Contribution of initial lymphatics to oral wound healing after tooth extraction.

Lymphatics are involved in the resolution of inflammation and wound healing, but their role in the oral wound healing process after tooth extraction has never been investigated. We therefore sought to evaluate the healing process following the extraction of maxillary molars in two transgenic mouse models: K14-VEGFR3-Ig mice, which lack initial mucosal lymphatic vessels, and K14-VEGFC mice, which have hyperplastic mucosal lymphatics. Maxillary molars were extracted from both transgenic mouse types and their corresponding wild-type (WT) controls. Mucosal and alveolar bone healing were evaluated. A delayed epithelialization and bone regeneration were observed in K14-VEGFR3-Ig mice compared with their WT littermates. The hampered wound closure was accompanied by decreased levels of epidermal growth factor (EGF) and persistent inflammation, characterized by infiltrates of immune cells and elevated levels of pro-inflammatory markers in the wounds. Hyperplastic mucosal lymphatics did not enhance the healing process after tooth extraction in K14-VEGFC mice. The findings indicate that initial mucosal lymphatics play a major role in the initial phase of the oral wound healing process.

Surgery induces neurocognitive disorder via neuroinflammation and glymphatic dysfunction in middle-aged mice with brain lymphatic drainage impairment.

Background: Brain lymphatic drainage impairment is a prevalent characteristic in both aging and neurodegeneration. Surgery is more likely to induce excessive neuroinflammation and postoperative neurocognitive disorder (PND) among patients with aging and neurodegeneration. We hypothesized that surgical trauma may aggravate PND through preexisting cerebral lymphatic drainage impairment. However, there remains limited understanding about the role of surgery in changes of neurocognitive function in the populations with preoperative brain lymphatic drainage impairment. This study aims to expand our insight into surgery-induced glymphatic dysfunction, neuroinflammation and PND in middle-aged mice with preoperative brain lymphatic drainage impairment. Materials and methods: Deep cervical lymph nodes ligation (LdcLNs) was performed on middle-aged mice to establish preoperative brain lymphatic drainage impairment. A month later, laparotomy was performed on these mice with or without LdcLNs followed by analysis of brain neuroinflammation, glymphatic function, neuronal damage, and behavioral test. Results: LdcLNs disrupted meningeal lymphatic drainage. In middle-aged mice with LdcLNs, surgery exacerbated more serious glymphatic dysfunction accompanied by aggravation of A1 astrocytes activation and AQP4 depolarization. Furthermore, surgery caused neuronal damage via reducing expression of neuronal nuclei (NeuN), post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), as well as impairment in exploratory behavior and spatial working memory in middle-aged mice with LdcLNs. Additionally, surgery induced neuroinflammation with elevated microglia activation and increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, as well as activated more expression of HMGB1/TLR-4/NF-κB pathway in middle-aged mice with LdcLNs. Conclusion: Surgery exacerbates neuroinflammation and glymphatic dysfunction, ultimately resulting in neuronal damage and neurocognitive disorder in middle-aged mice with preoperative brain lymphatic drainage impairment. These results suggest that brain lymphatic drainage impairment may be a deteriorating factor in the progression of PND, and restoring its function may serve as a potential strategy against PND.

Isolated unilateral ovarian cystic lymphangioma: A case report.

Ovarian lymphangiomas are rare benign neoplasms characterized by the proliferation of lymphatic vessels within the ovarian tissue. While lymphangiomas can manifest in various anatomical locations, their occurrence within the ovaries is exceptionally uncommon, posing diagnostic and therapeutic challenges for clinicians. The aetiology of ovarian lymphangiomas remains elusive, with theories suggesting congenital malformations, lymphatic obstruction, or acquired lymphatic proliferation as potential contributing factors. The clinical presentation of ovarian lymphangiomas often includes nonspecific symptoms such as abdominal pain, swelling, or discomfort, leading to difficulties in early detection and diagnosis. Radiological imaging, particularly Ultrasound, CT (computed tomography) and MRI (magnetic resonance imaging), plays a crucial role in identifying these lesions and guiding subsequent management strategies. Despite their generally benign nature, ovarian lymphangiomas can attain significant sizes, causing complications such as torsion, rupture, or compression of adjacent structures. Surgical intervention, typically in cystectomy or oophorectomy, is frequently pursued to alleviate symptoms and prevent potential complications. This paper aims to comprehensively review the existing literature on ovarian lymphangiomas, addressing their clinical presentation, diagnostic challenges, and management strategies. By synthesizing available data, we seek to enhance our understanding of this rare entity, providing valuable insights for clinicians encountering similar cases. Improved awareness and knowledge of ovarian lymphangiomas are essential for timely diagnosis and optimal patient outcomes.

An Unusual Neck Tumor in Adult: A Case Report.

Cystic Hygroma (CH) also referred to as lymphangioma, is a cystic malformation of the lymphatic vessels that can occur anywhere in the body. Its incidence in adulthood is considered rare and its occurrence in the neck is even rarer and only a few case reports are available till date. We present a case of adult CH of the neck and the literature review of the same. A 30-year-old male presented with painless swelling in the left side of the neck of 2 years duration. Investigations showed a cystic mass on the left lower anterior part of the neck which was surgically removed in-toto with the intact capsule. The biopsy report confirmed the diagnosis. A differential diagnosis of CH should be considered when a cystic lesion is encountered in the neck of an adult, cytological and radiological evaluation is necessary for defining its location and diagnosis. Although various conservative modalities of management are available, they are employed only in certain situations, and surgical excision of CH is considered the gold standard. The chances of recurrence range from 15 to 20%.

Neurosurgery and the glymphatic system.

The discovery of the glymphatic system has fundamentally altered our comprehension of cerebrospinal fluid transport and the removal of waste from brain metabolism. In the past decade, since its initial characterization, research on the glymphatic system has surged exponentially. Its potential implications for central nervous system disorders have sparked significant interest in the field of neurosurgery. Nonetheless, ongoing discussions and debates persist regarding the concept of the glymphatic system, and our current understanding largely relies on findings from experimental animal studies. This review aims to address several key inquiries: What methodologies exist for evaluating glymphatic function in humans today? What is the current evidence supporting the existence of a human glymphatic system? Can the glymphatic system be considered distinct from the meningeal-lymphatic system? What is the human evidence for glymphatic-meningeal lymphatic system failure in neurosurgical diseases? Existing literature indicates a paucity of techniques available for assessing glymphatic function in humans. Thus far, intrathecal contrast-enhanced magnetic resonance imaging (MRI) has shown the most promising results and have provided evidence for the presence of a glymphatic system in humans, albeit with limitations. It is, however, essential to recognize the interconnection between the glymphatic and meningeal lymphatic systems, as they operate in tandem. There are some human studies demonstrating deteriorations in glymphatic function associated with neurosurgical disorders, enriching our understanding of their pathophysiology. However, the translation of this knowledge into clinical practice is hindered by the constraints of current glymphatic imaging modalities.

Cannabidiol alleviates suture-induced corneal pathological angiogenesis and inflammation by inducing myeloid-derived suppressor cells.

BACKGROUND: Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action. METHOD: An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action. RESULTS: Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD. CONCLUSION: This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.

Meningeal lymphatic vasculature, a general target for glioblastoma therapy?

Glioblastoma (GBM) causes nearly universal mortality as a result of the failure of conventional therapies including surgical resection, targeted radiation therapy, and chemotherapy. An increasingly important treatment option is combining immunotherapy with other therapies in both preclinical and clinical studies. The central nervous system (CNS) has been historically considered an immune privileged area, but increasing evidence, including the recent rediscovery of meningeal lymphatic vessels (MLVs), has overturned this notion. MLVs are populated by multiple immune cells and connect the CNS to the periphery by draining cerebrospinal fluid with soluble CNS antigens and immune cells into cervical lymph nodes. In the past few years, more and more studies have indicated that MLVs are involved in the regulation of inflammation and the immune response in the pathogenesis of various CNS diseases including GBM. Here, we explore the critical interlinkages between MLVs and GBM therapies including chemotherapy, radiotherapy and immunotherapy, and propose the meningeal lymphatic vasculature as a general target for GBM therapy.

The extracellular matrix protein EMILIN-1 impacts on the microenvironment by hampering gastric cancer development and progression.

BACKGROUND: The contribution of the tumor microenvironment and extracellular matrix to the aggressive biology of Gastric Cancer (GC) has been recently characterized; however, the role of EMILIN-1 in this context is unknown. EMILIN-1 is an essential structural element for the maintenance of lymphatic vessel (LV) integrity and displays anti-proliferative properties as demonstrated in skin and colon cancer. Given the key role of LVs in GC progression, the aim of this study was to investigate the role of EMILIN-1 in GC mouse models. METHODS: We used the syngeneic YTN16 cells which were injected subcutaneously and intraperitoneally in genetically modified EMILIN-1 mice. In alternative, carcinogenesis was induced using N-Methyl-N-nitrosourea (MNU). Mouse-derived samples and human biopsies were analyzed by IHC and IF to the possible correlation between EMILIN-1 expression and LV pattern. RESULTS: Transgenic mice developed tumors earlier compared to WT animals. 20 days post-injection tumors developed in EMILIN-1 mutant mice were larger and displayed a significant increase of lymphangiogenesis. Treatment of transgenic mice with MNU associated with an increased number of tumors, exacerbated aggressive lesions and higher levels of LV abnormalities. A significant correlation between the levels of EMILIN-1 and podoplanin was detected also in human samples, confirming the results obtained with the pre-clinical models. CONCLUSIONS: This study demonstrates for the first time that loss of EMILIN-1 in GC leads to lymphatic dysfunction and proliferative advantages that sustain tumorigenesis, and assess the use of our animal model as a valuable tool to verify the fate of GC upon loss of EMILIN-1.

The Impact of VEGF-C-Induced Dural Lymphatic Vessel Growth on Ischemic Stroke Pathology.

Timely relief of edema and clearance of waste products, as well as promotion of anti-inflammatory immune responses, reduce ischemic stroke pathology, and attenuate harmful long-term effects post-stroke. The discovery of an extensive and functional lymphatic vessel system in the outermost meningeal layer, dura mater, has opened up new possibilities to facilitate post-stroke recovery by inducing dural lymphatic vessel (dLV) growth via a single injection of a vector encoding vascular endothelial growth factor C (VEGF-C). In the present study, we aimed to improve post-stroke outcomes by inducing dLV growth in mice. We injected mice with a single intracerebroventricular dose of adeno-associated viral particles encoding VEGF-C before subjecting them to transient middle cerebral artery occlusion (tMCAo). Behavioral testing, Gadolinium (Gd) contrast agent-enhanced magnetic resonance imaging (MRI), and immunohistochemical analysis were performed to define the impact of VEGF-C on the post-stroke outcome. VEGF-C improved stroke-induced behavioral deficits, such as gait disturbances and neurological deficits, ameliorated post-stroke inflammation, and enhanced an alternative glial immune response. Importantly, VEGF-C treatment increased the drainage of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF), as shown by Gd-enhanced MRI. These outcomes were closely associated with an increase in the growth of dLVs around the region where we observed increased vefgc mRNA expression within the brain, including the olfactory bulb, cortex, and cerebellum. Strikingly, VEGF-C-treated ischemic mice exhibited a faster and stronger Gd-signal accumulation in ischemic core area and an enhanced fluid outflow via the cribriform plate. In conclusion, the VEGF-C-induced dLV growth improved the overall outcome post-stroke, indicating that VEGF-C has potential to be included in the treatment strategies of post-ischemic stroke. However, to maximize the therapeutic potential of VEGF-C treatment, further studies on the impact of an enhanced dural lymphatic system at clinically relevant time points are essential.

Borneol regulates meningeal lymphatic valve plasticity to clear Aß aggregates in the prevention of AD-like symptoms.

BACKGROUND: Meningeal lymphatic vessels (mLVs) have great potential to be the therapeutic target for ß Amyloid protein (Aß) clearing in Alzheimer's disease (AD), but the regulatory methods of the mLVs are limited. The lymphatic valve, marked by FOXC2, is the fundamental structure for maintaining stable lymphatic drainage function. Preliminary evidence suggested that borneol (BO) as the classical phytochemicals could enhance the expression of FOXC2 in the mLVs of healthy mice. PURPOSE: This study aims to explore the regulatory ability of BO on lymphatic valves of mLVs in the AD model mice. STUDY DESIGN: We used the intracerebroventricular injection of Aß42 oligomers to construct the AD-like symptoms model induced by toxic protein deposition. We administered BO nano micelles(BO-Ms) orally before and after to simulate the AD prevention and treatment strategy. METHODS: Herein, this study characterized the efficacy and pathways of BO-Ms for regulating mLVs in AD model by Rt-PCR, WB and confocal microscopy, and determined the effects of BO-Ms on Aß clearance, behavior and safety of AD mice. RESULTS: The AD modeling process severely impaired the expression of lymphatic valves. However, after oral administering BO-Ms for prevention and treatment, an increase in the lymphatic valves of the transverse sinus was observed, which derived from the up-regulation of the transcription factor (FOXC2 and Akt) and the down-regulation of the transcription inhibitors (FOXO1 and PRDM1). Furthermore, the effects of BO-Ms on the lymphatic valves could enhance the lymphatic drainage of the mLVs in AD-like mice, promoting the clearance of toxicity aggregates, protecting neurons, and alleviating AD-like symptoms. Simultaneously, continuous oral BO-Ms for 30 days didn't show any significant organ toxicity. The most important thing was that the preventive effect of BO administration was superior to therapeutic administration in all data. CONCLUSION: In summary, our research indicated that BO is a promoter of lymphatic valve formation in the mLVs, and could prevent or repair damage caused by toxic Aß42. BO was the only bioactive natural product with the ability to regulate mLVs valves. Thus, BO has the potential to become phytochemicals for alleviating AD symptoms by enhancing the drainage function of mLVs.

Andrographolide promotes lymphangiogenesis and lymphatic vessel remodeling to alleviate secondary lymphedema.

Lymphedema, a prevalent, multifaceted, and chronic ailment, is mainly managed through physical manipulation and suffers from a lack of specific pharmacological treatments. Secondary lymphedema is mainly caused by impaired lymphatic drainage. Therapeutic lymphangiogenesis is a promising strategy in the treatment of lymphedema. Andrographolide, a natural product from Andrographis paniculata, is unknown whether andrographolide promotes lymphangiogenesis to improve secondary lymphedema. By using the murine tail lymphedema model, we demonstrated that andrographolide can reduce the thickness of subcutaneous tissue in the mice's tail and enhance lymphatic drainage. Moreover, immunofluorescence staining showed that the number of capillary lymphatic vessels in the ANDRO25 group was significantly more than that in the ANDRO50 and Model groups. Near-infrared lymphography images showed that highlighted sciatic lymph nodes could be seen in the ANDRO25 and ANDRO50 groups. In vitro, andrographolide could promote the proliferation and migration of LEC. In conclusion, andrographolide enhanced the recovery of lymphatic vessels, and promoted lymphatic drainage in the murine tail lymphedema model by promoting the proliferation of lymphatic endothelial cells, thereby reducing the symptoms of lymphedema. This suggested andrographolide may be used as a potential therapeutic drug or medical food ingredient to help patients with secondary lymphedema.

Hyaluronic Acid as a LYVE-1 Receptor Ligand in the Lymphatic System of Healthy Human Skin.

Immunohistochemical detection of the LYVE-1 marker in healthy human full-thickness skin (the epidermis and the dermis) was carried out. LYVE-1 expression was found in the endothelium of lymphatic capillaries located in the papillary dermis, in the endothelium of larger lymphatic vessels of the reticular dermis, and in fibroblasts, which indicates their joint participation in hyaluronan metabolism. LYVE-1+ staining detected for the first time in cells of the stratum basale, the stratum spinosum, and the stratum granulosum of healthy human epidermis indicates their participation in hyaluronan metabolism and allows us to consider the spaces between epidermis cells as prelimphatics.

New Insights on Mechanisms and Therapeutic Targets of Cerebral Edema.

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to bloodbrain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

Networks of Nerve Fibers, and Blood and Lymphatic Vessels in the Mouse Auricle: The Structural Basis of Ear Acupuncture.

Objective: Ear acupuncture, as a system for treating and preventing diseases through stimulation of points on the auricle, has been systematically introduced during the last 60 years. Although the auricular cartography was described somatotopically as an inverted fetus by Paul Nogier, MD, the underlying mechanism of auricular stimulation remains unclear. The aim of this research was to gain an understanding of the structural basis of auricular stimulation, as well as showing the distribution of the nerve fibers, and the blood and lymphatic vessels. Materials and Methods: The distribution of nerve fibers, and blood and lymphatic vessels was examined in whole-mount auricular skins of mice by combining the biomarkers protein gene product 9.5, cluster of differentiation 31, and lymphatic-vessel endothelial hyaluronan receptor-1 following tissue-clearing treatment with multiple immunofluorescent staining. Results: The labeled nerve fibers, and the blood and lymphatic vessels were distributed extensively in the inner and outer parts of the auricular skin. Auricular nerves aligning with blood vessels ran from the basal region to the peripheral region and crossed over lymphatic vessels, thus forming the neural, vascular, and lymphatic networks. Conclusions: As these are important tissue components of auricular skin, this result implies that the auricular nerve fibers, and blood and lymphatic vessels may coordinate with each other to respond directly to auricular stimulation.

Impaired meningeal lymphatic drainage in Listeria monocytogenes infection.

Previous studies have demonstrated an association between lymphatic vessels and diseases caused by bacterial infections. Listeria monocytogenes (LM) bacterial infection can affect multiple organs, including the intestine, brain, liver and spleen, which can be fatal. However, the impacts of LM infection on morphological and functional changes of lymphatic vessels remain unexplored. In this study, we found that LM infection not only induces meningeal and mesenteric lymphangiogenesis in mice, but also impairs meningeal lymphatic vessels (MLVs)-mediated macromolecules drainage. Interestingly, we found that the genes associated with lymphatic vessel development and function, such as Gata2 and Foxc2, were downregulated, suggesting that LM infection may affect cellular polarization and valve development. On the other hand, photodynamic ablation of MLVs exacerbated inflammation and bacterial load in the brain of mice with LM infection. Overall, our findings indicate that LM infection induces lymphangiogenesis and may affect cell polarization, cavity formation, and valve development during lymphangiogenesis, ultimately impairing MLVs drainage.

Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression.

The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.

Novel erectile analyses revealed augmentable penile Lyve-1, the lymphatic marker, expression.

Purpose: The pathophysiology of penis extends to erectile dysfunction (ED) to conditions including sexually transmitted diseases (STDs) and cancer. To date, there has been little research evaluating vascular drainage from the penis. We aimed to evaluate penile blood flow in vivo and analyze its possible relationship with the lymphatic maker. Materials and Methods: We established an in vivo system designed to assess the dynamic blood outflow from the corpus cavernosum (CC) by dye injection. To analyze lymphatic characteristics in the CC, the expression of Lyve-1, the key lymphatic endothelium marker, was examined by the in vitro system and lipopolysaccharide (LPS) injection to mimic the inflammatory conditions. Results: A novel cavernography methods enable high-resolution morphological and functional blood drainage analysis. The expression of Lyve-1 was detected along the sinusoids. Furthermore, its prominent expression was also observed after penile LPS injection and in the erectile condition. Conclusions: The current in vivo system will potentially contribute to the assessment of penile pathology from a novel viewpoint. In addition, current analyses revealed inducible Lyve-1 expression for LPS injection and the erection state, which requires further analyses on penile lymphatic system.

Peripheral nervous system lymphatic vessels: A simple delivery route to promote nerve regeneration.

The structural and functional features of lymphatic vessels in the peripheral nervous system (pLVs) is still unclear. Here, we clarify the existence of pLVs in rats, PROX1-EGFP transgenic mice and human, and exhibit a clear three-dimensional structure for helping understand its structural features. Moreover, two specific phenotypes of lymphatics endothelial cells (Rnd1Hi LECs and Ccl21Hi LECs) in peripheral nerves are well characterized by single-cell sequencing. Subsequently, the ability of trans-lymphatic delivery to peripheral nerves via pLVs has been dynamically demonstrated. After peripheral nerve injury (PNI), extensive lymphangiogenesis occurs in the lesion area and further enhances the efficiency of retrograde lymphatic-nerve transport. In PNI animal models, subcutaneously footpad-injected exosomes are efficiently delivered to sciatic nerve via pLVs which can promote nerve regeneration. The trans-lymphatic delivery to peripheral nerves via pLVs can subtly bypass BNB which provides an easy and alternative delivery route for PNI treatment.

Spinal Lymphatic Dysfunction Aggravates the Recovery Process After Spinal Cord Injury.

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.