular power, touch sensation and pain sensation were also significantly improved as compared to the neurolysis group.

    Studies of UCMSCs in diabetic neuropathy

    Figure 1 PRlSMA Flow diagram.

    One study explored the role of UCMSCs in femoral nerve neuropathy[54](Table 1). The authors modelled diabetic neuropathy in murine subjects by inducing diabetes with streptozotocin and created a dorsal hind foot ulcer through empyrosis. UCMSCs were delivered intravascularly through the femoral artery in the treatment group. Saline injections were used in the control group. Serum NGF and neurofilament 200 (NF-200) were measured by Enzyme Linked Immunosorbent Assay (ELISA). The results demonstrated that serum NGF and NF-200 increased in the UCMSC treated rats.Additionally, functional studies using electroneurogram showed that femoral nerve conduction was improved in the UCMSC subjects.

    DISCUSSION

    The studies in this review reported compelling positive outcomes for the use of human UCMSC to repair peripheral nerve lesions. None of the studies reported immunogenic nor significant complications. While the source cell utilised was consistent among the studies, there were significant variability in cell treatment and methods of transplantation with variable effectiveness as determined by several different outcome measures. There was also moderate heterogeneity in thein vivomodels used. It is therefore difficult to draw conclusions on the optimal method of cell delivery to nerve lesions. Nevertheless, it does imply that UCMSCs are a useful cell source.

    The process of cell harvest did not vary greatly between the studies. Human umbilical cord and umbilical cord blood are generally considered medical waste and so there are minimal ethical barriers to tissue sampling[55]. This provides a practical advantage for the use of UCMSCs and may explain why it is commonly used in tissue engineering experiments. The biochemical properties of UCMSCs may also be of advantage as studies comparing different source cells for MSCs have found UCMSCs to possess a greater ability to proliferateex vivoand express a higher level of Vascular Endothelial Growth Factor (VEG-F) and Human Growth Factor (HGF) at late passages[56,57]. One study in this review compared UCMSCs to BMMSCs in sciatic nerve regeneration and found BMMSCs to produce superior results. The authors however, evaluated cell architecture on microscopy but did not carry out nerve conduction studies or functional analysis which may better inform clinical relevance[11]. UCMSCs also appear to have a different multilineage differentiation profiles to other MSC, and is able to be induced into neuron-like cellsin vitro, which may favour applications in nerve regeneration[58]. There is some evidence to suggest that characteristics of the donor affect the ability of UCMSCs to differentiate. For example, undifferentiated UCMSCs obtained from patients with pre-eclampsia may produce greater levels of neuronal markers[59]. Therefore, exploration of different patient and gestational characteristics, such as age could help determine optimal source conditions.

    Figure 2 Summary of overall bias.

    There is no set protocol for theex vivoexpansion of UCMSCs in the literature. In our article, UCMSCs were generally transplanted between the third and fifth passage.Indeed, the gene expression profile of UCMSC is known to vary according to the number of passages, with some studies showing that UCMSCs do not express CD105,a defining marker for MSCs, until passage-5[60]. In view of this, it would be meaningful to identify and investigate the expression of important neurogenic markers as a function of stages of passage in future experiments. Some of the studies in this review pre-treated UCMSCs in order to induce them into particular cellular phenotypes prior to transplantation. Pereiraet al[52]and Gartneret al[49]utilised a similar culture protocol and pre-treated UCMSCs with neurogenic media. They observed a neuroglial-like morphology on microscopy and a transcriptomic profile showing upregulation of neuroglial genes including Glial Fibrillary Acidic Protein (GFAP), Growth Associated Protein 43 (GAP43) and Neuronal Specific Nuclear Protein (NeuN). Both studies found differentiated MSCs to be more effective than undifferentiated UCMSCs. Aside from gene expression, it would be important to clarify the exact mechanism through which these differentiated cells act to promote nerve regeneration. The optimal protocol for differentiation is also ill-defined as Matsuseet al[35]used a different set of culture condition to induce UCMSCs into Schwann-like cells and found the latter to be more effective. Furthermore, there is a lack of agreement on the primary mode of action of MSCs in promoting nerve regeneration. It is unclear whether transplanted cells directly replicate and replace cells in the lesion. Some experiments of optic nerve lesions suggest that transplanted MSCs remain local and replicate[61]. Emergingin vitroevidence points towards paracrine effects as the predominant mechanism of action. It appears that pre-treatment of Schwann cells with UCMSC conditioned media increases BDNF and NGF expression which are surrogate measures of neurogenic potential[29]. In our review, Maket al[17]examined the effectiveness of UCMSC-derived exosomes in nerve repair. Through peripheral intravenous injection of UCMSC EVs,they demonstrated that it could act systemically to encourage nerve regeneration at a nerve gap without off-site complications. As the use of EVs in this endeavour gains attention, further studies would be required to establish a dose-response relationship and the best method for delivering EVs to lesions.

    Figure 3 Risk of bias in individual studies.

    It is difficult to determine the best UCMSC implantation method. Our review has captured studies that directly implanted UCMSCs and reported good outcomes.Studies investigating the use of conduits to guide nerve regeneration suggest that this is superior to direct implantation of MSCs alone[14,50]. The use of conduit that elude growth factors such as NGF along with UCMSC implantation appear to confer additional benefit[50]. Additionally, intravenous injection of UCMSC-EVs at a peripheral site also produce positive outcomes[17]. Interestingly, a comparison of local and intravenous BMMSC administration in sciatic nerve injury models suggest that systemic treatment provides a more significant improvement in nerve conduction,whereas local treatment improved neuronal fibre counts[62]. Other experiments have shown that peripherally injected MSCs localise to nerve lesions in murine models of sciatic nerve injury[63]. It could be inferred from these findings that there are differing mechanisms and sites of action for the two methods of implantation, suggesting that a treatment regime including both delivery methods concomitantly may produce the best outcome.

    There are several issues pertaining to translating the findings derived fromin vivoanimal models for therapeutic application in humans. The majority of studies in our review employed a murine surgical sciatic nerve defect model to assess nerve regeneration. The critical nerve gap length, defined as a gap across which regeneration would not occur without nerve grafting or bridging is considered to be greater in humans than murine subjects[64,65]. Therefore, studies assessing murine nerve gaps may overestimate the therapeutic potential of treatments. Furthermore, it may be difficult to scale-up effective concentrations of transplanted UCMSCs to humans. In a study of rat nerve defects treated with tacrolimus, functional recovery tapers off at 9 wk following treatment and becomes indistinguishable from untreated rats at 10 wk[66]. Therefore, at later time points, which are more relevant to clinical presentations of nerve injury, the regenerative biology of murine nerve appears to differ from that of humans. Our interpretation from thein vivoanimal studies in this review is complicated by the use of the sciatic nerve, which possesses a sensory and motor component, and thus renders functional analysis difficult. It is conceivable for sensory loss to mask a post-surgical motor defect on gait analysis, similarly, it may be possible for loss in motor function to cause underestimation of sensory recovery.Owing to the heterogeneity in starting points for different functional measures, a pooled analysis of quantitative outcomes could not be performed in this review.Therefore, clinically relevant and robust quantifiable outcome measures remain a significant barrier to the reliability of animal studies. One study in this review assessed UCMSC transplantation in human radial nerve defects and reported improved motor and sensory function and electrophysiological measures[53]. The group however, delivered the MSCs through a scaffold, and did not compare outcomes with a control group of the scaffold alone.

    According to the results of our risk of bias analysis, 13 of 14 studies had a moderate risk of bias, and one study had a high risk of bias (Figure 1). The reporting of outcome measures contributed to an increased risk of bias in all studies, as most of the studies reported improvement in some but not all outcomes yet concluded that UCMSCs were effective overall. This could be owing to the significant heterogeneity in cell treatment and delivery methods which as the literature suggests, could contribute to different aspects of nerve regeneration.

    Table 2 Studies of umbilical cord derived mesenchymal stem cells in Peripheral Nerve Neurotmesis in vivo

    Li et al[53],2012 Case Control Human Murine 40 amnion tube with UCMSCs 40 amnion tube with saline implant Human umbilical cords obtained from fullterm deliveries Passage 3-4 UCMSCs were cultured and loaded on an amniotic scaffold Xenogenic transplantati on into transected sciatic nerve tissue specimens 20 Significant improvement in SFI and CMAP in UCMSC group compared to control.Gradual improvement in threshold stimulus and maximum stimulus intensity in UCMSC group compared to control Li et al[6],2013 Case Control Human Human 12 neurolysis followed by 10 mL UCMSCs injection of 1.75 × 107 cells 20 neurolysis only Human umbilical cords obtained from fullterm deliveries Passage 2 UCMSCs were loaded on an amniotic membrane scaffold.Both groups received 3 days of oral cephalosporin Allogenic transplantati on into radial nerve injury following radial shaft fracture 12 Significant improvement in muscular strength,touch and pain sensations in UCMSC group compared to control.Improved electrophysiologica l function in UCMSC group as compared to control Matsuse et al[35], 2010 Case Control Human Murine 6 UCMSCs;10 Induced UCMSC 6 negative control; 5 induced UCMSC Wharton’s Jelly extracted from umbilical cords of fullterm caesarean deliveries Passage 3 UCMSCs were induced into Schwannlike cells Xenogenic transplantation into transected sciatic nerve tissue specimens 3 Significant improvement in SFI in all treated as compared to control with the greatest improvement in UCMSC group Xiao et al[51],2015 Case Control Human Rabbit 10 chitosan conduit anastomosis bridge filled with UCMSCs 10 chitosan conduit anastomosis only; 10 untreated Not specified UCMSCs were loaded into a chitosan conduit Xenogenic transplantati on into tibialcommon peroneal nerve endto-side anastomosis 12 Significant improvement in myelin sheath thickness,Schwann cell growth,growth of axis bud and growth velocity of regenerated fibre in UCMSC group compared to controls. No significant difference observed between either control groups

    UCMSCs: Umbilical cord derived mesenchymal stem cells; LOCC: Longitudinally orientated collagen conduit; SFI: Sciatic function index; NGF: Nerve growth factor; PBS: Phosphate buffered saline; HC: Heparinized collagen; PLC: Poly (DL-lactide-ε-caprolactone); EV: Extracellular vesicle.

    In conclusion, while there are homeostatic responses that promote nerve regeneration following injury, the body’s natural capacity is inadequate for the recovery of satisfactory nerve function. The evidence summarised in this systematic review supports the notion that UCMSC transplantation is an effective treatment option for nerve injury. Several barriers must be overcome before these findings can be translated into the clinical setting. Importantly, development of a reliablein vivoanimal model, and a standardised method of assessing nerve regeneration would allow the optimal method of cell transplantation to be determined.

    ARTICLE HIGHLIGHTS

    Research background

    Peripheral nerve injury can be a debilitating condition. Traditional treatment options are often ineffective. There is an urgent need for new treatment modalities. Mesenchymal stem cell (MSC)transplantation holds promise as a cell-based regenerative approach in treating nerve lesions.MSCs can be sourced from various tissues, and this may affect their regenerative capacity. Here,we appraise thein vivoevidence for the use of human umbilical cord-derived MSCs (UCMSCs)in peripheral nerve regeneration.

    Research motivation

    There is contention regarding the optimal cell-source for the harvest of MSCs. Some evidence suggests that MSCs from certain tissue types have superior neurogenic capacity. It is critical that we determine the best cell-source for nerve repair, in order to facilitate an efficient production protocol and maximise clinical benefit.

    Research objectives

    To investigate whether UCMSCs are effective in nerve regeneration inin vivomodels of nerve injury.

    Research methods

    We performed a systematic literature review according to the PRISMA statement. A search was conducted on three databases (PubMed, EMBASE and Web of Science) by two independent investigators from inception to September 2019 for studies examining the use of UCMSCs inin vivomodels of nerve injury. The evidence was appraised using Cochrane’s RoB 2.0 Tool.

    Research results

    A total of 14 studies were included in the review, with a total of 279 subjects. The studies reported that transplantation of human umbilical cord MSCs were effective in regenerating nerve lesions. There were general improvements in histological and functional outcomes. The studies did not report significant complications.

    Research conclusions

    Human umbilical cord-derived MSCs were effective in repairing nerve lesions in both animal and human models of nerve injury. Additional studies are required to correlate histological outcomes with functional improvements, as not all studies assessed both. More human studies are necessary to inform the efficacy in humans. High quality randomized controlled trials would be instructive in this case. Long-term follow up in these types of study will help inform the safety of MSC transplantation.

    Research perspectives

    There is limited evidence examining the use of MSCs derived from other tissues in their capacity to regenerate nerve lesions. Further studies comparing different tissue cell-source directly would be highly informative.In vitrostudies of MSC-biomaterial scaffolds may aid the development of more efficient MSC delivery methods. As the nature of nerve injury can vary significantly, the approach to transplantation, such as dose delivery may need to be catered to the individual lesion. Studies comparing the effect of MSCs on differentin vivomodels could help delineate this.

    猜你喜歡
    所帶科學(xué)合理閱讀課
    基于主題意義的“生本”高中英語閱讀課
    初中英語閱讀課有效詞匯教學(xué)策略
    深山狩獵
    薪酬管理在企業(yè)人才激勵中發(fā)揮的作用
    淺談小學(xué)語文高年級課前預(yù)習(xí)有效指導(dǎo)的研究
    速讀·中旬(2017年3期)2017-05-06 08:18:53
    生活化教學(xué)法在小學(xué)科學(xué)教育中的作用
    “電流和電路”“電壓電阻”易錯題練習(xí)
    合作學(xué)習(xí)在大學(xué)德語閱讀課中的應(yīng)用
    實(shí)現(xiàn)小學(xué)數(shù)學(xué)課堂教學(xué)的高效性
    AneCan戀愛觀大調(diào)查!
    秀·媛尚(2013年6期)2013-09-12 03:17:06
    亚洲精品一二三| 一边摸一边抽搐一进一出视频| 免费黄色在线免费观看| videos熟女内射| 国产成人精品福利久久| 波多野结衣一区麻豆| 日本猛色少妇xxxxx猛交久久| 亚洲自偷自拍图片 自拍| 亚洲av在线观看美女高潮| 一本一本久久a久久精品综合妖精| 制服丝袜香蕉在线| 精品午夜福利在线看| 精品久久久精品久久久| 女人高潮潮喷娇喘18禁视频| 久久精品人人爽人人爽视色| 精品国产一区二区久久| 99九九在线精品视频| 国产爽快片一区二区三区| 精品少妇黑人巨大在线播放| 街头女战士在线观看网站| 久久久久精品国产欧美久久久 | 这个男人来自地球电影免费观看 | 黄片小视频在线播放| 亚洲精品aⅴ在线观看| 久久久久视频综合| 欧美日韩国产mv在线观看视频| 久久久久久人人人人人| 国产一区二区激情短视频 | 亚洲精品视频女| www.精华液| 久久久久网色| 日韩一区二区视频免费看| 午夜福利网站1000一区二区三区| 国产精品免费大片| 9热在线视频观看99| 天天躁狠狠躁夜夜躁狠狠躁| 久久人妻熟女aⅴ| 成人国产av品久久久| 大香蕉久久网| 日韩伦理黄色片| 天美传媒精品一区二区| 三上悠亚av全集在线观看| 国产在线视频一区二区| 91国产中文字幕| 久久热在线av| 欧美日韩亚洲高清精品| 午夜福利在线免费观看网站| 桃花免费在线播放| 老司机亚洲免费影院| 亚洲欧美色中文字幕在线| 欧美激情高清一区二区三区 | 少妇被粗大的猛进出69影院| 亚洲激情五月婷婷啪啪| 国产日韩一区二区三区精品不卡| 欧美日韩国产mv在线观看视频| 一本久久精品| 久久久久视频综合| www.熟女人妻精品国产| 色视频在线一区二区三区| 亚洲国产欧美网| 自线自在国产av| 亚洲中文av在线| 久久久久精品久久久久真实原创| 亚洲精品av麻豆狂野| 亚洲国产成人一精品久久久| 成人亚洲欧美一区二区av| 99久久精品国产亚洲精品| 咕卡用的链子| 日韩 欧美 亚洲 中文字幕| 欧美xxⅹ黑人| 夫妻午夜视频| 妹子高潮喷水视频| 在线精品无人区一区二区三| 亚洲国产av新网站| 最近手机中文字幕大全| 久久婷婷青草| 成人手机av| 久久99热这里只频精品6学生| 亚洲精品国产区一区二| 高清视频免费观看一区二区| 国产精品久久久久久精品电影小说| 精品福利永久在线观看| 深夜精品福利| 成人亚洲精品一区在线观看| 久久99一区二区三区| 天天躁夜夜躁狠狠久久av| 美女主播在线视频| 国产精品免费大片| 久久人人爽av亚洲精品天堂| 久久影院123| 精品少妇内射三级| 久久久久网色| 老熟女久久久| 免费少妇av软件| 国产免费又黄又爽又色| 看十八女毛片水多多多| 男女之事视频高清在线观看 | 亚洲久久久国产精品| 观看av在线不卡| 国产免费视频播放在线视频| 国产免费又黄又爽又色| 国产精品无大码| 免费观看性生交大片5| 黑人巨大精品欧美一区二区蜜桃| 国产成人精品久久久久久| 亚洲av福利一区| 国产精品99久久99久久久不卡 | 中文字幕高清在线视频| 午夜影院在线不卡| 18在线观看网站| 久久人人爽av亚洲精品天堂| videos熟女内射| 亚洲一码二码三码区别大吗| 国产精品欧美亚洲77777| 麻豆精品久久久久久蜜桃| 日本黄色日本黄色录像| av片东京热男人的天堂| 五月天丁香电影| 亚洲人成网站在线观看播放| 哪个播放器可以免费观看大片| 黄色毛片三级朝国网站| 免费少妇av软件| 视频在线观看一区二区三区| 久久 成人 亚洲| 国产日韩欧美亚洲二区| 亚洲一区二区三区欧美精品| 91精品国产国语对白视频| videos熟女内射| 交换朋友夫妻互换小说| av国产精品久久久久影院| www.自偷自拍.com| 人成视频在线观看免费观看| 天美传媒精品一区二区| 亚洲欧美色中文字幕在线| 男女边摸边吃奶| 精品一区二区三区av网在线观看 | 国产 一区精品| 国产成人免费无遮挡视频| videos熟女内射| 美女大奶头黄色视频| 国产日韩一区二区三区精品不卡| 亚洲成人免费av在线播放| 伊人亚洲综合成人网| 国产日韩一区二区三区精品不卡| 亚洲国产精品国产精品| 久久久亚洲精品成人影院| 国产成人av激情在线播放| 狠狠精品人妻久久久久久综合| 欧美日韩亚洲综合一区二区三区_| 2018国产大陆天天弄谢| 女人被躁到高潮嗷嗷叫费观| 亚洲欧美精品自产自拍| 精品一区二区三区av网在线观看 | 别揉我奶头~嗯~啊~动态视频 | av卡一久久| 天天影视国产精品| 午夜av观看不卡| 久久精品国产综合久久久| 欧美97在线视频| 香蕉国产在线看| 精品少妇内射三级| 国产成人午夜福利电影在线观看| 操美女的视频在线观看| 99热全是精品| 欧美日韩综合久久久久久| 国产成人啪精品午夜网站| 免费看av在线观看网站| 亚洲精品aⅴ在线观看| 青青草视频在线视频观看| 亚洲av成人不卡在线观看播放网 | 在线天堂最新版资源| 激情五月婷婷亚洲| 亚洲少妇的诱惑av| 两性夫妻黄色片| av国产久精品久网站免费入址| h视频一区二区三区| 日本色播在线视频| 久久久久网色| 国产免费现黄频在线看| 男女国产视频网站| 亚洲伊人色综图| 欧美在线一区亚洲| 亚洲欧洲日产国产| 黑人巨大精品欧美一区二区蜜桃| 国产精品久久久久久人妻精品电影 | 一区二区三区乱码不卡18| 日韩 欧美 亚洲 中文字幕| 国产 一区精品| 免费在线观看视频国产中文字幕亚洲 | 一级黄片播放器| 国产一区二区激情短视频 | 一级毛片 在线播放| 免费黄色在线免费观看| 国产伦人伦偷精品视频| 啦啦啦在线免费观看视频4| 国产一区有黄有色的免费视频| 国产精品偷伦视频观看了| 一区二区三区乱码不卡18| 18禁国产床啪视频网站| 大码成人一级视频| 亚洲美女搞黄在线观看| 成人手机av| 超碰成人久久| 国产免费现黄频在线看| 91老司机精品| 青春草视频在线免费观看| 男人操女人黄网站| 精品少妇内射三级| 精品国产一区二区三区四区第35| 日韩精品有码人妻一区| 在线观看www视频免费| 在线天堂最新版资源| 亚洲情色 制服丝袜| 丁香六月天网| 亚洲一卡2卡3卡4卡5卡精品中文| 日韩 亚洲 欧美在线| 日韩,欧美,国产一区二区三区| 中文精品一卡2卡3卡4更新| 国产成人欧美| 亚洲激情五月婷婷啪啪| 国产精品久久久久成人av| 国产精品久久久人人做人人爽| 人人妻人人澡人人看| 日韩 亚洲 欧美在线| 人人妻人人澡人人爽人人夜夜| √禁漫天堂资源中文www| 国产深夜福利视频在线观看| 国产精品无大码| 2021少妇久久久久久久久久久| 99re6热这里在线精品视频| av又黄又爽大尺度在线免费看| 欧美亚洲日本最大视频资源| 男的添女的下面高潮视频| 日日爽夜夜爽网站| 亚洲国产精品999| 在线观看三级黄色| 男女午夜视频在线观看| av福利片在线| 黄网站色视频无遮挡免费观看| 欧美日韩一区二区视频在线观看视频在线| 国产成人免费无遮挡视频| 少妇被粗大的猛进出69影院| 午夜激情久久久久久久| 十八禁高潮呻吟视频| av在线观看视频网站免费| 久久精品亚洲熟妇少妇任你| 久久国产精品大桥未久av| 久久热在线av| av视频免费观看在线观看| 桃花免费在线播放| 亚洲专区中文字幕在线 | 天天躁夜夜躁狠狠躁躁| 大香蕉久久成人网| 国产黄色视频一区二区在线观看| 在线看a的网站| 啦啦啦视频在线资源免费观看| 另类亚洲欧美激情| 狂野欧美激情性xxxx| 在线亚洲精品国产二区图片欧美| 国产精品无大码| 国产 精品1| 大陆偷拍与自拍| 天美传媒精品一区二区| 久久毛片免费看一区二区三区| 18禁裸乳无遮挡动漫免费视频| 老汉色∧v一级毛片| 精品福利永久在线观看| 五月天丁香电影| 亚洲成色77777| 青青草视频在线视频观看| 亚洲精品久久成人aⅴ小说| 国产成人免费观看mmmm| 黄色 视频免费看| 一级,二级,三级黄色视频| 高清欧美精品videossex| 黄色视频不卡| 免费观看性生交大片5| 久久毛片免费看一区二区三区| 少妇的丰满在线观看| 中文字幕亚洲精品专区| 美女主播在线视频| 悠悠久久av| 日韩大码丰满熟妇| 亚洲欧美一区二区三区国产| 国产成人精品久久二区二区91 | 国产在线免费精品| 亚洲 欧美一区二区三区| 国产xxxxx性猛交| 国产一区二区在线观看av| 亚洲精品中文字幕在线视频| 免费高清在线观看视频在线观看| 国产亚洲av高清不卡| 午夜福利网站1000一区二区三区| 一本大道久久a久久精品| 成人亚洲精品一区在线观看| 久久韩国三级中文字幕| 女性生殖器流出的白浆| 在线观看免费高清a一片| 欧美激情 高清一区二区三区| 亚洲精品国产一区二区精华液| 亚洲少妇的诱惑av| 99热网站在线观看| 国产乱人偷精品视频| 亚洲天堂av无毛| 国产亚洲av高清不卡| 中文天堂在线官网| 亚洲欧美中文字幕日韩二区| 免费女性裸体啪啪无遮挡网站| 少妇猛男粗大的猛烈进出视频| 99国产精品免费福利视频| 2018国产大陆天天弄谢| 久久婷婷青草| 国产精品欧美亚洲77777| 巨乳人妻的诱惑在线观看| 七月丁香在线播放| 久久精品国产a三级三级三级| 婷婷色综合大香蕉| 欧美成人精品欧美一级黄| 超色免费av| 国产精品久久久久久精品电影小说| 中文字幕人妻丝袜制服| av电影中文网址| 成人免费观看视频高清| 久久国产亚洲av麻豆专区| 亚洲在久久综合| 欧美久久黑人一区二区| 尾随美女入室| 欧美久久黑人一区二区| 在线精品无人区一区二区三| 免费观看性生交大片5| 亚洲,欧美,日韩| 中文字幕最新亚洲高清| 欧美激情 高清一区二区三区| 激情五月婷婷亚洲| 欧美老熟妇乱子伦牲交| 9色porny在线观看| 不卡视频在线观看欧美| 综合色丁香网| 黄色视频不卡| 亚洲成人手机| 国产成人精品在线电影| 人妻人人澡人人爽人人| 你懂的网址亚洲精品在线观看| 精品国产国语对白av| 久久久国产精品麻豆| 91精品国产国语对白视频| 九草在线视频观看| 91精品伊人久久大香线蕉| 美女高潮到喷水免费观看| av国产精品久久久久影院| 亚洲精品美女久久久久99蜜臀 | 久久久久久人人人人人| 视频区图区小说| 久久久久久久大尺度免费视频| 香蕉国产在线看| 啦啦啦啦在线视频资源| 成人黄色视频免费在线看| 妹子高潮喷水视频| av福利片在线| 亚洲伊人色综图| 精品久久久久久电影网| 极品少妇高潮喷水抽搐| 18禁裸乳无遮挡动漫免费视频| 日本91视频免费播放| 女人精品久久久久毛片| 国产亚洲av片在线观看秒播厂| 桃花免费在线播放| 国产日韩欧美在线精品| av网站在线播放免费| 免费少妇av软件| 啦啦啦在线观看免费高清www| 久久国产精品男人的天堂亚洲| 精品久久蜜臀av无| 成年动漫av网址| 一边亲一边摸免费视频| 久久久欧美国产精品| 亚洲欧洲精品一区二区精品久久久 | 亚洲一码二码三码区别大吗| 水蜜桃什么品种好| 欧美日韩成人在线一区二区| 老司机靠b影院| 99香蕉大伊视频| 午夜精品国产一区二区电影| 极品人妻少妇av视频| 精品亚洲成a人片在线观看| 亚洲免费av在线视频| 日本91视频免费播放| 国产一区亚洲一区在线观看| 一区二区日韩欧美中文字幕| av天堂久久9| 国产伦理片在线播放av一区| 无限看片的www在线观看| 大陆偷拍与自拍| 夜夜骑夜夜射夜夜干| 亚洲成色77777| 咕卡用的链子| 午夜福利网站1000一区二区三区| 一级黄片播放器| 中文欧美无线码| 晚上一个人看的免费电影| 又大又黄又爽视频免费| 久久久国产欧美日韩av| 免费久久久久久久精品成人欧美视频| 国产成人午夜福利电影在线观看| 久久影院123| 国产精品二区激情视频| 午夜福利视频精品| 国产熟女欧美一区二区| 亚洲一区中文字幕在线| 亚洲av中文av极速乱| 国产精品国产三级国产专区5o| av在线观看视频网站免费| 国产精品久久久久久精品古装| 99香蕉大伊视频| 99久久人妻综合| 亚洲伊人久久精品综合| 男人添女人高潮全过程视频| 国产视频首页在线观看| 欧美日本中文国产一区发布| 9191精品国产免费久久| 你懂的网址亚洲精品在线观看| 久久久久网色| 免费人妻精品一区二区三区视频| 欧美日韩亚洲高清精品| 七月丁香在线播放| 欧美黑人精品巨大| 青青草视频在线视频观看| 黄色一级大片看看| 夜夜骑夜夜射夜夜干| 国产精品久久久久久人妻精品电影 | 久久人妻熟女aⅴ| 丝袜脚勾引网站| 又大又爽又粗| 欧美 日韩 精品 国产| 亚洲国产av影院在线观看| 在线观看人妻少妇| 一级毛片电影观看| 看免费成人av毛片| av国产久精品久网站免费入址| 成年美女黄网站色视频大全免费| 亚洲精品成人av观看孕妇| 波多野结衣一区麻豆| 99久久人妻综合| 777米奇影视久久| 国产又色又爽无遮挡免| 国产av国产精品国产| 美女脱内裤让男人舔精品视频| av不卡在线播放| 久久久亚洲精品成人影院| 超碰97精品在线观看| 国产极品粉嫩免费观看在线| tube8黄色片| 夫妻午夜视频| 亚洲国产日韩一区二区| 超碰成人久久| 超色免费av| 国产爽快片一区二区三区| 一本色道久久久久久精品综合| 中文字幕人妻熟女乱码| 国产黄色视频一区二区在线观看| 国产精品一国产av| 丁香六月天网| 男女国产视频网站| 日韩,欧美,国产一区二区三区| 咕卡用的链子| 日韩av在线免费看完整版不卡| 国产精品久久久久久久久免| 十分钟在线观看高清视频www| 日韩一区二区视频免费看| 欧美日韩视频高清一区二区三区二| 国产一区二区三区综合在线观看| 欧美乱码精品一区二区三区| 国产精品久久久久久人妻精品电影 | 精品国产露脸久久av麻豆| 丝袜脚勾引网站| 国产精品无大码| 日日啪夜夜爽| 色综合欧美亚洲国产小说| 亚洲国产精品999| 国产成人免费无遮挡视频| 成年美女黄网站色视频大全免费| 在线免费观看不下载黄p国产| 香蕉国产在线看| 97在线人人人人妻| 黑人猛操日本美女一级片| 亚洲在久久综合| 美国免费a级毛片| 麻豆av在线久日| 国产欧美日韩一区二区三区在线| 亚洲av福利一区| 人妻一区二区av| 午夜91福利影院| 久久天躁狠狠躁夜夜2o2o | 午夜福利免费观看在线| 亚洲欧美中文字幕日韩二区| 亚洲一卡2卡3卡4卡5卡精品中文| 国产一区有黄有色的免费视频| 搡老乐熟女国产| videosex国产| 曰老女人黄片| 在线观看免费午夜福利视频| 国产淫语在线视频| 国产av国产精品国产| 精品免费久久久久久久清纯 | 国产欧美亚洲国产| 在现免费观看毛片| av免费观看日本| 一级爰片在线观看| 欧美日韩视频高清一区二区三区二| 人体艺术视频欧美日本| 亚洲欧美激情在线| 免费不卡黄色视频| 赤兔流量卡办理| 啦啦啦视频在线资源免费观看| 最近最新中文字幕大全免费视频 | 欧美激情极品国产一区二区三区| 国产精品嫩草影院av在线观看| 国产黄频视频在线观看| 丝袜喷水一区| 丰满迷人的少妇在线观看| www.av在线官网国产| av不卡在线播放| 日本av免费视频播放| 涩涩av久久男人的天堂| 久久热在线av| 久久人妻熟女aⅴ| 国产无遮挡羞羞视频在线观看| 日日撸夜夜添| 亚洲欧美成人精品一区二区| 一区二区三区乱码不卡18| 欧美亚洲 丝袜 人妻 在线| av在线app专区| 国产人伦9x9x在线观看| 国产精品av久久久久免费| 在现免费观看毛片| 亚洲激情五月婷婷啪啪| 亚洲精品在线美女| 国产极品粉嫩免费观看在线| 亚洲精品一区蜜桃| 最近最新中文字幕免费大全7| 精品国产一区二区三区四区第35| 国产精品免费大片| 久久久欧美国产精品| 中国国产av一级| 亚洲成av片中文字幕在线观看| 精品少妇久久久久久888优播| 久久久久精品人妻al黑| 亚洲 欧美一区二区三区| 久久精品国产亚洲av涩爱| xxxhd国产人妻xxx| av有码第一页| 欧美乱码精品一区二区三区| 最近最新中文字幕大全免费视频 | 国产成人欧美| 日韩不卡一区二区三区视频在线| 十八禁高潮呻吟视频| 在线观看三级黄色| 久久毛片免费看一区二区三区| 久久人人爽av亚洲精品天堂| 19禁男女啪啪无遮挡网站| 午夜日韩欧美国产| 黄频高清免费视频| 777久久人妻少妇嫩草av网站| 欧美日韩成人在线一区二区| 国产欧美日韩一区二区三区在线| 亚洲伊人久久精品综合| 亚洲第一av免费看| 国产精品免费大片| 久久av网站| 中文字幕精品免费在线观看视频| 男人操女人黄网站| 亚洲精品久久成人aⅴ小说| 大片免费播放器 马上看| 超色免费av| 免费少妇av软件| 国产成人免费无遮挡视频| 亚洲一区二区三区欧美精品| 免费黄频网站在线观看国产| 国产99久久九九免费精品| 日韩人妻精品一区2区三区| 久久精品国产a三级三级三级| 亚洲av电影在线观看一区二区三区| 久久人妻熟女aⅴ| 中文字幕制服av| 国产亚洲午夜精品一区二区久久| 久久国产精品大桥未久av| 啦啦啦啦在线视频资源| 一边亲一边摸免费视频| 亚洲人成77777在线视频| 建设人人有责人人尽责人人享有的| 国产精品亚洲av一区麻豆 | 无限看片的www在线观看| 美女主播在线视频| 午夜免费男女啪啪视频观看| 日韩免费高清中文字幕av| 免费观看a级毛片全部| 精品一区二区三卡| 国产免费一区二区三区四区乱码| 亚洲美女黄色视频免费看| 在线观看免费视频网站a站| 咕卡用的链子| 69精品国产乱码久久久| 男女无遮挡免费网站观看| 久久久久久久精品精品| 亚洲激情五月婷婷啪啪| 欧美精品高潮呻吟av久久| 91老司机精品| 国产av码专区亚洲av| 一级a爱视频在线免费观看| 久久这里只有精品19| a级片在线免费高清观看视频| 一本久久精品| 十八禁人妻一区二区| 国产乱人偷精品视频| 国产亚洲欧美精品永久|