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  • 1.

    【2hr】Interspecies Organogenesis for Human Transplantation

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    机译 种间器官发生的人类移植
    摘要：Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.
  • 2.

    【2hr】Cells Involved in Urethral Tissue Engineering: SystematicReview

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    机译 细胞参与尿道组织工程：系统的评论
    摘要：The urethra is part of the lower urinary tract and its main role is urine voiding. Its complex histological structure makes urethral tissue prone to various injuries with complicated healing processes that often lead to scar formation. Urethral stricture disease can affect both men and women. The occurrence of this pathology is more common in men and thus are previous research has been mainly oriented on male urethra reconstruction. However, commonly used surgical techniques show unsatisfactory results because of complications. The new and progressively developing field of tissue engineering offers promising solutions, which could be applied in the urethral regeneration of both men´s and women´s urethras. The presented systematic review article offers an overview of the cells that have been used in urethral tissue engineering so far. Urine-derived stem cells show a great perspective in respect to urethral tissue engineering. They can be easily harvested and are a promising autologous cell source for the needs of tissue engineering techniques. The presented review also shows the importance of mechanical stimuli application on maturating tissue. Sufficient vascularization and elimination of stricture formation present the biggest challenges not only in customary surgical management but also in tissue-engineering approaches.
  • 3.

    【2hr】Stem Cell-Related Studies and Stem Cell-Based Therapies in LiverDiseases

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    机译 肝中与干细胞相关的研究和基于干细胞的疗法疾病
    摘要：Owing to the increasing worldwide burden of liver diseases, the crucial need for safe and effective interventions for treating end-stage liver failure has been a very productive line of inquiry in the discipline of hepatology for many years. Liver transplantation is recognized as the most effective treatment for end-stage liver disease; however, the shortage of donor organs, high medical costs, and lifelong use of immunosuppressive agents represent major drawbacks and demand exploration for alternative treatments. Stem cell-based therapies have been widely studied in the field of liver diseases and are considered to be among the most promising therapies. Herein, we review recent advances in the application of stem cell-related therapies in liver disease with the aim of providing readers with relevant knowledge in this field and inspiration to spur further inquiry.
  • 4.

    【2hr】Neural Repair in Stroke

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    机译 中风神经修复
    摘要：This article reviews the progress that has been made in the development of cell therapies for the repair of nervous system damage caused by strokes, since the first report on the use of cell transplants in animal models of ischemic brain injury in 1988. At that time neural progenitor cells derived from fetal brain tissue were used as sources of cells to replace specific subsets of neuronal cells that were lost in various regions of the brain following experimentally induced strokes. Since 1988, cells from other sources, such as embryonic stem cells and inducible pluripotent stem cells, have been investigated for their ability to replace neuronal cells and repair the damaged brain. Most recently, mesenchymal stem cells and cord blood stem cells have been studied for the ability to modulate the immune system and ameliorate the neuropathology and neurological deficits associated with experimental stroke. The preclinical investigation of different cell therapy approaches for treating stroke during the past three decades has now led to many ongoing clinical trials, with the clinical evaluation of stem cell therapies for stroke now involving global participants.
  • 5.

    【2hr】Harnessing Neurogenesis and Neuroplasticity with Stem Cell Treatment forAddictive Disorders

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    机译 利用干细胞治疗神经发生和神经可塑性上瘾性疾病
    摘要：Drug and alcohol addiction has become an emerging public health issue and is a great burden to patients, their families, and society. It is characterized by high relapse rates and significant morbidity and mortality, and most available treatments result in only modest improvement. These findings highlight the necessity for new approaches to treat addiction. Scientific reports in the past two decades suggest that addiction involves impaired neural plasticity and decreased hippocampal neurogenesis. Stem cell therapy and its derived neurotrophic factors can potentially target the underlying pathophysiology of addiction. Stem cell applications are showing promise in several preclinical studies and may provide new and noninvasive treatment strategies. Future clinical research is warranted to investigate whether stem cell-based therapy could support the treatment of addiction.
  • 6.

    【2hr】Neurotrophic Factor Secretion and Neural Differentiation Potential ofMultilineage-differentiating Stress-enduring (Muse) Cells Derived from Mouse AdiposeTissue

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    机译 神经营养因子的分泌和神经分化潜能小鼠脂肪衍生的多系分化应激持久（Muse）细胞组织
    摘要：Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent stem cells that can be isolated based on stage-specific embryonic antigen-3 (SSEA-3), a pluripotent stem cell-surface marker. However, their capacities for survival, neurotrophic factor secretion, and neuronal and glial differentiation are unclear in rodents. Here we analyzed mouse adipose tissue-derived Muse cells in vitro. We collected mesenchymal stem cells (MSCs) from C57BL/6 J mouse adipose tissue and separated SSEA-3+, namely Muse cells, and SSEA-3–, non-Muse cells, to assess self-renewability; pluripotency marker expression (Nanog, Oct3/4, Sox2, and SSEA-3); spontaneous differentiation into endodermal, mesodermal, and ectodermal lineages; and neural differentiation capabilities under cytokine induction. Neurally differentiated Muse and non-Muse cell functions were assessed by calcium imaging. Antioxidant ability was measured to assess survival under oxidative stress. Brain-derived neurotrophic factor (BDNF), vascular endothelial cell growth factor (VEGF), and hepatocyte growth factor (HGF) secretion were analyzed in enzyme-linked immunosorbent assays. SSEA-3+ Muse cells (6.3 ± 1.9% of mouse adipose-MSCs), but not non-Muse cells, exhibited self-renewability, spontaneous differentiation into the three germ layers, and differentiation into cells positive for Tuj-1 (27 ± 0.9%), O4 (17 ± 3.4%), or GFAP (23 ±1.3%) under cytokine induction. Neurally differentiated Muse cells responded to KCldepolarization with greater increases in cytoplasmic Ca2+ levels than non-Musecells. Cell survival under oxidative stress was significantly higher in Muse cells (50 ±2.7%) versus non-Muse cells (22 ± 2.8%). Muse cells secreted significantly more BDNF,VEGF, and HGF (273 ± 12, 1479 ± 7.5, and 6591 ± 1216 pg/mL, respectively) than non-Musecells (133 ± 4.0, 1165 ± 20, and 2383 ± 540 pg/mL, respectively). Mouse Muse cells wereisolated and characterized for the first time. Muse cells showed greater pluripotency-likecharacteristics, survival, neurotrophic factor secretion, and neuronal andglial-differentiation capacities than non-Muse cells, indicating that they may have betterneural-regeneration potential.
  • 7.

    【2hr】Immunological Characteristics and Properties of Glial Restricted Progenitorsof Mice, Canine Primary Culture Suspensions, and Human QSV40 Immortalized Cell Lines forProspective Therapies of Neurodegenerative Disorders

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    机译 胶质细胞限制性祖细胞的免疫学特性和特性小鼠，犬原代培养悬浮液和人类QSV40永生化细胞系的制备神经退行性疾病的前瞻性疗法
    摘要：Neurodegeneration can be defined as a process in which neuronal structures and functions undergo changes leading to reduced neuronal survival and increased cell death in the central nervous system (CNS). Neuronal degeneration in specific regions of the CNS is a hallmark of many neurodegenerative disorders, and there is reliable proof that neural stem cells bring therapeutic benefits in treatment of neurological lesions. However, effective therapy with neural stem cells is associated with their biological properties. The assessment of immunological properties and comprehensive studies on the biology of glial restricted progenitors (GRP) are necessary prior to the application of these cells in humans. This study provides an in vitro characterization of the QSV40 glial human cell line, as well as murine and canine primary culture suspensions of GRPs and their mature, astrocytic forms using flow cytometry and immunohistochemical staining. Cytokines and chemokines released by GRPs were assessed by Multiplex ELISA. Some immunological differences observed among species suggest the necessity of reconsidering the pre-clinical model, and that careful testing of immunomodulatory strategies is required before cell transplantation into the CNS can be undertaken.
  • 8.

    【2hr】TGF-β in Mice Ameliorates Experimental Autoimmune Encephalomyelitis inRegulating NK Cell Activity

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    机译 小鼠中的TGF-β改善了实验性自身免疫性脑脊髓炎调节NK细胞活性
    摘要：Multiple sclerosis is a disease characterized by inflammation and demyelination located in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for multiple sclerosis (MS). Although the roles of T cells in MS/EAE have been well investigated, little is known about the functions of other immune cells in the neuroinflammation model. Here we found that an essential cytokine transforming growth factor β (TGF-β) which could mediate the differentiation of Th17/regulatory T cells was implicated in the natural killer (NK) cells’ activity in EAE. In EAE mice, TGF-β expression was first increased at the onset and then decreased at the peak, but the expressions of TGF-β receptors and downstream molecules were not affected in EAE. When we immunized the mice with MOG antigen, it was revealed that TGF-β treatment reduced susceptibility to EAE with a lower clinical score than the control mice without TGF-β. Consistently, inflammatory cytokine production was reduced in the TGF-β treated group, especially with downregulated pathogenic interleukin-17 in the central nervous system tissue. Furthermore, TGF-β could increase the transcription level of NK cell marker NCR1 both in the spleen and in the CNS without changing other T cell markers. Meanwhile TGF-β promoted the proliferation of NK cell proliferation. Taken together, our data demonstrated that TGF-β could confer protection against EAE model in mice through NK cells, which wouldbe useful for the clinical therapy of MS.
  • 9.

    【2hr】Bexarotene Exerts Protective Effects Through Modulation of the CerebralVascular Smooth Muscle Cell Phenotypic Transformation by RegulatingPPARγ/FLAP/LTB4 After Subarachnoid Hemorrhage in Rats

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    机译 贝沙罗汀通过调节大脑发挥保护作用通过调节血管平滑肌细胞表型转化大鼠蛛网膜下腔出血后的PPARγ/ FLAP / LTB4
    摘要：Vascular smooth muscle cells (VSMCs) play an important role after a subarachnoid hemorrhage (SAH). The changes in VSMCs following bexarotene treatment after SAH are unknown. In the present study, neurological impairment, decreased cerebral cortical blood flow and transformation of cerebral VSMCs from a contractile to a synthetic phenotype were observed after SAH. Bexarotene reduced neurological impairment, improved cerebral cortical blood flow, inhibited VSMC phenotypic transformation and suppressed the expression of 5-lipoxygenase-activating protein (FLAP) and leukotriene B4 (LTB4), which was partly reversed by GW9662, an inhibitor of peroxisome proliferator-activated receptor gamma (PPARγ). Mechanistically, sh-PPARγ-mediated phenotypic transformation of VSMCs was partially suppressed by MK886, an antagonist of FLAP. Therefore, we conclude that bexarotene reduced neurological impairment, improved cerebral cortical blood flow and inhibited the VSMC phenotypic transformation after SAH, which was achieved by activating PPARγ-mediated inhibition of FLAP/LTB4 in VSMCs
  • 10.

    【2hr】Analysis of Synapses in Cerebral Organoids

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    机译 脑型器官突触的分析
    摘要：Cerebral organoids are an emerging cutting-edge technology to model human brain development and neurodevelopmental disorders, for which mouse models exhibit significant limitations. In the human brain, synaptic connections define neural circuits, and synaptic deficits account for various neurodevelopmental disorders. Thus, harnessing the full power of cerebral organoids for human brain modeling requires the ability to visualize and analyze synapses in cerebral organoids. Previously, we devised an optimized method to generate human cerebral organoids, and showed that optimal organoids express mature-neuron markers, including synaptic proteins and neurotransmitter receptors and transporters. Here, we give evidence for synaptogenesis in cerebral organoids, via microscopical visualization of synapses. We also describe multiple approaches to quantitatively analyze synapses in cerebral organoids. Collectively, our work provides sufficient evidence for the possibility of modeling synaptogenesis and synaptic disorders in cerebral organoids, and may help advance the use of cerebral organoids in molecular neuroscience and studies of neurodevelopmental disorders such as autism.
  • 11.

    【2hr】(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, andBehavioral Impairments Induced by Traumatic Brain Injury in Mice

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    机译 （-）-Phenserine改善挫伤体积，神经炎症和外伤性脑损伤在小鼠中引起的行为障碍
    摘要：Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer’s disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateralventricular size increase, motor asymmetry, motor coordination, and balance function,suggesting the improvement of these histological and behavioral tests by Phen treatmentoccur via pathways other than anti-acetylcholinesterase inhibition. However, the reductionof lesion size and improvement of sensorimotor function by Posiphen were much smaller thanwith equivalent doses of Phen. Taken together, these results show that post-injurytreatment with Phen over 5 days significantly ameliorates severity of TBI. These datasuggest a potential development of this compound for clinical use in TBI therapy.
  • 12.

    【2hr】Neural Stem Cell Transplantation Improves Locomotor Function in Spinal CordTransection Rats Associated with Nerve Regeneration and IGF-1 R Expression

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    机译 神经干细胞移植改善脊髓的运动功能横断大鼠与神经再生和IGF-1 R表达相关。
    摘要：Transplantation of neural stem cells (NSCs) is a potential strategy for the treatment of spinal cord transection (SCT). Here we investigated whether transplanted NSCs would improve motor function of rats with SCT and explored the underlying mechanism. First, the rats were divided into sham, SCT, and NSC groups. Rats in the SCT and NSC groups were all subjected to SCT in T10, and were administered with media and NSC transplantation into the lesion site, respectively. Immunohistochemistry was used to label Nestin-, TUNEL-, and NeuN-positive cells and reveal the expression and location of type I insulin-like growth factor receptor (IGF-1 R). Locomotor function of hind limbs was assessed by Basso, Beattie, Bresnahan (BBB) score and inclined plane test. The conduction velocity and amplitude of spinal nerve fibers were measured by electrophysiology and the anatomical changes were measured using magnetic resonance imaging. Moreover, expression of IGF-1 R was determined by real-time polymerase chain reaction and Western blotting. The results showed that NSCs could survive and differentiate into neurons in vitro and in vivo. SCT-induced deficits were reduced by NSC transplantation, including increase in NeuN-positive cells and decrease in apoptotic cells. Moreover, neurophysiological profiles indicated that the latent period was decreased and the peak-to-peak amplitude of spinal nerve fibers conduction was increased in transplanted rats, while morphological measuresindicated that fractional anisotropy and the number of nerve fibers in the site of spinalcord injury were increased after NSC transplantation. In addition, mRNA and protein levelof IGF-1 R were increased in the rostral segment in the NSC group, especially in neurons.Therefore, we concluded that NSC transplantation promotes motor function improvement ofSCT, which might be associated with activated IGF-1 R, especially in the rostral site. Allof the above suggests that this approach has potential for clinical treatment of spinalcord injury.
  • 13.

    【2hr】Reconstruction of the Damaged Dorsal Root Entry Zone by Transplantation ofOlfactory Ensheathing Cells

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    机译 移植重建受损的背根进入区。嗅鞘细胞
    摘要：The dorsal root entry zone is often used in research to examine the disconnection between the central and peripheral parts of the nervous system which occurs following injury. Our laboratory and others have used transplantation of olfactory ensheathing cells (OECs) to repair experimental spinal cord injuries. We have previously used a four dorsal root (C6–T1) transection model to show that transplantation of OECs can reinstate rat forelimb proprioception in a climbing task. Until now, however, we have not looked in detail at the anatomical interaction between OECs and the peripheral/central nervous system regions which form the transitional zone. In this study, we compared short- and long-term OEC survival and their interaction with the surrounding dorsal root tissue. We reveal how transplanted OECs orient toward the spinal cord and allow newly formed axons to travel across into the dorsal horn of the spinal cord. Reconstruction of the dorsal root entry zone was supported by OEC ensheathment of axons at the injured site and also at around 3 mm further away at the dorsal root ganglion. Quantitative analysis revealed no observable difference in dorsal column axonal loss between transplanted and control groups of rats.
  • 14.

    【2hr】Adipose-Derived Neural Stem Cells Combined with Acellular Dermal Matrix as aNeural Conduit Enhances Peripheral Nerve Repair

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    机译 脂肪来源的神经干细胞与无细胞真皮基质相结合神经导管可增强周围神经修复
    摘要：Reconstruction to close a peripheral nerve gap continues to be a challenge for clinical medicine, and much effort is being made to develop nerve conduits facilitate nerve gap closure. Acellular dermal matrix (ADM) is mainly used to aid wound healing, but its malleability and plasticity potentially enable it to be used in the treatment of nerve gaps. Adipose-derived stem cells (ADSCs) can be differentiated into three germ layer cells, including neurospheres. We tested the ability of ADSC-derived neural stem cells (NSCs) in combination with ADM or acellular sciatic nerve (ASN) to repair a transected sciatic nerve. We found that NSCs form neurospheres that express Nestin and Sox2, and could be co-cultured with ADM in vitro, where they express the survival marker Ki67. Following sciatic nerve transection in rats, treatment with ADM+NSC or ASN+NSC led to increases in relative gastrocnemius weight, cross-sectional muscle fiber area, and sciatic functional index as compared with untreated rats or rats treated with ADM or ASN alone. These findings suggest that ADM combined with NSCs can improve peripheral nerve gap repair after nerve transection and may also be useful for treating other types of neurological gaps.
  • 15.

    【2hr】The Efficacy of a Scaffold-free Bio 3D Conduit Developed from AutologousDermal Fibroblasts on Peripheral Nerve Regeneration in a Canine Ulnar Nerve Injury Model:A Preclinical Proof-of-Concept Study

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    机译 由Autologous开发的无支架Bio 3D导管的功效真皮成纤维细胞在犬尺神经损伤模型中对周围神经再生的作用：临床前概念验证研究
    摘要：Autologous nerve grafting is widely accepted as the gold standard treatment for segmental nerve defects. To overcome the inevitable disadvantages of the original method, alternative methods such as the tubulization technique have been developed. Several studies have investigated the characteristics of an ideal nerve conduit in terms of supportive cells, scaffolds, growth factors, and vascularity. Previously, we confirmed that biological scaffold-free conduits fabricated from human dermal fibroblasts promote nerve regeneration in a rat sciatic nerve injury model. The purpose of this study is to evaluate the feasibility of biological scaffold-free conduits composed of autologous dermal fibroblasts using a large-animal model. Six male beagle dogs were used in this study. Eight weeks before surgery, dermal fibroblasts were harvested from their groin skin and grown in culture. Bio 3D conduits were assembled from proliferating dermal fibroblasts using a Bio 3D printer. The ulnar nerve in each dog’s forelimb was exposed under general anesthesia and sharply cut to create a 5 mm interstump gap, which was bridged by the prepared 8 mm Bio 3D conduit. Ten weeks after surgery, nerve regeneration was investigated. Electrophysiological studies detected compound muscle action potentials (CMAPs) of the hypothenar muscles and motor nerve conduction velocity (MNCV) in all animals. Macroscopic observation showed regenerated ulnar nerves. Low-level hypothenarmuscle atrophy was confirmed. Immunohistochemical, histological, and morphometric studiesconfirmed the existence of many myelinated axons through the Bio 3D conduit. No severeadverse event was reported. Hypothenar muscles were re-innervated by regenerated nervefibers through the Bio 3D conduit. The scaffold-free Bio 3D conduit fabricated fromautologous dermal fibroblasts is effective for nerve regeneration in a canine ulnar nerveinjury model. This technology was feasible as a treatment for peripheral nerve injury andsegmental nerve defects in a preclinical setting.
  • 16.

    【2hr】Collagen VII Expression Is Required in Both Keratinocytes and Fibroblasts forAnchoring Fibril Formation in Bilayer Engineered Skin Substitutes

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    机译 角质形成细胞和成纤维细胞均需要胶原VII表达在双层工程皮肤替代物中锚定原纤维形成
    摘要：The blistering disease recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the gene encoding collagen VII (COL7), which forms anchoring fibrils that attach the epidermis to the dermis. Cutaneous gene therapy to restore COL7 expression in RDEB patient cells has been proposed, and cultured epithelial autograft containing COL7-modified keratinocytes was previously tested in clinical trials. Because COL7 in normal skin is expressed in both fibroblasts and keratinocytes, cutaneous gene therapy using a bilayer skin substitute may enable faster restoration of anchoring fibrils. Hypothetically, COL7 expression in either dermal fibroblasts or epidermal keratinocytes might be sufficient for functional anchoring fibril formation in a bilayer skin substitute. To test this, engineered skin substitutes (ESS) were prepared using four combinations of normal + RDEB cells: (1) RDEB fibroblasts + RDEB keratinocytes; (2) RDEB fibroblasts + normal keratinocytes; (3) normal fibroblasts + RDEB keratinocytes; and (4) normal fibroblasts + normal keratinocytes. ESS were incubated in vitro for 2 weeks prior to grafting to full-thickness wounds in immunodeficient mice. Biopsies were analyzed in vitro and at 1, 2, or 3 weeks after grafting. COL7 was undetectable in ESS prepared using all RDEB cells (group 1), and macroscopic blistering was observed by 2 weeks after grafting in ESS containing RDEB cells. COL7 was expressed, in vitro and in vivo, in ESSprepared using combinations of normal + RDEB cells (groups 2 and 3) or all normal cells(group 4). However, transmission electron microscopy revealed structurally normalanchoring fibrils, in vitro and by week 2 in vivo, only in ESS prepared using all normalcells (group 4). The results suggest that although COL7 protein is produced in engineeredskin when cells in only one layer express the COL7 gene, formation of structurally normalanchoring fibrils appears to require expression of COL7 in both dermal fibroblasts andepidermal keratinocytes.
  • 17.

    【2hr】The Impact of Limbal Mesenchymal Stromal Cells on Healing of Acute OcularSurface Wounds Is Improved by Pre-cultivation and Implantation in the Presence of LimbalEpithelial Cells

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    机译 角膜间质间质细胞对急性眼病愈合的影响通过在角膜缘存在下进行预培养和植入来改善表面伤口上皮细胞
    摘要：While limbal epithelial cells are used for treating ocular surface wounds, the therapeutic potential of mesenchymal cells cultivated from the limbal stroma (LMSC) is less clear. We have therefore examined the effects of LMSC when applied to acute ocular surface wounds. LMSC derived from male rabbits (RLMSC) were applied to the ocular surface of female rabbits immediately following removal of the corneal and limbal epithelium. Human amniotic membrane (HAM) was used as the vehicle for implanting the RLMSC. The effects of RLMSC were examined when applied alone (n = 3) and in conjunction with a stratified culture of human limbal epithelial cells (HLE) grown on the opposing surface of the HAM (n = 3). Outcomes were monitored over 3 months in comparison with animals receiving no treatment (n = 3) or treatment with HLE alone on HAM (n = 3). Animals treated with RLMSC (n = 6) displayed faster re-epithelialization (∼90% versus 70% healing after 12 weeks), with best results being observed when RLMSC were pre-cultivated and implanted in the presence of HLE (p < 0.01; 90% healing by 7 weeks). While all animals displayed conjunctival cells on the corneal surface (by presence of goblet cells and/or keratin 13 expression) and corneal neovascularization, evidence of corneal epithelial regeneration was observed in animals that received RLMSC in thepresence of HLE (by staining for keratin 3 and the absence of goblet cells). Conversely,corneal neovascularization was significantly greater when RLMSC were applied in theabsence of HLE (<0.05; 90% of cornea compared with 20–30% in other cohorts).Nevertheless, neither human nuclear antigen nor rabbit Y chromosome were detected withinthe regenerated epithelium. Our results demonstrate that while cultured LMSC encouragecorneal re-epithelialization, healing is improved by the pre-cultivation and implantationof these mesenchymal cells in the presence of limbal epithelial cells.
  • 18.

    【2hr】Metabolic Syndrome Induces Release of Smaller Extracellular Vesicles fromPorcine Mesenchymal Stem Cells

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    机译 代谢综合症诱导释放较小的细胞外囊泡猪间充质干细胞
    摘要：Mesenchymal stromal/stem cells (MSCs) belong to the endogenous cellular reparative system, and can be used exogenously in cell-based therapy. MSCs release extracellular vesicles (EVs), including exosomes and microvesicles, which mediate some of their therapeutic activity through intercellular communication. We have previously demonstrated that metabolic syndrome (MetS) modifies the cargo packed within swine EV, but whether it influences their phenotypical characteristics remains unclear. This study tested the hypothesis that MetS shifts the size distribution of MSC-derived EVs. Adipose tissue-derived MSC-EV subpopulations from Lean (n = 6) and MetS (n = 6) pigs were characterized for number and size using nanoparticle-tracking analysis, flow cytometry, and transmission electron microscopy. Expression of exosomal genes was determined using next-generation RNA-sequencing (RNA-seq). The number of EV released from Lean and MetS pig MSCs was similar, yet MetS-MSCs yielded a higher proportion of small-size EVs (202.4 ± 17.7 nm vs. 280.3 ± 15.1 nm), consistent with exosomes. RNA-seq showed that their EVs were enriched with exosomal markers. Lysosomal activity remained unaltered in MetS-MSCs. Therefore, MetS alters the size distribution of MSC-derived EVs in favor of exosome release. These observations may reflect MSC injury and membrane recycling in MetS or increased expulsion of wasteproducts, and may have important implications for development of adequate cell-basedtreatments.
  • 19.

    【2hr】B Lymphocytes Are the Target of Mesenchymal Stem Cells ImmunoregulatoryEffect in a Murine Graft-versus-Host Disease Model

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    机译 B淋巴细胞是间充质干细胞免疫调节的目标。在小鼠移植物抗宿主疾病模型中的作用
    摘要：There is growing clinical interest in the utilization of mesenchymal stem cells (MSCs) in the management of acute graft-versus-host disease (aGvHD), yet the effect of major histocompatibility complexes (MHCs) on B lymphocytes in this process has been less well documented. Working in an MHC fully mismatched murine aGvHD model, we found that MSC co-transfer significantly prolonged the survival time of the recipients. More interestingly, analysis on immunophenotypic profiles of posttransplant splenocytes showed that surface expression of CD69 (an early activation marker) and CD86 (a costimulatory molecule) was suppressed predominantly on donor derived B lymphocytes by MSC infusion. Additionally, mRNA level of interleukin-4, a potent B lymphocyte stimulator, was strikingly reduced from MSC-treated mice, while interleukin-10, the regulatory B lymphocytes inductor, was increased; these may underlie the lesser activation of B lymphocytes. In consistence, depletion of B lymphocytes in the transfusion inoculum further prolonged the survival time of aGvHD mice regardless of MSC administration. Therefore, B lymphocytes played an important role in the development of aGvHD, and they are targets in MSC-regulated immune response cascade in vivo. This study may provide a mechanistic clue for the treatment of human clinical aGvHD.
  • 20.

    【2hr】Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancervia HGF/c-Met Pathway

    包量

    机译 胰腺星状细胞促进胰腺癌的神经周浸润通过HGF / c-Met途径
    摘要：Pancreatic cancer (PC) is a highly lethal cancer that has a strong ability for invasion and metastasis, poor prognosis, and a stubbornly high death rate due to late diagnosis and early metastasis. Therefore, a better understanding of the mechanisms of metastasis should provide novel opportunities for therapeutic purposes. As a route of metastasis in PC, perineural invasion (PNI) occurs frequently; however, the molecular mechanism of PNI is still poorly understood. In this study, we show that the hepatocyte growth factor (HGF)/c-Met pathway plays a vital role in the PNI of PC. We found that HGF promotes PC cell migration and invasion by activating the HGF/c-Met pathway, and enhances the expression of nerve growth factor (NGF) and matrix metalloproteinase-9 (MMP9) in vitro. Furthermore, HGF significantly increased PC cell invasion of the dorsal root ganglia (DRG) and promoted the outgrowth of DRG in cocultured models of PC cells and DRG. In contrast, the capacity for invasion and the phenomenon of PNI in PC cells were reduced when the HGF/c-Met pathway was blocked by siRNA. In conclusion, PSCs facilitate PC cell PNI via the HGF/c-Met pathway. Targeting the HGF/c-Met signaling pathway could be a promising therapeutic strategy for PC.
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