Regeneration In Animal Models Research Articles

CB1 Receptors In NG2 CELLS MEDIATE CANNABINOID-EVOKED FUNCTIONAL MYELIN REGENERATION

Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells. By using conditional genetic mouse models, here we found that cannabinoid CB1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway. Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB1-deficient mice. Overall, this study identifies CB1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.

The Potential Applications of Stem Cell Conditioned Medium Secretome in Knee Cartilage Regeneration: A Systematic Review

Background: Articular cartilage injuries often result from trauma, genetic predisposition, and degeneration. These injuries lack inherent regeneration mechanisms due to the absence of blood vessels and limited progenitor cell entry. Osteoarthritis is characterized by gradual cartilage deterioration. Mesenchymal stem cells (MSCs), particularly their secretome including exosomes, hold promise as a regenerative therapy. This review explores the application of MSCs and their secretome to address cartilage defects.Methods: This review was conducted based on PRISMA guidelines. Animal model studies focusing on the use of stem cell secretomes for cartilage regeneration were explored. The search, encompassing PubMed, MEDLINE, the Cochrane Library, Scopus, Web of Science, and Science Direct from January 10, 2023, to July 27, 2023, was conducted utilizing Google Chrome as the search engine. Studies with outcomes based on OARSI or ICRS scores, as well as any additional outcomes related to MSC secretome utilization, cartilage regeneration, and proliferation, were included.Results: Our systematic review identified six studies using MSCs in vivo and in vitro. Synovial membrane-derived MSCs significantly enhanced cartilage regeneration by elevating chondrogenic capabilities. Hydrogel-based systems techniques and 3D-printed scaffolds have emerged for innovative delivery. Specific microRNAs, such as miR-92a-3p, have been recognized for enhancing cartilage regeneration. Strategies for the effective targeting of MSC exosomes to the precise cartilage damage site have been explored.Conclusions: The studies demonstrate the potential of MSC-derived secretomes and exosomes for knee cartilage regeneration in animal models. Further research and clinical trials are needed to refine these approaches for practical application.

Phosphatidylserine-mediated uptake of extracellular vesicles by hepatocytes ameliorates liver ischemia-reperfusion injury.

Compelling evidence suggests that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) promote regeneration in animal models of liver injury by delivering signaling molecules. However, their target cells and uptake mechanism remain elusive. In this study, MSC-EVs were intravenously administered in a mouse model of liver ischemia-reperfusion injury (IRI). Our results revealed that MSC-EVs exhibit enhanced liver targeting in IRI mice, and injured hepatocytes display a greater capacity for MSC-EV uptake. We found that phosphatidylserine (PS) displayed on the exterior of injured hepatocytes promotes MSC-EV internalization, possibly by binding to MFGE8, a protein expressed on the MSC-EV membrane. Furthermore, the therapeutic effect of MSC-EVs on liver IRI is highly dependent on this PS-mediated uptake pathway. Our findings provide evidence that MSC-EVs preferentially target injured hepatocytes, relying on a PS-dependent uptake route to exert hepatoprotective effects, which are critical for the future design of EV-based therapeutic strategies for liver IRI.

Increased efficiency of peripheral nerve regeneration using supercritical carbon dioxide-based decellularization in acellular nerve graft

Acellular nerve grafts (ANGs) are a promising therapeutic for patients with nerve defects caused by injuries. Conventional decellularization methods utilize a variety of detergents and enzymes. However, these methods have disadvantages, such as long processing times and the presence of detergents that remain on the graft. In this study, we aimed to reduce process time and minimize the risks associated with residual detergents by replacing them with supercritical carbon dioxide (scCO2) and compared the effectiveness to Hudson’s decellularization method, which uses several detergents. The dsDNA and the expression of MHC1 and 2 were significantly reduced in both decellularized groups, which confirmed the effective removal of cellular debris. The extracellular matrix proteins and various factors were found to be better preserved in the scCO2 ANGs compared to the detergent-ANGs. We conducted behavioral tests and histological analyses to assess the impact of scCO2 ANGs on peripheral nerve regeneration in animal models. Compared with Hudson’s method, the scCO2 method effectively improved the efficacy of peripheral nerve regeneration. Therefore, the decellularization method using scCO2 is not only beneficial for ANG synthesis, but it may also be helpful for therapeutics by enhancing the efficacy of peripheral nerve regeneration.

Antibacterial periodontal ligament stem cells enhance periodontal regeneration and regulate the oral microbiome

BackgroundThe transplantation of periodontal ligament stem cells (PDLSCs) has been shown to enhance periodontal regeneration in animal models and clinical trials. However, it is not known whether PDLSCs are antibacterial and whether this affects oral microbiota and periodontal regeneration.MethodsWe isolated human PDLSCs from periodontal ligament of extracted teeth. Rats’ periodontal fenestration defects were prepared, and treated with PDLSC injections (Cell group), using saline injections (Saline group) as the control. The oral microbiota was explored by 16 S rDNA sequencing and compared with that before surgery (PRE group). The antibacterial property of PDLSCs and its underlying mechanism were tested in vitro.ResultsMicrobiome analyses reveal a decreased biodiversity, a changed community structure, and downregulated community functions of the oral microbiome in the Saline group. PDLSCs injections enhance periodontal regeneration, reverse the decrease in diversity, and increase the abundance of non-pathogenic bacterial Bifidobacterium sp. and Lactobacillus sp., making the oral microbiome similar to that of the PRE group. In vitro, PDLSCs inhibit the growth of Staphylococcus aureus, Escherichia coli, and Fusobacterium nucleatum. The main mechanism of action is postulated to involve production of the cationic antimicrobial peptide LL-37.ConclusionsOur findings reveal that PDLSC injections enhance periodontal regeneration and regulate the oral microbiome to foster an oral cavity microenvironment conducive to symbiotic microbiota associated with health.

Comparative Efficacy of Endogenous Stem Cells Recruiting Hydrogels and Stem Cell-loaded Hydrogels in Knee Cartilage Regeneration: A Meta- analysis.

Cartilage defects remain a challenge in diseases such as osteoarthritis (OA) and fractures. Scientists have explored the use of hydrogels in conjunction with stem cell technology as a tissue engineering method to treat cartilage defects in joints. In recent years, research into hydrogels containing stem cell technology for cartilage repair has mainly focused on two categories: stem cell-loaded hydrogels and endogenous stem cell recruiting hydrogels. The latter, utilizing cell-free products, represents a novel concept with several advantages, including easier dose standardization, wider sources, and simpler storage. This meta-analysis aims to assess and compare the therapeutic effects of endogenous stem cell recruiting hydrogels and stem cell-loaded hydrogels in promoting articular cartilage regeneration in animal models, with the goal of exploring endogenous stem cell recruiting hydrogels as a promising replacement therapy for knee cartilage regeneration in preclinical animal studies. We systematically searched PubMed, Web of Science, Cochrane Library, and Embase until January 2023 using key words related to stem cells, cartilage regeneration and hydrogel. A random-effects meta-analysis was performed to evaluate the therapeutic effect on newborn cartilage formation. Stratified analyses were also carried out by independently classifying trials according to similar characteristics. The level of evidence was determined using the GRADE method. Twenty-eight studies satisfied the inclusion criteria. Comprehensive analyses revealed that the use of endogenous stem cell recruiting hydrogels significantly promoted the formation of new cartilage in the knee joint, as evidenced by the histological score (3.77, 95% CI 2.40, 5.15; p < 0.0001) and the International Cartilage Repair Society (ICRS) macroscopic score (3.00, 95% CI 1.83, 4.18; p = 0.04), compared with the control group. The stem cell-loaded hydrogels also increased cartilage regeneration in the knee with the histological score (3.13, 95% CI 2.22, 4.04; p = 0.02) and the ICRS macroscopic score (2.49, 95% CI 1.16, 3.82; p = 0.03) in comparison to the control. Significant heterogeneity between studies was observed, and further stratified and sensitivity analyses identified the transplant site and modelling method as the sources of heterogeneity. The current study indicates that both endogenous stem cell recruiting hydrogels and stem cell loaded hydrogels can effectively promote knee joint cartilage regeneration in animal trials.

Adipose Tissue Derivatives in Peripheral Nerve Regeneration after Transection: A Systematic Review.

Peripheral nerve injury (PNI) is increasingly prevalent and challenging to treat despite advances in microsurgical techniques. In this context, adipose tissue derivatives, such as adipose-derived stem cells, nanofat, and stromal vascular fraction have been gaining attention as potential allies in peripheral nerve regeneration. This study aims to explore the use of adipose tissue derivatives in nerve regeneration following peripheral nerve transection in murine models. Thus, we assess and synthesize the key techniques and methods used for evaluating the obtained nerve regeneration to guide future experimental research and clinical interventions. A systematic review was conducted in February 2024, adhering to the Cochrane and PRISMA 2020 guidelines, using the PubMed, SciELO, and LILACS databases. The focus was on experimental studies involving adipose tissue derivatives in nerve regeneration in animal models post-transection. Only experimental trials reporting nerve regeneration outcomes were included; studies lacking a comparator group or evaluation methods were excluded. Out of 273 studies initially identified from MEDLINE, 19 were selected for detailed analysis. The average study included 32.5 subjects, with about 10.2 subjects per intervention subgroup. The predominant model was the sciatic nerve injury with a 10 mm gap. The most common intervention involved unprocessed adipose-derived stem cells, utilized in 14 articles. This review underscores the significant potential of current methodologies in peripheral nerve regeneration, particularly highlighting the use of murine models and thorough evaluation techniques.

Rodent Model of Masseter Volumetric Muscle Loss for Studying Bioengineering Materials.

Craniofacial volumetric muscle loss (VML) injuries can occur as a result of severe trauma, surgical excision, inflammation, and congenital or other acquired conditions. Treatment of craniofacial VML involves surgical, functional muscle transfer. However, these procedures are unable to restore normal function, sensation, or expression, and more commonly, these conditions go untreated. Very little research has been conducted on skeletal muscle regeneration in animal models of craniofacial VML. This manuscript describes a rat model for the study of craniofacial VML injury and a protocol for the histological evaluation of biomaterials in the treatment of these injuries. Liquid hydrogel and freeze-dried scaffolds are applied at the time of surgical VML creation, and masseters are excised at terminal time points up to 12 weeks with high retention rates and negligible complications. Hematoxylin and eosin (HE), Masson's Trichrome, and immunohistochemical analysis are used to evaluate parameters of skeletal muscle regeneration as well as biocompatibility and immunomodulation. While we demonstrate the study of a hyaluronic-acid-based hydrogel, this model provides a means for evaluating subsequent iterations of materials in VML injuries.

Microbial- and host immune cell-derived extracellular vesicles in the pathogenesis and therapy of periodontitis: A narrative review.

Periodontitis is a chronic inflammatory disease caused by dysbiotic biofilms and destructive host immune responses. Extracellular vesicles (EVs) are circulating nanoparticles released by microbes and host cells involved in cell-to-cell communication, found in body biofluids, such as saliva and gingival crevicular fluid (GCF). EVs are mainly involved in cell-to-cell communication,and may hold promise for diagnostic and therapeutic purposes. Periodontal research has examined the potential involvement of bacterial- and host-cell-derived EVs in disease pathogenesis, diagnosis, and therapy, but data remains scarce on immune cell- or microbial-derived EVs. In this narrative review, we first provide an overview of the role of microbial and host-derived EVs on disease pathogenesis. Recent studies reveal that Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans-derived outer membrane vesicles (OMVs) can activate inflammatory cytokine release in host cells, while M1 macrophage EVs may contribute to bone loss. Additionally, we summarised current invitro and pre-clinical research on the utilisation of immune cell and microbial-derived EVs as potential therapeutic tools in the context of periodontal treatment. Studies indicate that EVs from M2 macrophages and dendritic cells promote bone regeneration in animal models. While bacterial EVs remain underexplored for periodontal therapy, preliminary research suggests that P. gingivalis OMVs hold promise as vaccine candidates. Finally, we acknowledge the current limitations present in the field of translating immune cell derived EVs and microbial derived EVs in periodontology. It is concluded that microbial and host immune cell-derived EVs have a role in periodontitis pathogenesis and hence may be useful for studying disease pathophysiology, and as diagnostic and treatment monitoring biomarkers.

Optimizing Tissue Engineering for Clinical Relevance in Rotator Cuff Repair.

Rotator cuff tear (RCT) is the most common cause of disability in the upper extremity. It results in 4.5 million physician visits in the United States every year and is the most common etiology of shoulder conditions evaluated by orthopedic surgeons. Over 460,000 RCT repair surgeries are performed in the United States annually. Rotator cuff (RC) retear and failure to heal remain significant postoperative complications. Literature suggests that the retear rates can range from 29.5% to as high as 94%. Weakened and irregular enthesis regeneration is a crucial factor in postsurgical failure. Although commercially available RC repair grafts have been introduced to augment RC enthesis repair, they have been associated with mixed clinical outcomes. These grafts lack appropriate biological cues such as stem cells and signaling molecules at the bone-tendon interface. In addition, they do little to prevent fibrovascular scar tissue formation, which causes the RC to be susceptible to retear. Advances in tissue engineering have demonstrated that mesenchymal stem cells (MSCs) and growth factors (GFs) enhance RC enthesis regeneration in animal models. These models show that delivering MSCs and GFs to the site of RCT enhances native enthesis repair and leads to greater mechanical strength. In addition, these models demonstrate that MSCs and GFs may be delivered through a variety of methods including direct injection, saturation of repair materials, and loaded microspheres. Grafts that incorporate MSCs and GFs enhance anti-inflammation, osteogenesis, angiogenesis, and chondrogenesis in the RC repair process. It is crucial that the techniques that have shown success in animal models are incorporated into the clinical setting. A gap currently exists between the promising biological factors that have been investigated in animal models and the RC repair grafts that can be used in the clinical setting. Future RC repair grafts must allow for stable implantation and fixation, be compatible with current arthroscopic techniques, and have the capability to deliver MSCs and/or GFs.

Therapeutic Effect of Schwann Cell-Like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells on Diabetic Neuropathy in db/db Mice.

Diabetic neuropathy (DN) is the most common complication of diabetes, and approximately 50% of patients with this disease suffer from peripheral neuropathy. Nerve fiber loss in DN occurs due to myelin defects and is characterized by symptoms of impaired nerve function. Schwann cells (SCs) are the main support cells of the peripheral nervous system and play important roles in several pathways contributing to the pathogenesis and development of DN. We previously reported that human tonsil-derived mesenchymal stem cells differentiated into SCs (TMSC-SCs), named neuronal regeneration-promoting cells (NRPCs), which cells promoted nerve regeneration in animal models with peripheral nerve injury or hereditary peripheral neuropathy. In this study, NRPCs were injected into the thigh muscles of BKS-db/db mice, a commonly used type 2 diabetes model, and monitored for 26weeks. Von Frey test, sensory nerve conduction study, and staining of sural nerve, hind foot pad, dorsal root ganglia (DRG) were performed after NRPCs treatment. Von Frey test results showed that the NRPC treatment group (NRPC group) showed faster responses to less force than the vehicle group. Additionally, remyelination of sural nerve fibers also increased in the NRPC group. After NRPCs treatment, an improvement in response to external stimuli and pain sensation was expected through increased expression of PGP9.5 in the sole and TRPV1 in the DRG. The NRPCs treatment may alleviate DN through the remyelination and the recovery of sensory neurons, could provide a better life for patients suffering from complications of this disease.

The Role of Vitamin D in Skeletal Muscle Repair and Regeneration in Animal Models and Humans: A Systematic Review.

Vitamin D deficiency, prevalent worldwide, is linked to muscle weakness, sarcopenia, and falls. Muscle regeneration is a vital process that allows for skeletal muscle tissue maintenance and repair after injury. PubMed and Web of Science were used to search for studies published prior to May 2023. We assessed eligible studies that discussed the relationship between vitamin D, muscle regeneration in this review. Overall, the literature reports strong associations between vitamin D and skeletal myocyte size, and muscle regeneration. In vitro studies in skeletal muscle cells derived from mice and humans showed vitamin D played a role in regulating myoblast growth, size, and gene expression. Animal studies, primarily in mice, demonstrate vitamin D's positive effects on skeletal muscle function, such as improved grip strength and endurance. These studies encompass vitamin D diet research, genetically modified models, and disease-related mouse models. Relatively few studies looked at muscle function after injury, but these also support a role for vitamin D in muscle recovery. The human studies have also reported that vitamin D deficiency decreases muscle grip strength and gait speed, especially in the elderly population. Finally, human studies reported the benefits of vitamin D supplementation and achieving optimal serum vitamin D levels in muscle recovery after eccentric exercise and surgery. However, there were no benefits in rotator cuff injury studies, suggesting that repair mechanisms for muscle/ligament tears may be less reliant on vitamin D. In summary, vitamin D plays a crucial role in skeletal muscle function, structural integrity, and regeneration, potentially offering therapeutic benefits to patients with musculoskeletal diseases and in post-operative recovery.

Generating Retinal Injury Models in Xenopus Tadpoles.

Retinal neurodegenerative diseases are the leading causes of blindness. Among numerous therapeutic strategies being explored, stimulating self-repair recently emerged as particularly appealing. A cellular source of interest for retinal repair is the Müller glial cell, which harbors stem cell potential and an extraordinary regenerative capacity in anamniotes. This potential is, however, very limited in mammals. Studying the molecular mechanisms underlying retinal regeneration in animal models with regenerative capabilities should provide insights into how to unlock the latent ability of mammalian Müller cells to regenerate the retina. This is a key step for the development of therapeutic strategies in regenerative medicine. To this aim, we developed several retinal injury paradigms in Xenopus: a mechanical retinal injury, a transgenic line allowing for nitroreductase-mediated photoreceptor conditional ablation, a retinitis pigmentosa model based on CRISPR/Cas9-mediated rhodopsin knockout, and a cytotoxic model driven by intraocular CoCl2 injections. Highlighting their advantages and disadvantages, we describe here this series of protocols that generate various degenerative conditions and allow the study of retinal regeneration in Xenopus.

Human Lacrimal Gland Derived Mesenchymal Stem Cells - Isolation, Propagation, and Characterization.

The existing treatment options for dry eye disease (DED) due to lacrimal gland (LG) dysfunction are mainly palliative. Mesenchymal stem cells (MSCs) based therapies and 3D-LG organoids have been explored as a curative option for LG regeneration in animal models. Human LG epithelial cultures are previously established and, here, we aim to isolate and characterize the spindle-shaped cells obtained from primary human LG cultures in order to unveil its MSC property. Normal human lacrimal glands were obtained from individuals undergoing LG debulking surgery. The conditions for human LG-MSC culture were standardized to obtain pure population of LG-MSCs at passage 3. Population doubling time (PDT), expression of phenotypic markers, tri-lineage differentiation, colony forming potential, and gene expression analysis were carried out to assess the phenotypic and genotypic characteristics compared to bone marrow-MSCs (BM-MSCs). Our data show that these spindle-shaped cells exhibit similar phenotypic expression, colony-forming ability, and trilineage differentiation like BM-MSCs. Moreover, the gene expression also did not show any significant difference, except for increased IL1-β in LG-MSCs. The LG-MSCs do not express any lacrimal epithelial markers unlike LG tissue. This study reveals the first-time evidence for the presence of MSC population within the human LGs, and these cells might play a role in maintaining healthy microenvironment within normal LG and repair in diseased LGs.

Losartan in Combination With Bone Marrow Stimulation Showed Synergistic Effects on Load to Failure and Tendon Matrix Organization in a Rabbit Model

To investigate the effects of combining bone marrow stimulation (BMS) with oral losartan to block transforming growth factor β1 (TGF-β1) on biomechanical repair strength in a rabbit chronic injury model. Forty rabbits were randomly allocated into 4 groups (10 in each group). The supraspinatus tendon was detached and left alone for 6 weeks to establish a rabbit chronic injury model and was then repaired in a surgical procedure using a transosseous, linked, crossing repair construct. The animals were divided into the following groups: control group (group C), surgical repair only; BMS group (group B), surgical repair with BMS of the tuberosity; losartan group (group L), surgical repair plus oral losartan (TGF-β1 blocker) for 8 weeks; and BMS-plus-losartan group (group BL), surgical repair plus BMS plus oral losartan for 8 weeks. At 8 weeks after repair, biomechanical and histologic evaluations were performed. The biomechanical testing results showed significantly higher ultimate load to failure in group BL than in group B (P= .029) but not compared with group C or group L. A 2× 2 analysis-of-variance model found that the effect of losartan on ultimate load significantly depended on whether BMS was performed (interaction term F1,28= 5.78, P= .018). No difference was found between the other groups. No difference in stiffness was found between any groups. On histologic assessment, groups B, L, and BL showed improved tendon morphology and an organized type I collagen matrix with less type III collagen compared with group C. Group BL showed the most highly organized tendon matrix with more type I collagen and less type III collagen, which indicates less fibrosis. Similar results were found at the bone-tendon interface. Rotator cuff repair combined with oral losartan and BMS of the greater tuberosity showed improved pullout strength and a highly organized tendon matrix in this rabbit chronic injury model. Tendon healing or scarring is accompanied by the formation of fibrosis, which has been shown to result in compromised biomechanical properties, and is therefore a potential limiting factor in healing after rotator cuff repair. TGF-β1 expression has been shown to play an important role in the formation of fibrosis. Recent studies focusing on muscle healing and cartilage repair have found that the downregulation of TGF-β1 by losartan intake can reduce fibrosis and improve tissue regeneration in animal models.

Growth Factor Delivery Using a Collagen Membrane for Bone Tissue Regeneration.

The use of biomaterials and bioactive agents has shown promise in bone defect repair, leading to the development of strategies for bone regeneration. Various artificial membranes, especially collagen membranes (CMs) that are widely used for periodontal therapy and provide an extracellular matrix-simulating environment, play a significant role in promoting bone regeneration. In addition, numerous growth factors (GFs) have been used as clinical applications in regenerative therapy. However, it has been established that the unregulated administration of these factors may not work to their full regenerative potential and could also trigger unfavorable side effects. The utilization of these factors in clinical settings is still restricted due to the lack of effective delivery systems and biomaterial carriers. Hence, considering the efficiency of bone regeneration, both spaces maintained using CMs and GFs can synergistically create successful outcomes in bone tissue engineering. Therefore, recent studies have demonstrated a significant interest in the potential of combining CMs and GFs to effectively promote bone repair. This approach holds great promise and has become a focal point in our research. The purpose of this review is to highlight the role of CMs containing GFs in the regeneration of bone tissue, and to discuss their use in preclinical animal models of regeneration. Additionally, the review addresses potential concerns and suggests future research directions for growth factor therapy in the field of regenerative science.

Fine-Tuning Regulation of Surface Mobility by Acrylate Copolymers and Its Effect on Cell Adhesion and Differentiation.

Fibronectin (FN) mediates cell-material interactions during events such as tissue repair, and therefore the biomimetic modeling of this protein in vitro benefits regeneration. The nature of the interface is crucial in determining cell adhesion, morphology, and differentiation. Poly(ethyl acrylate) (PEA) spontaneously organizes FN into biological nanonetworks, resulting in exceptional bone regeneration in animal models. Spontaneous network organization of FN is also observed in poly(buthyl acrylate) (PBA) substrates that have higher surface mobility than PEA. C2C12 myoblasts differentiate efficiently on PEA and PBA substrates. In this study, we investigate if intermediate surface mobilities between PEA and PBA induce cell differentiation more efficiently than PEA. A family of P(EA-co-BA) copolymers were synthesized in the entire range of compositions to finely tune surface mobility between PEA and PBA. Surface characterization demonstrates that FN mobility steadily increased with the PBA content. All compositions allowed the biological organization of FN with similar exposure of cell binding domains. C2C12 myoblasts adhered well in all the materials, with higher focal adhesions in PEA and PBA. The increase of the interfacial mobility had an impact in cell adhesion by increasing the number of FAs per cell. In addition, cell differentiation decreased proportionally with surface mobility, from PEA to PBA.

The Effect of Acetyl-L-Carnitine (ALCAR) on Peripheral Nerve Regeneration in Animal Models: A Systematic Review.

Peripheral neuropathies caused by the peripheral nervous system (PNS) damage can occur due to trauma and other disorders. They present as altered sensation, weakness, autonomic symptoms, and debilitating pain syndrome with a wide range of clinical signs. Acetyl-L-Carnitine (ALCAR) is a biological compound with essential roles in mitochondrial oxidative metabolism and anti-oxidant effects that protects mitochondria from oxidative damage and inhibits apoptosis caused by mitochondrial damage. This study is a systematic review and meta-analysis of the effects of ALCAR on peripheral nerve injuries. This review examines studies on treating traumatic peripheral neuropathies in which ALCAR is administered to rats with sciatic nerve injury with an appropriate control group. The articles were divided based on the mode of ALCAR administration. If one method was used in more than one article, their results were entered in the "Revman5.4" software and were meta-analyzed. Studies were selected from 1994 to 2018 on rats with varying physical injuries to their sciatic nerves. In one study, ALCAR was provided to rats in their drinking water, while in other studies, ALCAR was injected intra-peritoneally. Different mechanisms of ALCAR actions have been suggested in this study, but the underpinnings of the neuroprotective effects of ALCAR are still unclear. Further studies are mandatory to clarify the actual mechanisms of the neuroprotective activity of ALCAR. Based on the results of existing studies, ALCAR effectively increases the tolerance threshold of thermal and mechanical stimuli, reduces latency, and reduces apoptosis; finally, adjusting the dose and duration of administration may increase the dose and duration axon diameter.

Soft tissue regeneration in animal models using grafts from adipose mesenchymal stem cells and peripheral blood fibrin gel.

Our study aimed to evaluate the effect of soft tissue regeneration in nude mice using grafts made from the combination of adipocytes from fat tissue mesenchymal stem cells and fibrin gel from peripheral blood. Mesenchymal stem cells were isolated from adipose tissue and identified according to ISCT criteria. The scaffold used was fibrin obtained from peripheral blood. The grafts in this study were generated by transferring mesenchymal stem cells onto a fibrin scaffold. Two types of grafts, the research sample (fibrin scaffold containing adipocytes differentiated from mesenchymal stem cells) and the control sample (fibrin scaffold only), were grafted under the dorsal skin of the same mouse. After each research period, samples were collected and evaluated by histological methods to observe the existence and growth of cells inside the grafts. The results showed that the study group's graft integrated better within the tissue when compared with the control group. In addition, the grafts in the study group showed the presence of cells with characteristic morphology of adipocytes one week after transplantation. In contrast, control samples showed dimorphous shapes and features mainly composed of non-homogenous fragments. These initial conclusions might be considered a first step in generating safe bio-compatible engineered grafts specifically usable in post-traumatic tissue regeneration procedures.

Injection of Ultra-Purified Stem Cells with Sodium Alginate Reduces Discogenic Pain in a Rat Model.

Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue repair and reduces discogenic pain, and a combination of ultra-purified, Good Manufacturing Practice (GMP)-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs), and the UPAL gel increasingly enhanced IVD regeneration in animal models. This study investigated the therapeutic efficacy of injecting a mixture of REC and UPAL non-gelling solution for discogenic pain and IVD regeneration in a rat caudal nucleus pulposus punch model. REC and UPAL mixture and UPAL alone suppressed not only the expression of TNF-α, IL-6, and TrkA (p < 0.01, respectively), but also IVD degeneration and nociceptive behavior compared to punching alone (p < 0.01, respectively). Furthermore, REC and UPAL mixture suppressed these expression levels and nociceptive behavior compared to UPAL alone (p < 0.01, respectively). These results suggest that this minimally invasive treatment strategy with a single injection may be applied to treat discogenic pain and as a regenerative therapy.