Abstract Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area. 

Clinical applications of stem cell-derived exosomes

MicroRNAs (miRNAs) are a group of small non-coding RNAs that regulate gene expression by targeting mRNA. Moreover, it has been shown that miRNAs expression are changed in various diseases, such as cancers, autoimmune disease, infectious diseases, and neurodegenerative Diseases. The suppression of miRNA function can be easily attained by utilizing of anti-miRNAs. In contrast, an enhancement in miRNA function can be achieved through the utilization of modified miRNA mimetics. The discovery of appropriate miRNA carriers in the body has become an interesting subject for investigators. Exosomes (EXOs) therapeutic efficiency and safety for transferring different cellular biological components to the recipient cell have attracted significant attention for their capability as miRNA carriers. Mesenchymal stem cells (MSCs) are recognized to generate a wide range of EXOs (MSC-EXOs), showing that MSCs may be effective for EXO generation in a clinically appropriate measure as compared to other cell origins. MSC-EXOs have been widely investigated because of their immune attributes, tumor-homing attributes, and flexible characteristics. In this article, we summarized the features of miRNAs and MSC-EXOs, including production, purification, and miRNA loading methods of MSC-EXOs, and the modification of MSC-EXOs for targeted miRNA delivery in various diseases. Video abstract. 

/pdf/the-potential-use-of-mesenchymal-stem-cells-derived-exosomes-1fimanih.pdf

The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases

Traumatic spinal cord injury (SCI) can cause severe neurological impairments. Clinically available treatments are quite limited, with unsatisfactory remediation effects. Residing endogenous neural stem/progenitor cells (eNSPCs) tend to differentiate towards astrocytes, leaving only a small fraction towards oligodendrocytes and even fewer towards neurons; this has been suggested as one of the reasons for the failure of autonomous neuronal regeneration. Thus, finding ways to recruit and facilitate the differentiation of eNSPCs towards neurons has been considered a promising strategy for the noninvasive and immune-compatible treatment of SCI. The present manuscript first introduces the responses of eNSPCs after exogenous interventions to boost endogenous neurogenesis in various SCI models. Then, we focus on state-of-art manipulation approaches that enhance the intrinsic neurogenesis capacity and reconstruct the hostile microenvironment, mainly consisting of pharmacological treatments, stem cell-derived exosome administration, gene therapy, functional scaffold implantation, inflammation regulation, and inhibitory element delineation. Facing the extremely complex situation of SCI, combined treatments are also highlighted to provide more clues for future relevant investigations.

Recent advances in endogenous neural stem/progenitor cell manipulation for spinal cord injury repair

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs as transporters of Tf to the central nervous system (CNS) through the intranasal (IN) route. For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTf enter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways, releasing the cargo and exerting a pro-maturation effect on OPCs. These effects were also observed in vivo using the animal model of demyelination induced by cuprizone (CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasma reached the brain parenchyma, internalizing into OPCs, promoting their differentiation, and accelerating remyelination. Furthermore, in vivo experiments demonstrated that EVs protected the Tf cargo and significantly reduced the amount of Tf required to induce remyelination as compared to soluble Tf. Collectively, these findings unveil EVs as functional nanocarriers of Tf to induce remyelination.

Remyelinating effect driven by transferrin-loaded extracellular vesicles.

Exosomes are membrane-bound vesicles secreted by various cell types into the extracellular environment, and contain kinds of bioactive molecules. These molecules can mediate various biological processes such as cell differentiation, proliferation, and survival, making them attractive for tissue regeneration and repair. Owing to their nanoscale-size, bilayer membrane structure and receptor-mediated transcytosis, exosomes can cross the blood-brain barrier (BBB) and reach the central nervous system (CNS) tissue. Additionally, exosomes can be loaded with exogenous substances after isolation. It has been suggested that exosomes could be used as natural drug carriers to transport therapeutic agents across the BBB and have great potential for CNS disease therapy by promoting tissue regeneration and repair. Herein, we discuss perspectives on therapeutic strategies to treat neurodegenerative disease or spinal cord injury using a variety of cell types-derived exosomes with kinds of exosomal contents, as well as engineering strategies of specific functional and exosome administration routes.&#xD. 

The role of exosomes in central nervous system tissue regeneration and repair

Objective The purpose of this study was to retrospectively collect the relevant clinical data of lumbar disc herniation (LDH) patients treated with the tubular microdiscectomy (TMD) technique, and to develop and validate a prediction model for predicting the treatment improvement rate of TMD in LDH patients at 1 year after surgery. Methods Relevant clinical data of LDH patients treated with the TMD technology were retrospectively collected. The follow-up period was 1 year after surgery. A total of 43 possible predictors were included, and the treatment improvement rate of the Japanese Orthopedic Association (JOA) score of the lumbar spine at 1 year after TMD was used as an outcome measure. The least absolute shrinkage and selection operator (LASSO) method was used to screen out the most important predictors affecting the outcome indicators. In addition, logistic regression was used to construct the model, and a nomogram of the prediction model was drawn. Results A total of 273 patients with LDH were included in this study. Age, occupational factors, osteoporosis, Pfirrmann classification of intervertebral disc degeneration, and preoperative Oswestry Disability Index (ODI) were screened out from the 43 possible predictors based on LASSO regression. A total of 5 predictors were included while drawing a nomogram of the model. The area under the ROC curve (AUC) value of the model was 0.795. Conclusions In this study, we successfully developed a good clinical prediction model that can predict the effect of TMD for LDH. A web calculator was designed on the basis of the model (https://fabinlin.shinyapps.io/DynNomapp/).

https://www.frontiersin.org/articles/10.3389/fsurg.2023.1024302/pdf

Development, validation, and visualization of a web-based nomogram to predict the effect of tubular microdiscectomy for lumbar disc herniation

Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.

https://www.frontiersin.org/articles/10.3389/fncel.2022.882306/pdf

The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury

To compare the efficacy and safety of different surgical procedures for patients with single‐segment lumbar spinal stenosis (LSS), Bayesian network meta‐analysis (NMA) was conducted in this study. Randomized controlled trials (RCTs) which reported 2 years' results after surgery were searched from PubMed, Embase, and Cochrane Register of Controlled Trials up to February 2021. Eligible RCTs that contained at least two of the following surgical procedures, bilateral decompression via the unilateral approach (BDUL), decompression with conventional laminectomy (CL), decompression with fusion (DF), endoscopic decompression (ED), interspinous process devices only (IPDs), decompression with interlaminar stabilization (DILS), decompression with lumbar spinal process‐splitting laminectomy (LSPSL), and minimally invasive tubular decompression (MTD), would be included after screening based on the inclusion and exclusion criteria. The primary outcome was Oswestry Disability Index (ODI). Twenty eligible RCTs were included, with a total of 2201 patients enrolled. The NMA showed that the following surgical procedures ranked first (surface under the cumulative ranking) when compared with CL and DF: DILS for ODI (SUCRA 87.8%); LSPSL for back pain (95%); and MTD for leg pain (95.6%). MTD ranked among the top three surgical procedures for most outcomes. The quality of the synthesized evidence was low according to the Grading of Recommendations Assessment, Development, and Evaluation criteria. DILS, LSPSL, MTD, IPDs, and ED are the most effective procedures for patients with single‐segment LSS. Because of combining efficacy and safety, MTD may be the most promising routine surgical option for treating single‐segment LSS.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/os.13269

Clinical Evaluation of Surgery for Single‐Segment Lumbar Spinal Stenosis: A Systematic Review and Bayesian Network Meta‐Analysis

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Papers

Development, validation, and visualization of a web-based nomogram to predict the effect of tubular microdiscectomy for lumbar disc herniation

The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury

Clinical Evaluation of Surgery for Single‐Segment Lumbar Spinal Stenosis: A Systematic Review and Bayesian Network Meta‐Analysis