Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Taurine: a promising nutraceutic in the prevention of retinal degeneration

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

Metastatic pancreatic and lung cancer patient in complete remission following immunotherapy: A case report and review of literature

BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.

Differential response of injured and healthy retinas to syngeneic and allogeneic transplantation of a clonal cell line of immortalized olfactory ensheathing glia:a double-edged sword

Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.

Pan-retinal ganglion cell markers in mice, rats, and rhesus macaques

Univocal identification of retinal ganglion cells(RGCs) is an essential prerequisite for studying their degeneration and neuroprotection. Before the advent of phenotypic markers, RGCs were normally identified using retrograde tracing of retinorecipient areas. This is an invasive technique, and its use is precluded in higher mammals such as monkeys. In the past decade, several RGC markers have been described. Here, we reviewed and analyzed the specificity of nine markers used to identify all or most RGCs, i.e., pan-RGC markers, in rats, mice, and macaques. The best markers in the three species in terms of specificity, proportion of RGCs labeled, and indicators of viability were BRN3A, expressed by vision-forming RGCs, and RBPMS, expressed by vision-and non-vision-forming RGCs. NEUN, often used to identify RGCs, was expressed by non-RGCs in the ganglion cell layer, and therefore was not RGC-specific. γ-SYN, TUJ1, and NF-L labeled the RGC axons, which impaired the detection of their somas in the central retina but would be good for studying RGC morphology. In rats, TUJ1 and NF-L were also expressed by non-RGCs. BM88, ERRβ,and PGP9.5 are rarely used as markers, but they identified most RGCs in the rats and macaques and ERRβ in mice. However, PGP9.5 was also expressed by non-RGCs in rats and macaques and BM88 and ERRβ were not suitable markers of viability.

Peripheral nerve regeneration through nerve conduits evokes differential expression of growth-associated protein-43 in the spinal cord

Growth-associated protein 43 plays a key role in neurite outgrowth through cytoskeleton remodeling.We have previously demonstrated that structural damage of peripheral nerves induces growth-associated protein 43 upregulation to promote growth cone formation.Conversely,the limited regenerative capacity of the central nervous system due to an inhibitory environment prevents major changes in neurite outgrowth and should be presumably associated with low levels of growth-associated protein 43 expression.However,central alterations due to peripheral nerve damage have never been assessed using the growthassociated protein 43 marker.In this study,we used the tubulization technique to repair 1 cm-long nerve gaps in the rat nerve injury/repair model and detected growth-associated protein 43 expression in the peripheral and central nervous systems.First,histological analysis of the regeneration process confirmed an active regeneration process of the nerve gaps through the conduit from 10 days onwards.The growth-associated protein 43 expression profile varied across regions and follow-up times,from a localized expression to an abundant and consistent expression throughout the regeneration tissue,confirming the presence of an active nerve regeneration process.Second,spinal cord changes were also histologically assessed,and no apparent changes in the structural and cellular organization were observed using routine staining methods.Surprisingly,remarkable differences and local changes appeared in growth-associated protein 43 expression at the spinal cord level,in particular at 20 days post-repair and beyond.Growth-associated protein 43 protein was first localized in the gracile fasciculus and was homogeneously distributed in the left posterior cord.These findings differed from the growth-associated protein 43 pattern observed in the healthy control,which did not express growth-associated protein 43 at these levels.Our results revealed a differential expression in growth-associated protein 43 protein not only in the regenerating nerve tissue but also in the spinal cord after peripheral nerve transection.These findings open the possibility of using this marker to monitor changes in the central nervous system after peripheral nerve injury.

Comparative effects of different types of exercise on health-related quality of life during and after active cancer treatment:A systematic review and network meta-analysis

Background The positive influence of most types of exercise has been reported repeatedly,but what the most effective exercise approaches are for improving health-related quality of life(HRQoL)in people with cancer remains unknown.The aim of this systematic review and network meta-analysis was to synthesize the evidence from intervention studies to assess the effects of different types of exercise on HRQoL during and after cancer treatment.Methods MEDLINE,SPORTDiscus,the Cochrane Library,Web of Science,and Scopus were searched for randomized controlled trials aimed at testing the effects of exercise interventions meant to improve HRQoL in people with cancer.Separate analyses were conducted for HRQoL as measured by general and cancer-specific questionnaires.We also evaluated whether the effects of exercise were different during and after cancer treatment in both the physical and mental HRQoL domains.Results In total,93 studies involving 7435 people with cancer were included.Network effect size estimates comparing exercise intervention vs.usual care were significant for combined exercise(0.35,95%confidence interval(95%CI):0.14–0.56)for HRQoL as measured by general questionnaires,and for combined(0.31,95%CI:0.13–0.48),mind–body exercise(0.54,95%CI:0.18–0.89),and walking(0.39,95%CI:0.04–0.74)for HRQoL as measured by cancer-specific questionnaires.Conclusion Exercise programs combining aerobic and resistance training can be recommended to improve HRQoL during and after cancer treatment.The scarcity and heterogeneity of these studies prevents us from making recommendations about other exercise modalities due to insufficient evidence.

Taurine:an essential amino sulfonic acid for retinal health

Taurine(2-amino-ethanesulfonic acid)is a naturally occurring amino sulfonic acid derived from cysteine and methionine metabolism.Its common name derives from the ox,as it was first isolated from the bile of an ox(Froger et al.,2014).The molecular structure of taurine differs from that of amino acids by the presence of a sulfonic acid,instead of the more common carboxylic acid group in the structure of amino acids.

Role of microglial cells in photoreceptor degeneration

Inherited photoreceptor degeneration in humans constitutes a major cause of irreversible blindness in the world.They comprise various diseases,but retinitis pigmentosa is the most frequently observed.Retinitis pigmentosa is commonly limited to the eye,where there is progressive photoreceptor degeneration,rods and secondarily cones.The mechanisms of cone and rod degeneration continue to be investigated,since most of the mutations causing retinitis pigmentosa affect rods and thus,the secondary death of cones is an intriguing question but,ultimately,the cause of blindness.Understanding the mechanisms of rod and cone degeneration could help us to develop therapies to stop or,at least,slow down the degeneration process.Secondary cone degeneration has been attributed to the trophic dependence between rods and cones,but microglial cell activation could also have a role.In this review,based on previous work carried out in our laboratory in early stages of photoreceptor degeneration in two animal models of retinitis pigmentosa,we show that microglial cell activation is observed prior to the the initiation of photoreceptor death.We also show that there is an increase of the retinal microglial cell densities and invasion of the outer retinal layers by microglial cells.The inhibition of the microglial cells improves photoreceptor survival and morphology,documenting a role for microglial cells in photoreceptor degeneration.Furthermore,these results indicate that the modulation of microglial cell reactivity can be used to prevent or diminish photoreceptor death in inherited photoreceptor degenerations.

The paradigm of protein acetylation in Parkinson's disease

Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it(Yakhine-Diop et al.,2018b).The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes,among others,gene expression,autophagy etc.,leading finally to cell death.Both enzymes are associated with Parkinson’s disease(PD)pathogenesis.In dopaminergic cells,neurotoxins provoke apoptotic cell death by increasing histone acetylation levels.While paraquat(Song et al.,2011)and rotenone(Feng et al.,2015)reduce HDAC activity,dieldrin(Song et al.,2010)enhances HAT activity.However in vivo,paraquat-induced upregulation ofα-synuclein triggers histone hypoacetylation.

Analysis of hepatitis C virus-positive organs in liver transplantation

The authors of this study note that in liver transplantation(LT),the survival rates of hepatitis C virus(HCV)-positive donors and HCV-negative receivers are compa-rable to those of HCV-negative donors and recipients.Direct-acting antiviral(DAA)therapies have nearly 100%effectiveness in treating HCV.Between 2006 and 2016,the percentages of HCV-positive patients on the waiting list and HCVpositive LT recipients fell by 8.2 percent and 7.6 percent,respectively.Records from April 1,2014,in which the donor and receiver were both at least 18 years old and had a positive HCV status,were the only ones eligible for the study.The analysis for this study was restricted to the first transplant recorded for each patient using a data element that documented the number of prior transplants for each recipient,although some recipients appeared multiple times in the data set.HCV-positive recipients or people with fulminant hepatic failure were the main beneficiaries of primary biliary cirrhosis among HCV-positive donors.However,there is still a reticence to use HCV-positive donor organs in HCV recipients due to clinical and ethical considerations.Similar survival rates between HCV-positive donors and recipients and HCV-negative donors and receivers illustrate the efficacy of these DAA regimens.

Identifying specific RGC types may shed light on their idiosyncratic responses to neuroprotection

Retinal ganglion cells（RGCs）are located in the innermost layer of the retina and are the only retinal output neurons,conveying light information to the main retinorecipient target regions of the brain responsible for the image-and non-image-forming visual functions.There are well over twenty RGC types,each with its own dendritic morphology and physiological characteristics,

Hepatitis C virus NS5A region mutation in chronic hepatitis C genotype 1 patients who are non-responders to two or more treatments and its relationship with response to a new treatment

To determine the number of mutations in the NS5A region of the hepatitis C virus (HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments. METHODSSequences within HCV NS5A [PKR binding domain (PKRBD) and the interferon-sensitivity-determining region (ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha (IFN-α), n = 49; IFN-α + ribavirin (RBV), n = 75; pegylated (peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals (DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response (SVR) and 153/201 achieved no virological response (NVR). RESULTSFor both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR (SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment (PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/mL and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR (P = 0.001). CONCLUSIONThe obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region (≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/mL.

Bone marrow-derived mononuclear stem cells in the treatment of retinal degenerations

Retinal degenerative diseases affecting the outer retina in its many forms(inherited,acquired or induced)are characterized by photoreceptor loss,and represent currently a leading cause of irreversible vision loss in the world.At present,there are very few treatments capable of preventing,recovering or reversing photoreceptor degeneration or the secondary retinal remodeling,which follows photoreceptor loss and can also cause the death of other retinal cells.Thus,these diseases are nowadays one of the greatest challenges in the field of ophthalmological research.Bone marrow derived-mononuclear stem cell transplantation has shown promising results for the treatment of photoreceptor degenerations.These cells may have the potential to slow down photoreceptor loss,and therefore should be applied in the early stages of photoreceptor degenerations.Furthermore,because of their possible paracrine effects,they may have a wide range of clinical applications,since they can potentially impact on several retinal cell types at once and photoreceptor degenerations can involve different cells and/or begin in one cell type and then affect adjacent cells.The intraocular injection of bone marrow derived-mononuclear stem cells also enhances the outcomes of other treatments aimed to protect photoreceptors.Therefore,it is likely that future investigations may combine bone marrow derived-mononuclear stem cell therapy with other systemic or intraocular treatments to obtain greater therapeutic effects in degenerative retinal diseases.

Mesenchymal stem cells and cell-free preparations for treating atopic dermatitis

Atopic dermatitis(AD)is a chronic cutaneous inflammatory disease caused by an interaction between genetic,immune and epidermal barrier factors.Several treatments can be used to treat this disease but there are patients that do not respond to actual drugs.So,there is a need to develop effective therapies for AD.Mesenchymal stem cells(MSCs)are non-hematopoietic multipotent adult progenitor cells with immunomodulatory power and self-regenerating capacity to repair tissue damage,so they could be a potential effective treatment for AD.MSCs-Conditioned Medium(CM)and MSCs-exosomes are cell-free preparation with molecules secreted by stem cells that could be also beneficial for AD.This viewpoint reviews the actual development of MSCs,MSCs-CM and MSCs-exosomes for treating patients with AD.

Alcohol-related diseases and liver metastasis:Role of cell-free network communication

Alcohol intake is a risk factor for cancer development and metastatic disease progression.Extracellular vesicle(EV)-mediated interorgan communication is assumed to be significant in boosting tumorigenic pathways and disease progression.Recent research indicates that exosomes have a variety of roles in the development of cancer during pathophysiological conditions.The involvement of EV signaling during cancer progression in the alcohol environment is unknown.Therefore,understanding communication networks and the role of EVs as biomarkers can contribute significantly to developing strategies to address the serious public health problems associated with alcohol consumption and cancer.

Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

Objectives To evaluate whether there is an association between the serum levels of the novel insulin-like adipokine isthmin-1(ISM1)and obesity-related phenotypes in a population of Spanish children and to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity.Methods The study population is a sub-cohort of the PUBMEP research project,consisting of a cross-sectional population of 119 pubertal children with overweight(17 boys,19 girls),obesity(20 boys,25 girls),and normal weight(17 boys,21 girls).All subjects were classified into experimental groups according to their sex,obesity,and insulin resistance(IR)status.They were counted anthropometry,glucose and lipid metabolism,inflammation and cardiovascular biomarkers as well as isthmin-1(ISM1)serum levels.This population was intended as a discovery population to elucidate the relationship between obesity and ISM1 levels in children.Furthermore,the study population had blood whole-genome DNA methylation examined,allowing deepening into the obesity–ISM1 molecular relationship.Results Higher serum ISM1 levels were observed in boys with obesity than in normal weight(P=0.004)and overweight(P=0.007)boys.ISM1 serum levels were positively associated with body mass index(BMI)Z-score(P=0.005)and fat mass(P=0.058)and negatively associated with myeloperoxidase(MPO)(P=0.043)in boys.Although we did not find associations between ISM1 serum levels and metabolic outcomes in girls,which may indicate a putative sexual dimorphism,fat mass was positively associated in all children,including boys and girls(P=0.011).DNA methylation levels in two-enhancer-related CpG sites of ISM1(cg03304641 and cg14269097)were associated with serum levels of ISM1 in children.Conclusions ISM1 is associated with obesity in boys at the pubertal stage,elucidating how this protein might be of special relevance as a new biomarker of obesity in children.Further studies including a longitudinal design during puberty are needed.

INMA-Sabadell队列中孕期双酚A及邻苯二甲酸酯暴露与胎儿发育的超声测量(续完)

暴露于ΣMWPm与任何胎儿大小或胎儿发育结局（见补充材料，表8）及所评估的出生结局（表2及补充材料表S7）都没有显著相关性。代谢物MnBP与12-20孕周HC增长降低有显著相关性（-4．88％；95％CI：-8．36，-1．36），且与EFW增长减低也有显著相关性（-4．32％；95％CI：-8．33，-0．27）（图3及补充材料表S8）。

INMA-Sabadell队列中孕期双酚A及邻苯二甲酸酯暴露与胎儿发育的超声测量(待续)

[背景]产前暴露于双酚A（BPA）及邻苯二甲酸酯会影响胎儿发育；然而该类研究很少，且得出的结果不一致。[目的]对一个西班牙出生队列中488对母婴进行研究，评估产前暴露于BPA及邻苯二甲酸酯是否与胎儿发育相关。[方法]检测第一和第三孕期两次尿液样本中BPA及8种邻苯二甲酸酯[4种邻苯二甲酸二（2-乙基己基）酯代谢物（DEHPm），邻苯二甲酸单卞酯（MBzP）以及3种低分子量邻苯二甲酸酯代谢物（LMWPm）]。另外，估计股骨长度（FL）、头围（HC）、腹围（AC）、双顶径（BPD）的生长曲线，估计孕期（12—20周，20～34周）的胎儿体重，并测量出生体重、出生长度、出生头围以及胎盘重量。[结果]总体上，结果并不支持孕期暴露于BPA或DEHPm与胎儿发育参数相关。产前MBzP暴露与20～34孕周的FL呈正相关，MBzP浓度每增加一倍，平均FL增加3．7％（95％CI：0．75，6．63％）。MBzP与男婴出生体重呈正相关（48g；95％CI：6，90），但在女婴中没有相关性（-27g；95％CI：-79，25）（交互作用P=0．04）。LMWPm邻苯二甲酸单丁酯（MnBP）与12—20孕周的HC呈负相关[平均HC降低了4．88％（95％CI：-8．36，-1．36％）]。[结论]本研究首次将暴露生物标志重复测量值与胎儿期多种发育参数相结合，发现暴露于BPA或邻苯二甲酸酯与胎儿发育不相关。邻苯二甲酸酯代谢物MBzP与MnBP与部分胎儿发育参数相关，但这些结果还需要重复验证。

Optimizing strategies to reduce alcohol consumption and relapses,improving abstinence in liver transplant recipients

We have read with great attention and special interest the paper by Carrique and collaborators entitled:Results of Early Transplantation for Alcohol-Related Cirrhosis:Integrated Addiction Treatment with Low Rate of Relapse(1).In this prospective study,the authors initiated a pilot program to challenge the paradigm of the“6-month rule”of abstinence for patients with alcohol-related liver disease(ALD)requiring a transplant(2).