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Acute respiratory distress syndrome (ARDS) is a critical, life-threatening condition marked by severe inflammation and impaired lung function. Mesenchymal stromal/stem cells (MSCs) present a promising therapeutic avenue due to their immunomodulatory, anti-inflammatory, and regenerative capabilities. This review comprehensively evaluates MSC-based strategies for ARDS treatment, including direct administration, tissue engineering, extracellular vesicles (EVs), nanoparticles, natural products, artificial intelligence (AI), gene modification, and MSC preconditioning. Direct MSC administration has demonstrated therapeutic potential but necessitates optimization to overcome challenges related to effective cell delivery, homing, and integration into damaged lung tissue. Tissue engineering methods, such as 3D-printed scaffolds and MSC sheets, enhance MSC survival and functionality within lung tissue. EVs and MSC-derived nanoparticles offer scalable and safer alternatives to cell-based therapies. Likewise, natural products and bioactive compounds derived from plants can augment MSC function and resilience, offering complementary strategies to enhance therapeutic outcomes. In addition, AI technologies could aid in optimizing MSC delivery and dosing, and gene editing tools like CRISPR/Cas9 allow precise modification of MSCs to enhance their therapeutic properties and target specific ARDS mechanisms. Preconditioning MSCs with hypoxia, growth factors, or pharmacological agents further enhances their therapeutic potential. While MSC therapies hold significant promise for ARDS, extensive research and clinical trials are essential to determine optimal protocols and ensure long-term safety and effectiveness.
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BACKGROUND:Mesenchymal stem cells have great potential in the treatment of ischemia-reperfusion injury of skin flaps.However,their defects and the decline of their role in the treatment of ischemia-reperfusion injury of skin flaps restrict their wide application. OBJECTIVE:To review the strategies for improving the treatment of ischemia-reperfusion injury of skin flaps with mesenchymal stem cells,and provide a reference for its further theoretical research and clinical application. METHODS:Relevant documents included in CNKI,WanFang and PubMed were searched.The Chinese and English search terms were"mesenchymal stem cell,ischemia-reperfusion adjustment of skin flap,mesenchymal stem cells,stem cells,skin flap,ischemia-reperfusion injury,pretreatment,gene modification,biomaterial packaging,joint application".The relevant documents since 2007 were retrieved,and the documents with little relationship between the research content and the article theme,poor quality and outdated content were eliminated through reading the article,and finally 75 documents were included for summary. RESULTS AND CONCLUSION:(1)Mesenchymal stem cells can inhibit inflammatory reactions,resist oxidative stress and induce angiogenesis,which has great potential in the treatment of skin flap ischemia-reperfusion injury.(2)Although mesenchymal stem cells have shown great potential in the treatment of skin flap ischemia-reperfusion injury,their shortcomings in treatment have limited their widespread clinical application.Through pre-treatment(cytokines,hypoxia,drugs,and other pre-treatment mesenchymal stem cells),gene-modified mesenchymal stem cells,biomaterial encapsulation of mesenchymal stem cells,as well as the combined use of mesenchymal stem cells and other drugs or therapeutic methods,can not only overcome the shortcomings of mesenchymal stem cells in treatment,but also improve their therapeutic effectiveness in skin flap ischemia-reperfusion injury.(3)Therefore,further improving the effectiveness of mesenchymal stem cells in treating skin flap ischemia-reperfusion injury and exploring its therapeutic potential are of great significance for the research of mesenchymal stem cells and the treatment of skin flap ischemia-reperfusion injury.
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BACKGROUND:Previous studies have successfully constructed erythropoietin-overexpressed umbilical cord mesenchymal stem cells.It was found that the apoptosis of ischemic and hypoxic human neuroblastoma cell line(SH-SY5Y)was significantly reduced by erythropoietin-overexpressed umbilical cord mesenchymal stem cells. OBJECTIVE:To explore the possible neuroprotective mechanisms of erythropoietin-overexpressed umbilical cord mesenchymal stem cells against ischemic-hypoxic SH-SY5Y and their associated epigenetic mechanisms. METHODS:Oxygen-glucose deprivation was applied to ischemia-hypoxia-induced SH-SY5Y cell injury,and multifactorial assays were applied to detect the expression levels of inflammatory factors in the cells before and after hypoxia and co-culture,respectively,with mesenchymal stem cells,as well as lentiviral-transfected null-loaded plasmids of the negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression levels of supernatant inflammatory factors were detected by multifactor assay after co-culture.Proteomics was used to detect the differentially expressed proteins of negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.Cleavage under targets and tagmentation sequencing was applied to detect genomic H3K4me2 modification,and joint analysis was conducted with RNA-sequencing.Lentiviral vector infection was applied to construct the stable knockdown of REST in SH-SY5Y cells.qRT-PCR and western blot assay were performed to detect the expression level of REST.The apoptosis was detected by flow cytometry after co-culture of oxygen-glucose deprivation treatment with erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression difference of H3K36me3 group proteins was detected by western blot assay,and transcriptome sequencing was performed to analyze the differentially expressed genes. RESULTS AND CONCLUSION:(1)Compared with the control group,monocyte chemotactic protein 1,interleukin-6,interleukin-18,and interleukin-1 beta,interferon α2,and interleukin-23 levels significantly increased in the cerebrospinal fluid supernatant of patients with ischemic-hypoxic encephalopathy(P<0.01).(2)After co-culturing SH-SY5Y cells with erythropoietin-overexpressed umbilical cord mesenchymal stem cells under ischemia and hypoxia,the expression levels of monocyte chemotactic protein 1 and interleukin-6 were significantly reduced.(3)Analysis of protein network interactions revealed significant downregulation of monocyte chemotactic protein 1,interleukin-6 related regulatory proteins CXCL1 and BGN.(4)Transcriptome sequencing analysis found that pro-inflammatory genes were down-regulated,and functional enrichment of histone modifications,and the expression of transcription factors REST and TET3 significantly up-regulated in the erythropoietin-overexpressed umbilical cord mesenchymal stem cell group compared with the negative control mesenchymal stem cell group.(5)Combined analysis of transcriptome sequencing and cleavage under targets and tagmentation revealed changes in epigenetic levels as well as significant activation of the promoter regions of transcription factors REST and TET3.(6)Stable knockdown REST in SH-SY5Y cells was successfully constructed;the transcript levels of REST mRNA and protein expression were both decreased.(7)After the REST knockdown SH-SY5Y cells were co-cultured with erythropoietin-overexpressed umbilical cord mesenchymal stem cells,apoptosis was significantly increased and H3K36me3 expression was significantly decreased.Transcriptome sequencing results showed that the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2 was reduced at mRNA transcription level(P<0.01).(8)It is concluded that erythropoietin-overexpressed umbilical cord mesenchymal stem cells activated the expression of REST and TET3 by altering the kurtosis of H3K4me2 and upregulated the modification level of H3K36me3,which in turn regulated the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2,and facilitated neuronal survival.
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Objective @#To investigate the imunomodulatory effects of umbilical cord mesenchymal stem cells(UC⁃MSCs) modified by miR⁃125b⁃5p through JAK2/STAT3 pathway on systemic lupus erythematosus(SLE) . @*Methods@#UC⁃MSCs were isolated and cultured under aseptic conditions ; Peripheral blood mononuclear cells ( PBMCs)were separated from SLE patients by density gradient centrifugation. The relative expressions of IL⁃17A , Foxp3 ,IFN⁃γ , IL⁃4 genes in PBMCs cultured with UC⁃MSCs for 48 h were detected by RT⁃qPCR; The relative expressions of JAK2 , p ⁃JAK2 , STAT3 , p ⁃STAT3 and IL⁃18 proteins in kidney tissues of MRL/lpr mice were detected by west⁃ern blot. @*Results @#Compared with the PBMCs culture group , the expression of IFN⁃γ and IL⁃17A and the propor⁃tion of Th17/Treg cells were significantly down⁃regulated in UC⁃MSCs + miR⁃125b⁃5p group , UC⁃MSCs + miR⁃NC group and UC⁃MSCs group(P < 0. 01) , the expression of the proportion of Th1/Th2 cells (P < 0. 05) was down⁃regulated in UC⁃MSCs + miR⁃125b⁃5p group and UC⁃MSCs + miR⁃NC group ; Compared with the untreated group of MRL/lpr mice , the relative expressions of JAK2 , p ⁃JAK2 , STAT3 , p ⁃STAT3 and IL⁃18 proteins in kidney tissues of MRL/lpr mice were significantly down⁃regulated in UC⁃MSCs + miR⁃125b⁃5p group (P < 0. 01) , and the rela⁃tive expressions of IL⁃18 proteins was significantly down⁃regulated in UC⁃MSCs + miR⁃NC group and UC⁃MSCs group (P < 0. 01) .@*Conclusion@#miR⁃125b⁃5p plays a synergistic role in UC⁃MSCs ,which regulates the differenti⁃ation of Th2 cells in PBMCs of SLE patients and the relative expressions of p ⁃JAK2/JAK2 , p ⁃STAT3/STAT3 , and IL⁃18 proteins in kidney tissues of MRL/lpr mice. UC⁃MSCs modified by miR⁃125b⁃5p may play immunomodulato⁃ry effect on SLE by JAK2/STAT3 signaling pathway.
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In 2016,the world's first birth by mitochondrial replacement technology was born.In 2017,UK Human Fertilisation & Embryology Authority approved the first application by Newcastle Fertility at Life for the use of mitochondrial replacement to treat patients.The technology has aroused controversy over gene modification of hu-man reproductive system,and some scholars have expressed their concerns and objections from the perspective of ethics.This paper would respond to these ethical concerns from three aspects of technical security,reproductive system gene modification and parenthood,oppose to call the technique of mitochondria replacement as the term"three parent test-tube baby technology",and clear that the application of mitochondrial replacement technology can be justified by ethics on the premise of ensuring safety and effectiveness.
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Objective To investigate the role of neurotrophin-3 (NT-3) gene modified bone marrow mesenchymal stem cells (BMSCs) in treatment of acute cerebral infarction and its underlying mechanism.Methods Seventy-two SD male rats were randomly divided into model group,BMSCs group,and BMSCs+NT-3 group (n=24).Focal cerebral ischemia rat models were established by middle cerebral artery occlusion (MCAO);24 h after MCAO,rats in the BMSCs group and BMSCs+NT-3 group were given BMSCs and NT-3 gene modified BMSCs via tail intravenous injection,respectively.Modified neurological severity scale (mNSS) was performed one,6,12 and 24 d after MCAO;infarct sizes were measured by TTC staining one,12 and 24 d after MCAO;expressions of neuronspecific enolase (NSE) and nestin in the surrounding areas of infarction were detected by Western blotting 6 d after MCAO.Results As compared with those in the BMSCs group,significantly decreased mNSS scores in BMSCs+NT-3 group were noted 6,12 and 24 d after MCAO (P＜0.05).Rats in the BMSCs+NT-3 group had significantly smaller brain infarct sizes than the BMSCs group 12 and 24 d after MCAO (P＜0.05).Expressions of NSE and nestin in the BMSCs+NT-3 group were significantly higher than those in the BMSCs group 6 d after MCAO (P＜0.05).Conclusion Transplantation of NT-3 gene modified BMSCs can further improve neurological functions and reduce brain infarct sizes as compared with BMSCs transplantation,whose mechanism might be related to promote the differentiation of BMSCs into neurons.
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The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system was first identified in bacteria and archaea and can degrade exogenous substrates. It was developed as a gene editing technology in 2013. Over the subsequent years, it has received extensive attention owing to its easy manipulation, high efficiency, and wide application in gene mutation and transcriptional regulation in mammals and plants. The process of CRISPR/Cas is optimized constantly and its application has also expanded dramatically. Therefore, CRISPR/Cas is considered a revolutionary technology in plant biology. Here, we introduce the mechanism of the type II CRISPR/Cas called CRISPR/Cas9, update its recent advances in various applications in plants, and discuss its future prospects to provide an argument for its use in the study of medicinal plants.
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Genetically modified tool animal models are the animal models,which are generated by modifying a defined gene and can be used as a tool to help realize other objective.Genetically modified large animals have wide applications in agriculture and biomedicine.Tool animal models play important role in biological research and development of new drugs in biomedicine,especially,have made tremendous contribution in revealing gene function and pathway of signal transduction.Pigs are not only an economically important agriculture animals,but also an ideal animal model in biomedicine due to its close similarity to human in physiology,as well as organ structure and size.Thanks to the breakthrough of newly emerged gene editing technology,striking progress has made in establishment of genetically modified tool pig models which include the ones used for monitoring pluripotency of cells,tracing cell lineages,replacing genes mediated by Cre recombinase,mimicking immunodeficiency,as well as gene editing in vivo.These tool models have been widely applied in biological research.Here,we will review the progress in generation of genetically modified tool pig models and their applications.
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The established immunodeficient animal models could be used as valuable resource for mechanism re-search of related disease in humans, drug discovery and development, translational research and stem cell research.How-ever, it is difficult and low-efficient to establish the genetic modified animal models using traditional technologies.The re-ports for immunodeficient animal models are few in middle-size and large animals.Recently, several effective gene-targeting tools, including ZFNs, TALENs, CRISPR/Cas9, develop quickly and provide technology basis for the establishment of im-munodeficient animal models.In this paper, the technology principles and research progresses of ZFNs, TALENs, CRISPR/Cas9 are introduced.The significant progresses of these emerging technologies achieved in immunodeficient ani-mal models are also elaborated, including KO Rag1/Rag2 rabbit, KO Rag1/Rag2 pig, KO IL2rg pig, KO Ppar-g/Rag1 monkey, and so on.In addition to being models for researching SCID-related diseases in humans, and evaluating the effica-cy and safety of stem-cell engraftment, these models may be also useful to develop surgical procedures for placement of grafts before clinical trials in humans, to produce humanized animals and bridge the gap between laboratory animal and medicical research.The immunodeficient animal models described here represent a step toward the comprehensive evalua-tion of preclinical cellular regenerative strategies.
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Objective We want to study the therapeutic efficiency of autologous ADMSC transplantation in myocardial infarction.And we try to find out a good way to improve the therapeutic efficiency by using the combination of gene therapy and cell therapy.Anti-apoptotic protein XIAP was selected to fight against the ischemic environment of myocardic infaction.Methods ADMSC was isolated from rat inguinal fat tissue.ADMSC was cultivated with DMEM.XIAP experession plasmid was elertco-transduced to ADMSC.The anti-apototic function of XIAP was tested by serum stavation induced apotosis.The method of ligation of the left anterior descending artery was used to prepare the Myocardial infarction model.Then rats were randomly separated into three groups to receive direct epicardial injections of normal saline,or ADMSCs cell suspension or XIAP modified ADMSCs cell suspension at five sites in central zones of myocardial infarction and border zone.Cardiac function and the infarct size were evaluated 4 weeks after ADMSCs transplantation.Results West blotting suggest that,XIAP over-expression block serum starvation induced apotosis.It showed that there are significant statistic difference among XIAP modified ADMSC transplantation group,ADMSC transplantation group and control group 4 weeks after myocardial infarction (P ＜ 0.05).Left ventricular ejection fraction(LVEF) showed a significant improvement in ADMSCs transplantation group compared to control group (P ＜0.05).Left ventricular end systolic diameter(LVDs) and left ventricular end diastolic diameter(LVDd) of ADMSCs group were smaller than control group(P ＜ 0.05).The area of myocardial infarction was significantly reduced in the ADMSCs transplantation group compared to the saline group(P ＜0.05).Compared to ADMSCs transplantation group,effect of the XIAP modified ADMSC in rats with myocardial infarction is more obvious.The reduction of LVEF of XIAP modified ADMSCs group was signific antly lower(9％) than the ADMSCs group(16％) (P ＜ 0.01).Infarction area in XIAP modified ADMSCs group(3.26 ±0.95)％ was smaller than ADMSCs group(5.17 ±2.03)％ (P ＜0.05).Conclusion Autologus ADMSC transplantation is an efficient therapeutic tool in myocardial infarction therapy.Over expression of XIAP can partly inhibit lowserum induced apotosis of ADMSC in vitro,and it can improve left ventricular function better in vivo.Over expression XIAP of ADMSC can improve the therapeutic efficiency compare to ADMSC transplantation.
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Although adoptive T cell therapy (ACT) has become a promising immunotherapeutic regime for cancer treatment, its effectiveness has been hindered by several inherent shortcomings regarding safety and efficacy. During the past few decades, several strategies for enhancing the efficacy of ACT have been developed and introduced in clinic. This review will summarize not only the past approaches but also the latest strategies which have been shown to enhance the anticancer activity of ACT.
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Inmunoterapia , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Objective To observe the toxicity and adverse reaction of interleukin(IL) 2 gene modified allogenic gastric cancer cell line in far advanced gastric cancer patients. Methods A phase Ⅰ clinical trial was conducted for sixteen far advanced gastric cancer patients with IL 2 gene modified gastric cancer cell line. By gene recombinant technique, human IL 2 cDNA was transfected into human gastric cancer cell line MKN45 via retrovirus based vector.These cells were then inactivated by irradiation (100 Gy) and were cryopreserved for the vaccine. The immunization were administrated subcutaneously at the first, 8 th , 15 th , 29 th and 58 th day. The patients were divided into 4 dosage groups, which the dosage of the vaccine was administrated in each subsequent level. The toxicity and adverse reaction were evaluated by WHO criteria. Results Fifteen of the 16 patients completed the immunization. Side effects of treatment consisted of mild to moderate fever, redness and swelling at the site of injection, which were the most common symptoms. Only one patient abandoned after the third injection due to rapidly progressive disease. Other reactions including allergic shock, bone marrow depression and disturbance of hepatorenal function were not observed during the immunization.In some patients, the serum transferrin, humoral immune parameters such as IgG, IgA, IgM,IL 2 and cellular immune parameters such as CD + 3,CD + 4,CD + 8 had been improved after treatment.Conclusions This trial demonstrates the feasibility, safety and potential therapeutic effects of vaccination of gastric cancer patients with allogenic, gene modified gastric cancer cell line. The dosage of the vaccine recommended for phase Ⅱ clinical trail is 5?10 7 cells per time.
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Objective To observe the changes of the gene expressions at spinal cord injury site of rat after transplantation of BDNF genetically modified neural stem cells(NSCs) so as to provide basic data for the repair of spinal cord injury. Methods The Wistar rats were randomly divided into 4 groups: control group, operation group, NSCs transplantation group, BDNF NSCs transplantation group. Four time points(7 day, 1 month, 2 month, 3 month) were divided for each group. The expressions of ? galactosidase and BDNF, GFAP, NF 200 at the site of spinal cord injury were observed by cell transplantation, X gal histochemistry, immunocytochemistry, in situ hybridization, etc. Results After transplantation of BDNF genetically modified NSCs, some X gal positive cells were found at the sections of spinal cord injury. The expressions of BDNF were strong, especially at 1 week and 1 month post transplantation in transplantation group. The GFAP and NF 200 positive cells were also found at each time point in each group. Conclusion BDNF genetically modified NSCs can survive at the site of spinal cord injury and can strongly express BDNF, suggesting that BDNF genetically modified NSCs can be used as the material for the repair of spinal cord injury.