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Rong Xu*, Nan Ma*, Fang Wang, Lei Ma, Rui Chen, Ru Chen, Mijiti Kebinu, Lili Ma, Zhongcheng Han, Ayixiamu, Mahemiti Mayier, Pengcheng Su, Yiming Naman, Haliyazimu Jieensi, Haixuan Yang, Abulizi Adili, Saiding Aili, Jiang LiuDepartment of Medical Oncology, People’s Hospital of Xinjiang, Urumqi, People’s Republic of China*These authors contributed equally to this workObjectives: We aimed to evaluate the efficacy and safety of combination therapy of Endostar (recombinant human endostatin) and S-1 combined with oxaliplatin (SOX) in patients with advanced gastric cancer.Methods: In this randomized, controlled trial, 165 late-stage gastric cancer patients were assigned to the experimental arm with Endostar in combination with SOX (80 patients) and the control arm with SOX alone (85 patients). The end points of this study included progression-free survival, response rate, and disease-control rate.Results: There was no statistically significant difference in response rate between the experimental arm and the control arm (53.8% vs 42.4%, P=0.188). The difference in disease-control rate was also statistically insignificant between the two arms (85.0% vs 72.9%, P=0.188). Progression-free survival in the experimental arm was significantly higher than that in the control arm (15.0 months vs 12.0 months, P=0.0001). Common adverse events included immunosuppression, gastrointestinal distress, and neuropathy. There was no statistical difference in the incidences of adverse events.Conclusion: Combination therapy of Endostar and SOX provides therapeutic benefits to advanced gastric cancer patients, with tolerable adverse effects.Keywords: endostatin, gastric cancer, SOX, oxaliplatin, Endostar, S-1

Background: The fusion rate, clinical efficacy, and complications of minimally invasive fusion surgery and open fusion surgery in the treatment of lumbar degenerative disease are still unclear., Methods: We conducted a literature search using PubMed, Embase, Cochrane Library, CNKI, and WANFANG databases., Results: This study included 38 retrospective studies involving 3097 patients. Five intervention modalities were considered: unilateral biportal endoscopic-lumbar interbody fusion (UBE-LIF), percutaneous endoscopic-lumbar interbody fusion (PE-LIF), minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF), transforaminal lumbar interbody fusion (TLIF), and posterior lumbar interbody fusion (PLIF). Quality assessment indicated that each study met acceptable quality standards. PE-LIF demonstrated reduced low back pain (Odds Ratio = 0.50, Confidence Interval: 0.38-0.65) and lower complication rate (Odds Ratio = 0.46, Confidence Interval: 0.25-0.87) compared to PLIF. However, in indirect comparisons, PE-LIF showed the lowest fusion rates, with the ranking as follows: UBE-LIF (83.2%) > MIS-TLIF (59.6%) > TLIF (44.3%) > PLIF (39.8%) > PE-LIF (23.1%). With respect to low back pain relief, PE-LIF yielded the best results, with the order of relief as follows: PE-LIF (96.4%) > MIS-TLIF (64.8%) > UBE-LIF (62.6%) > TLIF (23.0%) > PLIF (3.2%). Global and local consistency tests showed satisfactory results, and heterogeneity tests indicated good stability., Conclusions: Compared to conventional open surgery, minimally invasive fusion surgery offered better scores for low back pain and Oswestry Disability Index, lower complication rates, reduced bleeding, and shorter hospital stays. However, minimally invasive fusion surgery did not show a significant advantage in terms of fusion rate and had a longer operative time., (Copyright © 2024 Elsevier Inc. All rights reserved.)

PACS (Phosphofurin Acidic Cluster Sorting Protein) proteins are known for their roles in sorting cargo proteins to organelles and can physically interact with WD40 repeat-containing protein WDR37. PACS1, PACS2, and WDR37 variants are associated with multisystemic syndromes and neurodevelopmental disorders characterized by intellectual disability, seizures, developmental delays, craniofacial abnormalities, and autism spectrum disorder. However, the functional effects of syndromic variants at the cellular level remain unknown. Here, we report the expression pattern of C. elegans orthologs of PACS and WDR37 and their interaction. We show that cePACS-1 and ceWDR-37 co-localize to somatic cytoplasm of many types of cells, and are mutually required for expression, supporting a conclusion that the intermolecular dependence of PACS1/PACS2/PACS-1 and WDR37/WDR-37 is evolutionarily conserved. We further show that editing in PACS1 and PACS2 variants in cePACS-1 changes protein localization in multiple cell types, including neurons. Moreover, expression of human PACS1 can functionally complement C. elegans PACS-1 in neurons, demonstrating conserved functions of the PACS-WDR37 axis in an invertebrate model system. Our findings reveal effects of human variants and suggest potential strategies to identify regulatory network components that may contribute to understanding molecular underpinnings of PACS/WDR37 syndromes., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Previous studies have highlighted the antitumor effects of mesenchymal stem cell‑derived extracellular vesicles (MSC‑EVs), positioning them as a promising therapeutic avenue for cancer treatment. However, some researchers have proposed a bidirectional influence of MSC‑EVs on tumors, determined by the specific tissue origin of the MSCs and the types of tumors involved. The present study aimed to elucidate the effects of human placenta MSC‑derived extracellular vesicles (hPMSC‑EVs) on the malignant behavior of a mouse breast cancer model of 4T1 cells in vitro and in vivo . The findings revealed that hPMSC‑EVs significantly inhibited the proliferation, migration and colony formation of cultured 4T1 mouse breast cancer cells without inducing apoptosis. Exposure to conditioned medium from 4T1 cells pretreated with hPMSC‑EVs resulted in decreased angiogenic activity, accompanied by the downregulation of angiogenesis‑promoting genes in human umbilical vein endothelial cells. In murine xenograft models derived from the 4T1 cell line, local administration of hPMSC‑EVs substantially hindered tumor growth. Further results revealed that hPMSC‑EVs inhibited angiogenesis in vivo , as reflected by the use of a vascular growth factor receptor 2‑Fluc transgenic mouse model. In summary, the results confirmed that hPMSC‑EVs negatively modulated breast cancer growth by suppressing tumor cell proliferation and migration via an indirect antiangiogenic mechanism. These results underscored the therapeutic potential of EVs, suggesting a promising avenue for alternative anticancer treatments in the future.

We conducted in a common garden experiment to explore the differences in soil enzyme activity, stoichiometry, and their influencing factors among a secondary Castanopsis carlesii forest, 10-year-old C. carlesii plantation, and Cunninghamia lanceolata plantation. The results showed that compared to the secondary forest, the soil organic carbon, total nitrogen, and dissolved organic carbon significantly decreased by 42.6%, 47.4%, and 60.9% in C. carlesii plantation, and by 42.9%, 36.7%, and 61.1% in C. lanceolata plantation. Soil microbial biomass C, microbial biomass N (MBN), and microbial biomass phosphorus decreased significantly by 40.6%, 35.5%, and 45.9% in C. carlesii plantation, and by 53.7%、56.4%, and 61.7% in C. lanceolata plantation. Compared to the secondary forest, soil enzymes activities in C. carlesii plantation did not change significantly, but in C. lanceolata plantation, the activities of β-1,4-glucosidase and cellobiohydrolase significantly decreased by 51.2% and 59.8%, β- N -acetyl glucosaminidase and acid phosphatase decreased significantly by 41.0% and 29.8%, and enzymatic C:N acquisition ratio and enzymatic C:P acquisition ratio significantly decreased by 11.3% and 7.7%, respectively. Results of redundancy analysis indicated that MBN and NO 3 - -N were the primary factors influencing soil enzyme activity and enzymic stoichiometry. Collectively, there were significant differences in soil enzyme activity and microbial nutrient demands among different forest stands. Compared to secondary forests, the establishment of C. lanceolata plantations would intensify nutrient competition between plants and microbes, and exacerbate the N and P limitations for microbes.

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9 + stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9 + lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9 + stem cells, we set up an AKI model with prostaglandin E2 (PGE 2 ) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9 + lineage. Our results revealed that PGE 2 could activate renal Sox9 + cells and promote the differentiation of Sox9 + cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE 2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9 + stem cells with PGE 2 for the regenerative therapy of AKI., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Background: Bimekizumab, a humanized monoclonal IgG1 antibody targeting both interleukin (IL)-17A and IL-17F, could be effective for treating Psoriatic arthritis (PsA). This study aimed to systematically evaluate the efficacy and safety of bimekizumab in the management of PsA., Research Design and Methods: A comprehensive literature search by August 2023 was performed through PubMed, Embase, Cochrane Controlled Register of Trials, and ClinicalTrials.gov. investigating the efficacy or safety data of bimekizumab in the treatment of PsA. Data was pooled using the random-effects models. Egger tests were used to evaluate potential publication bias., Results: A total of 4 RCTs, involving 892 PsA patients and 467 placebo controls, were included in this analysis. Bimekizumab significantly increased the rates of PASI75 and PASI100 compared with placebos [RR = 7.22, 95% CI (5.24, 9.94), p < 0.001; RR = 10.12, 95% CI (6.00, 17.09), p  < 0.001]. The rate of overall adverse events was slightly higher in the bimekizumab group [RR = 1.42, 95% CI (1.05, 1.93) p  = 0.023). However, there were fewer adverse severe drug reactions in the bimekizumab group compared to the placebo., Conclusion: Bimekizumab had a significant clinical benefit in managing PsA and an acceptable safety profile.

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS., Competing Interests: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, ‘A multifunctional biomimetic nanoplatform for image-guideded photothermal-ferroptotic synergistic osteosarcoma therapy’., (© 2024 The Authors.)

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant β-galactosidase (β-GAL H363A ). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of β-GAL H363A . Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells., Competing Interests: HH, MQ, YL, SC, HL, XC, QZ, ZL No competing interests declared, ZH is an employee of AmCellGene Co., Ltd. The author has no further interests to declare, ZH is an employee of Health & Biotech Co and AmCellGene Co., Ltd. The author has no further interests to declare, (© 2023, Huang, Qian, Liu et al.)

Objective: To explore the similarities and variations of biological phenotype and cytotoxicity of human umbilical cord blood natural killer cells (hUC- NK) after human umbilical cord blood-derived mononuclear cells (hUC-MNC) activated and expanded by two in vitro high-efficient strategies., Methods: Umbilical cord blood mononuclear cells (MNC) from healthy donor were enriched by Ficoll-based density gradient centrifugation. Then, the phenotype, subpopulations, cell viability and cytotoxicity of NK cells derived from Miltenyi medium (denoted as M-NK) and X-VIVO 15 (denoted as X-NK) were compared using a "3IL" strategy., Results: After a 14-day's culture, the contents of CD3 - CD56 + NK cells were elevated from 4.25%±0.04% (d 0) to 71%±0.18% (M-NK) and 75.2%±1.1% (X-NK) respectively. Compared with X-NK group, the proportion of CD3 + CD4 + T cells and CD3 + CD56 + NKT cells in M-NK group decreased significantly. The percentages of CD16 + , NKG2D + , NKp44 + , CD25 + NK cells in X-NK group was higher than those in the M-NK group, while the total number of expanded NK cells in X-NK group was half of that in M-NK group. There were no significant differences between X-NK and M-NK groups in cell proliferation and cell cycle, except for the lower percentage of Annexin V+ apoptotic cells in M-NK group. Compared with X-NK group, the proportion of CD107a + NK cells in M-NK group were higher under the same effector-target ratio (E∶T) ( P <0.05)., Conclusion: The two strategies were adequate for high-efficient generation of NK cells with high level of activation in vitro , however, there are differences in biological phenotypes and tumor cytotoxicity.

Background: Mesenchymal stem cells (MSCs) have demonstrated remarkable therapeutic promise for acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). MSC secretomes contain various immunoregulatory mediators that modulate both innate and adaptive immune responses. Priming MSCs has been widely considered to boost their therapeutic efficacy for a variety of diseases. Prostaglandin E2 (PGE2) plays a vital role in physiological processes that mediate the regeneration of injured organs., Methods: This work utilized PGE2 to prime MSCs and investigated their therapeutic potential in ALI models. MSCs were obtained from human placental tissue. MSCs were transduced with firefly luciferase (Fluc)/eGFP fusion protein for real-time monitoring of MSC migration. Comprehensive genomic analyses explored the therapeutic effects and molecular mechanisms of PGE2-primed MSCs in LPS-induced ALI models., Results: Our results demonstrated that PGE2-MSCs effectively ameliorated lung injury and decreased total cell numbers, neutrophils, macrophages, and protein levels in bronchoalveolar lavage fluid (BALF). Meanwhile, treating ALI mice with PGE2-MSCs dramatically reduced histopathological changes and proinflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, our findings supported that PGE2 priming improved the therapeutic efficacy of MSCs through M2 macrophage polarization., Conclusion: PGE2-MSC therapy significantly reduced the severity of LPS-induced ALI in mice by modulating macrophage polarization and cytokine production. This strategy boosts the therapeutic efficacy of MSCs in cell-based ALI therapy., (© 2023. The Author(s).)

Endothelial cell injury plays a critical part in ischemic acute kidney injury (AKI) and participates in the progression of AKI. Targeting renal endothelial cell therapy may ameliorate vascular injury and further improve the prognosis of ischemic AKI. Here, P-selectin as a biomarker of ischemic AKI in endothelial cells is identified and P-selectin binding peptide (PBP)-engineered extracellular vesicles (PBP-EVs) with imaging and therapeutic functions are developed. The results show that PBP-EVs exhibit a selective targeting tendency to injured kidneys, while providing spatiotemporal information for the early diagnosis of AKI by quantifying the expression of P-selectin in the kidneys by molecular imaging. Meanwhile, PBP-EVs reveal superior nephroprotective functions in the promotion of renal repair and inhibition of fibrosis by alleviating inflammatory infiltration, improving reparative angiogenesis, and ameliorating maladaptive repair of the renal parenchyma. In conclusion, PBP-EVs, as an ischemic AKI theranostic system that is designed in this study, provide a spatiotemporal diagnosis in the early stages of AKI to help guide personalized therapy and exhibit superior nephroprotective effects, offering proof-of-concept data to design EV-based theranostic strategies to promote renal recovery and further improve long-term outcomes following AKI., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The capture and elimination of anions and cations from water have attracted a great deal of attention and are quite vital for clean production and environmental remediation. In this work, we present the synthesis of four porphyrin (Por)-based conjugated microporous polymers (CMPs, namely, Por-CMP-1-4), which were produced through a Sonogashira-Hagihara linked response using porphyrin and acetylene aromatic compounds as building blocks and used as absorbents to eliminate metal ions from water. The as-synthesized Por-CMP-1-4 exhibit an amorphous porous structure and outstanding caloric and physicochemical properties. Taking advantage of their larger specific surface areas, i.e., 541.47, 614.58, 382.38, and 677.90 m 2 g -1 for Por-CMP-1-4, respectively, and their chelating active site that originated from the porphyrin ring, Por-CMP-1-4 show better Zn 2+ , Cu 2+ , and Pb 2+ adsorption ability. Among them, Por-CMP-3 has the greatest adsorbability of 640 mg g -1 for Zn 2+ , with an adsorption efficiency of 80%, whereas its adsorption capacities for Cu 2+ and Pb 2+ ions were both 334 mg g -1 , with an adsorption efficiency of 42% for Cu 2+ and Pb 2+ . Employing Por-CMP-3 as a representative example, its adsorption kinetics has been systematically investigated. The adsorption behavior of Por-CMP-3 with respect to the Zn 2+ ion is shown to exhibit pseudo-first-order kinetics and Langmuir isotherm modes. Meanwhile, the adsorption mechanism is discussed in detail, and it was thought it might be chelation, in which the nitrogen atoms with a single pair of electrons on the porphyrin ring interacted with metal ions to form stable chelation coordination bonds, thus removing metal ions selectively and effectively. Furthermore, Por-CMP-3 exhibited good reusability, retaining 60% of its Zn 2+ removal rate after four continuous adsorptions.

Background: Intravenous administration of mesenchymal stromal cells (MSCs) has an acknowledged competence of cardiac repair, despite a lack of systematic description of the underlying biological mechanisms. The lung, but not the heart, is the main trapped site for intravenously transplanted MSCs, which leaves a spatial gap between intravenously transplanted MSCs and the injured myocardium. How lung-trapped MSCs after intravenous transplantation rejuvenate the injured myocardium remains unknown., Methods: MSCs were isolated from human placenta tissue, and DF-MSCs or Gluc-MSCs were generated by transduced with firefly luciferase (Fluc)/enhanced green fluorescence protein (eGFP) or Gaussia luciferase (Gluc) lactadherin fusion protein. The therapeutic efficiency of intravenously transplanted MSCs was investigated in a murine model of doxorubicin (Dox)-induced cardiotoxicity. Trans-organ communication from the lung to the heart with the delivery of blood was investigated by testing the release of MSC-derived extracellular vesicles (MSC-EVs), and the potential miRNA inner MSC-EVs were screened out and verified. The potential therapeutic miRNA inner MSC-EVs were then upregulated or downregulated to assess the further therapeutic efficiency RESULTS: Dox-induced cardiotoxicity, characterized by cardiac atrophy, left ventricular dysfunction, and injured myocardium, was alleviated by consecutive doses of MSCs. These cardioprotective effects might be attributed to suppressing GRP78 triggering endoplasmic reticulum (ER) stress-induced apoptosis in cardiomyocytes. Our results confirmed that miR-181a-5p from MSCs-derived EVs (MSC-EVs) inhibited GRP78. Intravenous DF-MSCs were trapped in lung vasculature, secreted a certain number of EVs into serum, which could be confirmed by the detection of eGFP + EVs. GLuc activity was increased in serum EVs from mice administrated with GLuc-MSCs. MiR-181a-5p, inhibiting GRP78 with high efficacy, was highly expressed in serum EVs and myocardium after injecting consecutive doses of MSCs into mice treated with Dox. Finally, upregulation or downregulation of miR-181a-5p levels in MSC-EVs enhanced or weakened therapeutic effects on Dox-induced cardiotoxicity through modulating ER stress-induced apoptosis., Conclusions: This study identifies intravenously transplanted MSCs, as an endocrine reservoir, to secrete cardioprotective EVs into blood continuously and gradually to confer the trans-organ communication that relieves Dox-induced cardiotoxicity., (© 2022. The Author(s).)

Metal clusters, such as iron-sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins. Herein we report the formation and crystal structure of a planar square tetranuclear silver cluster when silver ions were mixed with human copper chaperone Atox1. Quantum chemical studies reveal that two Ag 5s 1 electrons in the tetranuclear silver cluster fully occupy the one bonding molecular orbital, with the assumption that this Ag 4 cluster is Ag 4 2+ , leading to extensive electron delocalization over the planar square and significant stabilization. This bonding pattern of the tetranuclear silver cluster represents an aromatic all-metal structure that follows a 4 n + 2 electron counting rule ( n = 0). This is the first time an all-metal aromatic silver cluster was observed in a protein., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: The aim of this study was to investigate the clinical effectiveness of an indwelling transanal tube for the prevention of anastomotic leakage (AL) after a radical operation for Hirschsprung's disease (HD). Methods: We retrospectively analyzed the clinical data from 158 patients who had undergone laparoscopic-assisted Soave procedures for HD at our hospital from May 2015 to May 2019. Patients were divided into two groups depending upon whether the anal drainage tube was retained or not retained: an indwelling group (group A, n  = 86) and a no-indwelling group (group B, n  = 72). Results: All 158 children had a successful operation by a laparoscopic technique. There was no significant difference in the duration of the operation, the length of the incision, the amount of bleeding, or the postoperative hospitalization time between the two groups. Compared with the no-indwelling group, maintaining the transanal tube had significant advantages for preventing incidences of AL ( P  < .05). The 4-year follow-up showed that the incidence of postoperative enterocolitis with the indwelling transanal tube was significantly lower than in the group without the drainage tube ( P  < .05). Conclusions: The laparoscopic-assisted Soave procedure with an indwelling transanal tube is a safe and feasible method for the treatment of HD in children. This method can not only drain intestinal contents but also reduce the occurrence of AL.

Background: The promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E 2 (PGE 2 ), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE 2 has been well reported in tissue regeneration, the application of PGE 2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE 2 ., Results: In this study, we designed and synthesized a new PGE 2 release matrix by chemically bonding PGE 2 to collagen. Our results revealed that the PGE 2 matrix effectively extends the half-life of PGE 2 in vitro and in vivo. Moreover, the PGE 2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE 2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis., Conclusions: Our findings highlight the chemical bonding strategy of chemical bonding PGE 2 to collagen for sustained release and may facilitate the development of PGE 2 -based therapies to significantly improve tissue regeneration., (© 2022. The Author(s).)

Aim: To evaluate therapeutic outcomes of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) treatment in patients with refractory uveitis., Methods: A retrospective and noncomparative review was performed on four patients with refractory uveitis from December 2013 to December 2017. HUC-MSCs were administered intravenously at a dose of 1×10 6 cells/kg. Clinical response, relapse rate, change of visual acuity, and other metrics were evaluated., Results: All four patients presented with responses to HUC-MSCs treatment, with three males and one female. The numbers of uveitis attacks per year after the HUC-MSCs treatment (0, 2, 0, 0 respectively) all decreased compared with the numbers before the treatment (3, 6, 4, 4 respectively). The oral steroid and immunosuppressive agents were tapered in all patients without recrudescence of ocular inflammation, and three patients discontinued their oral medicine at the last visit. The best corrected visual acuity (BCVA) of 3 patients was improved to varying degrees, and the BCVA of 1 patient remained at 20/20 (Snellen chart) from the first to the last consultation., Conclusion: The study provides an effective therapy of HUC-MSCs in maintaining remission in patients affected by uveitis refractory to previous immunosuppressant treatments., (International Journal of Ophthalmology Press.)

Prostaglandin E 2 (PGE 2 ) has recently been recognized to play a role in immune regulation and tissue regeneration. However, the short half-life of PGE 2 limits its clinical application. Improving the delivery of PGE 2 specifically to the target organ with a prolonged release method is highly desirable. Taking advantage of the adequate space and proximity of the renal parenchyma, renal subcapsular delivery allows minimally invasive and effective delivery to the entire kidney. Here, we report that by covalently cross-linking it to a collagen matrix, PGE 2 exhibits an adequate long-term presence in the kidney with extensive intraparenchymal penetration through renal subcapsular delivery and significantly improves kidney function. Sox9 cell lineage tracing with intravital microscopy revealed that PGE 2 could activate the endogenous renal progenitor Sox9 + cells through the Yap signaling pathway. Our results highlight the prospects of utilizing renal subcapsular-based drug delivery and facilitate new applications of PGE 2 -releasing matrices for regenerative therapy., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people's life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Fructose-1,6-biphosphate aldolase (FBA) is a multifunctional enzyme in plants, which participates in the process of Calvin-Benson cycle, glycolysis and gluconeogenesis. Despite the importance of FBA genes in regulating plant growth, development and abiotic stress responses, little is known about their roles in cotton. In the present study, we performed a genome-wide identification and characterization of FBAs in Gossypium hirsutum . Totally seventeen GhFBA genes were identified. According to the analysis of functional domain, phylogenetic relationship, and gene structure, GhFBA genes were classified into two subgroups. Furthermore, nine GhFBAs were predicted to be in chloroplast and eight were located in cytoplasm. Moreover, the promoter prediction showed a variety of abiotic stresses and phytohormone related cis -acting elements exist in the 2k up-stream region of GhFBA . And the evolutionary characteristics of cotton FBA genes were clearly presented by synteny analysis. Moreover, the results of transcriptome and qRT-PCR analysis showed that the expression of GhFBAs were related to the tissue distribution, and further analysis suggested that GhFBAs could respond to various abiotic stress and phytohormonal treatments. Overall, our systematic analysis of GhFBA genes would not only provide a basis for the understanding of the evolution of GhFBAs , but also found a foundation for the further function analysis of GhFBAs to improve cotton yield and environmental adaptability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhang, Li, Su, Liu, Han, Wang and Zhu.)

Objective: This study investigated the effect of salvia miltiorrhiza-asarum ointment (SMAO) plus Chinese medical massage on knee osteoarthritis in a rat model., Methods: Hulth's method was used to establish a Sprague-Dawley rat model of knee osteoarthritis (OA). The levels of matrix metalloproteinase-13 (MMP-13), collagen-II, aggrecan, interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 were measured by enzyme-linked immunosorbent assays. The joint space was assessed by a Perlove X-ray system. Histopathology was examined by hematoxylin-eosin and Safranin O staining. The mRNA and protein expression levels of Notch1, MMP-13, collagen-II, and aggrecan were measured by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively., Results: SMAO plus Chinese medical massage significantly decreased the levels of MMP-13, IL-1β, TNF-α, and IL-6, and increased serum collagen-II and aggrecan levels. Pathological injury of the knee joint was improved by SMAO treatment. mRNA and protein expression of Notch1 and MMP-13 was remarkably downregulated, but collagen-II and aggrecan levels were significantly upregulated in cartilage tissues., Conclusion: SMAO combined with Chinese medical massage effectively relieves OA symptoms, which may involve inhibiting inflammation through the Notch1/MMP-13 signaling pathway.

Background: The senescence of dermal fibroblasts (DFLs) leads to an imbalance in the synthesis and degradation of extracellular matrix (ECM) proteins, presenting so-called senescence-associated secretory phenotype (SASP), which ultimately leads to skin aging. Recently, mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been recognized as a promising cell-free therapy for degenerative diseases, which opens a new avenue for skin aging treatment., Methods: In this study, we utilized chitosan (CS) hydrogel for effective loading and sustained release of EVs. In vitro, we explored the rejuvenation effects of CS hydrogel-incorporated EVs (CS-EVs) on replicative senescence DFLs through a series of experiments such as senescence-associated β-galactosidase (SA-β-gal) staining, RT-PCR, and Western blot analysis. Besides, we employed local multi-site subcutaneous injection to treat skin aging of naturally aged mice with CS-EVs and DiI fluorescent dye was used to label EVs to achieve in vivo real-time tracking., Results: CS-EVs can significantly improve the biological functions of senescent fibroblasts, including promoting their proliferation, enhancing the synthesis of ECM proteins, and inhibiting the overexpression of matrix metalloproteinases (MMPs). Moreover, CS hydrogel could prolong the release of EVs and significantly increase the retention of EVs in vivo. After CS-EVs subcutaneous injection treatment, the aging skin tissues showed a rejuvenation state, manifested explicitly as the enhanced expression of collagen, the decreased expression of SASP-related factors, and the restoration of tissue structures., Conclusions: CS hydrogel-encapsulated EVs could delay the skin aging processes by ameliorating the function of aging DFLs. Our results also highlight the potential of CS hydrogel-encapsulated EVs as a novel therapeutic strategy for improving aging skin to rejuvenation.

Perinatal-related tissues, such as the placenta, umbilical cord, and amniotic membrane, are generally discarded after delivery and are increasingly attracting attention as alternative sources for decellularized extracellular matrix (dECM) isolation. Recent studies indicate that glycosaminoglycans (GAGs) in the dECM play key roles during tissue regeneration. However, the dECM is organ specific, and the glycosaminoglycanomics of dECMs from perinatal tissues and the regulatory function of GAGs have been poorly investigated. In this study, we explored the glycosaminoglycanomics of dECMs from the placenta, umbilical cord and amniotic membrane. We hypothesized that the therapeutic effects of dECMs are related to the detailed composition of GAGs. Hydrogels of dECM derived from perinatal tissues were generated, and glycosaminoglycanomics analysis was employed to identify the cues that promote tissue repair and regeneration in a murine cutaneous wound-healing model. We utilized highly sensitive liquid chromatography-tandem mass spectrometry for glycosaminoglycanomics analysis. Our results revealed that placenta-derived dECM (PL-dECM) hydrogel has higher contents of chondroitin sulfate (CS) and heparan sulfate (HS). In addition, molecular imaging showed that the PL-dECM hydrogel exerted the best anti-inflammatory and proangiogenic effects in the skin wound healing model. Further in vitro analyses demonstrated that CS with 6-O-sulfo group (CS-6S) has an anti-inflammatory effect, while HS with 6-O-sulfo group (HS-6S) plays a crucial role in angiogenesis. In conclusion, this study highlights the critical roles of GAGs in perinatal tissue-derived dECMs by promoting angiogenesis and inhibiting inflammation and indicates that it is feasible to utilize 6-sulfated GAG-enriched placental dECM hydrogel as an attractive candidate for tissue engineering and drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Chemotherapy is an effective anti-tumor treatment. Mesenchymal stem cells (MSCs), exerting therapy effect on injured tissues during chemotherapy, may be damaged in the process. The possibility of self-healing through long-range paracrine and the mechanisms are unclear., Methods: Doxorubicin, a commonly used chemotherapy drug, was to treat human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) for 6 h as an in vitro cell model of chemotherapy-induced damage. Then we use extracellular vesicles derived from placental mesenchymal stem cells (hP-MSCs) to investigate the therapeutic potential of MSCs-EVs for chemotherapy injury. The mechanism was explored using microRNA sequencing., Results: MSC-derived extracellular vesicles significantly alleviated the chemotherapy-induced apoptosis. Using microRNA sequencing, we identified hsa-miR-11401, which was downregulated in the Dox group but upregulated in the EV group. The upregulation of hsa-miR-11401 reduced the expression of SCOTIN, thereby inhibiting p53-dependent cell apoptosis., Conclusions: Hsa-miR-11401 expressed by MSCs can be transported to chemotherapy-damaged cells by EVs, reducing the high expression of SCOTIN in damaged cells, thereby inhibiting SCOTIN-mediated apoptosis.

Mesenchymal stem cells (MSCs) are pluripotent cells that can be applied to the treatment of immune disorders, including inflammatory bowel disease (IBD). The therapeutic effects of MSCs have been mostly attributed to the secretion of soluble factors with paracrine actions, such as extracellular vesicles (EVs), which may play a relevant role in the repair of damaged tissues. In the present study, a mouse model of colitis was induced with the use of trinitrobenzene sulfonic acid (TNBS). EVs derived from human placental mesenchymal stem cells (hP‑MSCs) were used for the treatment of colitis by in situ injection. Clinical scores were applied to verify the therapeutic effects of EVs on mice with colitis. Inflammation in the colon was evaluated by measuring the levels of various inflammatory cytokines. The content of reactive oxygen species (ROS) was detected by the use of molecular imaging methods for real‑time tracking and the therapeutic effects of EVs on mucosal healing in mice with colitis were evaluated. The results revealed that the injection of EVs regulated the balance of pro‑inflammatory and anti‑inflammatory cytokines in colon tissue. Treatment with EVs also suppressed oxidative stress by decreasing the activity of myeloperoxidase (MPO) and ROS. Histological analysis further confirmed that the EVs significantly promoted mucosal healing, as reflected by the promotion of the proliferation of colonic epithelial cells and the maintenance of tight junctions. Taken together, the findings of the present study demonstrated that EVs derived from hP‑MSCs alleviated TNBS‑induced colitis by inhibiting inflammation and oxidative stress. These findings may provide a novel theoretical basis for the EV‑based treatment of IBD.

Therapeutic angiogenesis with mesenchymal stem cells (MSCs) is promising for the clinical treatment of peripheral artery disease (PAD). However, the heterogeneous proangiogenic nature of MSCs is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. Here, we propose to enhance the therapeutic function of human placenta-derived MSCs (hP-MSCs) in hindlimb ischemia therapy by using nitric oxide (NO)-releasing chitosan hydrogel (CS-NO). Our data showed that the co-transplantation of CS-NO hydrogel with hP-MSCs remarkably improved the grafting of hP-MSCs and ameliorated the functional recovery of ischemic hindlimbs. Moreover, we found that the neovascularization of damaged hindlimbs was significantly increased after co-transplanting CS-NO hydrogel and hP-MSCs, as confirmed by bioluminescence imaging (BLI). Further analysis revealed an endothelial-like status transformation of hP-MSCs in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. In conclusion, this study provides a promising approach for using NO hydrogel to improve the proangiogenic potency of MSCs in ischemic diseases, and the strategy used here facilitates the development of controlled-release scaffolds for enhancing the therapeutic efficiency of MSCs in angiogenic therapy. STATEMENT OF SIGNIFICANCE: The heterogeneous proangiogenic nature of mesenchymal stem cells (MSCs) is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. In this study, we investigated whether nitric oxide (NO)-releasing chitosan hydrogel (CS-NO) could improve the proangiogenic potency of MSCs in ischemic diseases. Our results revealed an endothelial-like status transformation of human placenta-derived MSCs (hP-MSCs) in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. The strategy for enhancing the pro-angiogenic activity of MSCs with biomaterials provides a practical idea for overcoming the challenges associated with the clinical application of MSCs in therapeutic angiogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to stimulate regeneration in the treatment of kidney injury. Renal regeneration is also thought to be stimulated by the activation of Sox9 + cells. However, whether and how the activation mechanisms underlying EV treatment and Sox9 + cell-dependent regeneration intersect is unclear. We reasoned that a high-resolution imaging platform in living animals could help to untangle this system. To test this idea, we first applied EVs derived from human placenta-derived MSCs (hP-MSCs) to a Sox9-Cre ERT2 ; R26 mTmG transgenic mouse model of acute kidney injury (AKI). Then, we developed an abdominal imaging window in the mouse and tracked the Sox9 + cells in the inducible Sox9-Cre transgenic mice via in vivo lineage tracing with two-photon intravital microscopy. Our results demonstrated that EVs can travel to the injured kidneys post intravenous injection as visualized by Gaussia luciferase imaging and markedly increase the activation of Sox9 + cells. Moreover, the two-photon living imaging of lineage-labeled Sox9 + cells showed that the EVs promoted the expansion of Sox9 + cells in kidneys post AKI. Histological staining results confirmed that the descendants of Sox9 + cells contributed to nephric tubule regeneration which significantly ameliorated the renal function after AKI. In summary, intravital lineage tracing with two-photon microscopy through an embedded abdominal imaging window provides a practical strategy to investigate the beneficial functions and to clarify the mechanisms of regenerative therapies in AKI., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Zhang et al.)

Background: Complete regeneration after skin injury remains a critical clinical challenge. Hydrogels, modified with growth factors or mimicking peptides, have been applied for functional tissue regeneration by increasing the bioactivity of engineered matrices. Methodology & results:  We synthesized an injectable biological hydrogel, C domain of IGF-1 (IGF-1C)-modified chitosan (CS-IGF-1C) hydrogel. Mouse model of cutaneous wound healing was established to investigate whether this hydrogel could promote wound healing. Our results demonstrated that CS-IGF-1C hydrogel exhibited superior proangiogenic effects, resulting in accelerated wound closure and improved extracellular matrix remodeling. Bioluminescence imaging and histology analysis confirmed the proangiogenic role of CS-IGF-1C hydrogel. Conclusion: CS-IGF-1C hydrogel could accelerate cutaneous wound healing by stimulating angiogenesis.

Background: Mesenchymal stem cell (MSC)-based therapies hold great promise for the treatment of inflammatory bowel disease (IBD). In order to optimize and maximize the therapeutic benefits of MSCs, we investigated whether cotransplantation of a chitosan (CS)-based injectable hydrogel with immobilized IGF-1 C domain peptide (CS-IGF-1C) and human placenta-derived MSCs (hP-MSCs) could ameliorate colitis in mice. Methods: IGF-1C hydrogel was generated by immobilizing IGF-1C to CS hydrogel. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. We initially applied hP-MSCs and CS-IGF-1C hydrogel for the treatment of colitis by in situ injection, and molecular imaging methods were used for real-time imaging of reactive oxygen species (ROS) and tracking of transplanted hP-MSCs by bioluminescence imaging (BLI). Furthermore, the effects of CS-IGF-1C hydrogel on prostaglandin E 2 (PGE 2 ) secretion of hP-MSCs and polarization of M2 macrophages were investigated as well. Results: The CS-IGF-1C hydrogel significantly increased hP-MSC proliferation and promoted the production of PGE 2 from hP-MSCs in vitro . Moreover, in vivo studies indicated that the CS-IGF-1C hydrogel promoted hP-MSC survival as visualized by BLI and markedly alleviated mouse colitis, which was possibly mediated by hP-MSC production of PGE 2 and interleukin-10 (IL-10) production by polarized M2 macrophages. Conclusions: The CS-IGF-1C hydrogel improved the engraftment of transplanted hP-MSCs, ameliorated inflammatory responses, and further promoted the functional and structural recovery of colitis through PGE 2 -mediated M2 macrophage polarization. Molecular imaging approaches and therapeutic strategies for hydrogel application provide a versatile platform for exploring the promising therapeutic potential of MSCs in the treatment of IBD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Inorganic membranes in wastewater treatment have captured increasing attention due to their numerous advantages. However, high cost and complicated producing process restricted their benign developments. This study proposed an novel inorganic geopolymer-zeolite composite membrane which was synthesized by using circulating fluidized bed fly ash (CFBFA) solid waste as initial material and via a low-cost and facile geopolymerization-hydrothermal treatment processes, further, the membrane was employed to separate Cr(VI) ion from aqueous solutions. X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectra results indicated that geopolymer-zeolite (Li-ABW) composite membrane was obtained successfully. Field emission scanning electron microscopy (FESEM) results demonstrated that the membrane had a compact zeolite layer with thickness about 1.5 μm. The effects of transmembrane pressures (TMP), Cr(VI) concentration, pH, ionic strength, and co-existing ions on Cr(VI) rejection were investigated, and the results revealed that the Cr(VI) rejection reached 85.45 % under 10 kPa of TMP, 1000 mg L -1 of Cr(VI), and pH 7. The separation mechanism of Cr(VI) on the geopolymer-zeolite composite membrane was considered to be size exclusion and electrostatic interaction. These results suggested that the geopolymer-zeolite composite membrane had a potential application for the effective removal of Cr(VI) contaminants from wastewater., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To explore the relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension and the interaction between telomere length and mtDNA-CN on hypertension in coal miners. Methods: A case control study was conducted in a coal mine of Shanxi province from July to December of 2013, in which 325 healthy workers were selected as the control group and 378 workers with hypertension as the case group. The information about general demographic characteristics and life behavior habits of the subjects were collected through questionnaire. Levels of telomere length and mtDNA-CN in peripheral blood were detected by real-time PCR. Unconditional logistic regression was used to examine the association between hypertension and telomere length, mtDNA-CN. The interaction test between telomere length and mtDNA-CN on hypertension was performed by adding the interaction term in the corresponding model. Results: The mean telomere length of the workers in the case group was (1.50±0.55) kb, and that of the control group was (2.01±0.62) kb, the difference between two groups was significant ( t =11.68, P <0.001). The correlation analysis showed that telomere length was positively correlated with mtDNA-CN ( r =0.157, P =0.002) in the case group. Multivariate analysis showed that telomere length ( OR =4.408, 95% CI : 3.012-6.452), age ( OR =0.417, 95% CI : 0.284-0.613), BMI ( OR =1.357, 95% CI : 1.162-1.584), monthly household income level ( OR =0.656, 95% CI : 0.553-0.778) and work duration ( OR =1.249, 95% CI : 1.100-1.417) were influencing factors of hypertension. The multiply interaction between telomere length and mtDNA-CN was significant on hypertension ( OR =1.267, 95% CI : 1.094-1.468). Conclusions: The results suggest shorter telomere length is a risk factor of hypertension. There is a multiply interaction between telomere length and mtDNA-CN on hypertension. However, the association between mtDNA-CN and hypertension was not found.

Background: Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to have therapeutic potential for ischemic diseases and are considered an alternative to cell therapy. However, the low retention and poor stability of EVs post-transplantation in vivo remain obstacle prior to the clinical application of EVs., Methods: This study was designed to investigate whether collagen matrix could increase the retention and stability of EVs and further improve the therapeutic effects in murine acute kidney injury (AKI) model. EVs were isolated from human placental MSCs (hP-MSC-EVs) and encapsulated in a collagen matrix. Then, we investigated whether collagen matrix can prolong the retention of EVs in vivo, further enhancing the therapeutic efficiency of EVs in AKI., Results: Our results indicated that collagen matrix could effectively encapsulate EVs, significantly increase the stability of EVs, and promote the sustained release of EVs. Collagen matrix has improved the retention of EVs in the AKI model, which was proved by Gaussia luciferase (Gluc) imaging. The application of collagen matrix remarkably facilitated the proliferation of renal tubular epithelial cells in AKI compared with EVs alone. Moreover, collagen matrix could further augment the therapeutic effects of hP-MSC-EVs as revealed by angiogenesis, fibrosis and apoptosis, and functional analysis. Finally, we found that EVs play a therapeutic role by inhibiting endoplasmic reticulum (ER) stress., Conclusions: Collagen matrix markedly enhanced the retention of EVs and further augmented the therapeutic effects of EVs for AKI. This strategy for improving the efficacy of EVs therapy provides a new direction for cell-free therapy.

With the immunoregulation potential, mesenchymal stem cells (MSCs) have been used for tissue regeneration by relieving inflammation in the injured tissues. When this repair process is interfered by immune disorders or pathological angiogenesis, the delays in corneal epithelial wound healing can lead to a persistent epithelial defect. Stem cell-derived extracellular vesicles (EVs), which carry abundant bioactive molecules from stem cells, have provided an alternative to regeneration therapy. In this study, we aimed to investigate if EVs from human placenta-derived MSCs (hP-MSCs) could ameliorate alkali injury of the cornea in the mouse model. 33.33  μ g/ μ L EVs in 10  μ L PBS were applied to the cornea. Repeat application three times, and 100  μ g EVs (in 30  μ L PBS) in total were administrated per day for two weeks. Our results revealed that EVs from hP-MSCs had preferable functions including enhancing proliferation and anti-inflammation and suppressing apoptosis of corneal epithelial cells. Furthermore, hP-MSC-derived EVs ameliorated mouse corneal wound healing by inhibiting angiogenesis and inflammation. Taken together, our current data suggested that hP-MSC-derived EVs have the beneficial effects of corneal wound healing, which provide alternative cell-free therapy with great practical value., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Hongyan Tao et al.)

Objective To analyze the differences in biological functions between bone marrow(BM)-derived CD106 + mesenchymal stem cells(MSCs)and the CD106 - subgroup. Methods The MSCs from normal BM were isolated and expanded.The subgroups of CD106 + and CD106 - MSCs were sorted.The cell proliferation and adhesion functions,chemotactic activities,adipogenic and osteogenic potentials,senescence,and senescence protein 21(p21)were detected.The capacity of translocation into nucleus of nuclear factor-kappa B(NF-κB)when stimulated by tumor necrosis factor(TNF-α)was measured. Results The proliferative ability was higher in CD106 + MSCs than that in CD106 - MSCs.In 48 hours,the value of optical density(OD)was significantly higher in CD106 + MSCs than that in CD106 - subgroup(1.004±0.028 vs. 0.659±0.023, t =3.946, P =0.0225).In 72 hours,this phenomenon was even more pronounced(2.574±0.089 vs. 1.590±0.074, t =11.240, P =0.0000).The adhesive capacity of CD106 + MSCs was significantly stronger than that of CD106 - subgroup(0.648±0.018 vs. 0.418±0.023, t =7.869, P =0.0002).Besides,the metastasis ability of CD106 + MSCs were significantly stronger than that of CD106 - subgroup(114.500±4.481 vs. 71.000±4.435, t =6.900, P =0.0005).The CD106 + MSCs had signifcnatly lower proportions of senescent cells.The expression of aging protein p21 in CD106 + MSCs was significantly lower than that in CD106 - MSCs [(17.560±1.421)% vs. (45.800±2.569)%, t =9.618, P =0.0000].Furthermore,there were no visible pigmenting cells after β-galactosidase staining in CD106 + MSCs subgroup.However,in CD106 - MSCs,some colored green cells were detected.The rate of NF-κB translocation into nucleus after stimulated by TNF-α was significantly higher in CD106 + MSCs than CD106 - MSCs [(37.780±3.268)% vs. (7.30±1.25)%, t =8.713, P =0.0001]. Conclusion Bone marrow-derived CD106 + MSCs possess more powerful biological functions than CD106 - MSCs.

Background: Poor cell engraftment and survival after transplantation limited the application of stem cell therapy. Synthetic biomaterials could provide an artificial microenvironment for stem cells, thereby improve cell survival and enhance the therapeutic efficiency of stem cells., Methods: We synthesized a hydrogel by conjugating C domain peptide of insulin-like growth factor-1 (IGF-1C) onto chitosan (CS-IGF-1C hydrogel). Human placenta-derived mesenchymal stem cells (hP-MSCs), which constitutively express a red fluorescent protein (RFP) and renilla luciferase (Rluc), were co-transplanted with CS-IGF-1C hydrogel into a murine hindlimb ischemia model. Transgenic mice expressing firefly luciferase (Fluc) under the promoter of vascular endothelial growth factor receptor 2 (VEGFR2-Luc) were used. Dual bioluminescence imaging (BLI) was applied for tracking the survival of hP-MSCs by Rluc imaging and the VEGFR2 signal pathway activation by Fluc imaging. To investigate the therapeutic mechanism of CS-IGF-1C hydrogel, angiographic, real-time PCR, and histological analysis were carried out., Results: CS-IGF-1C hydrogel could improve hP-MSCs survival as well as promote angiogenesis as confirmed by dual BLI. These results were consistent with accelerated skeletal muscle structural and functional recovery. Histology analysis confirmed that CS-IGF-1C hydrogel robustly prevented fibrosis as shown by reduced collagen deposition, along with increased angiogenesis. In addition, the protective effects of CS-IGF-1C hydrogel, such as inhibiting H 2 O 2 -induced apoptosis and reducing inflammatory responses, were proved by in vitro experiments., Conclusions: Taken together, IGF-1Cs provides a conducive niche for hP-MSCs to exert pro-mitogenic, anti-apoptotic, and pro-angiogenic effects, as well as to inhibit fibrosis. Thus, the incorporation of functional peptide into bioscaffolds represents a safe and feasible approach to augment the therapeutic efficacy of stem cells.

Increasing evidence has shown that mesenchymal stem cells (MSCs) isolated from body tissues are heterogeneous while being examined in vitro and in vivo. Besides some common characteristics, MSCs derived from different tissues exhibit unique biological properties. In addition, the therapeutic effects of MSCs may vary widely due to their heterogeneity and the technical differences in large-scale ex vivo expansion. In this chapter, the heterogeneity of MSCs will be discussed in three levels: the individual donors, the tissue sources, and the cell surface markers.

Wound healing is regulated by a complex series of events and overlapping phases. A delicate balance of cytokines and mediators in tissue repair is required for optimal therapy in clinical applications. Molecular imaging technologies, with their versatility in monitoring cellular and molecular events in living organisms, offer tangible options to better guide tissue repair by regulating the balance of cytokines and mediators at injured sites. Methods: A murine cutaneous wound healing model was developed to investigate if incorporation of prostaglandin E 2 (PGE 2 ) into chitosan (CS) hydrogel (CS+PGE 2 hydrogel) could enhance its therapeutic effects. Bioluminescence imaging (BLI) was used to noninvasively monitor the inflammation and angiogenesis processes at injured sites during wound healing. We also investigated the M1 and M2 paradigm of macrophage activation during wound healing. Results: CS hydrogel could prolong the release of PGE 2 , thereby improving its tissue repair and regeneration capabilities. Molecular imaging results showed that the prolonged release of PGE 2 could ameliorate inflammation by promoting the M2 phenotypic transformation of macrophages. Also, CS+PGE 2 hydrogel could augment angiogenesis at the injured sites during the early phase of tissue repair, as revealed by BLI. Furthermore, our results demonstrated that CS+PGE 2 hydrogel could regulate the balance among the three overlapping phases-inflammation, regeneration (angiogenesis), and remodeling (fibrosis)-during cutaneous wound healing. Conclusion: Our findings highlight the potential of the CS+PGE 2 hydrogel as a novel therapeutic strategy for promoting tissue regeneration via M2 macrophage polarization. Moreover, molecular imaging provides a platform for monitoring cellular and molecular events in real-time during tissue repair and facilitates the discovery of optimal therapeutics for injury repair by regulating the balance of cytokines and mediators at injured sites., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective To investigate the vascularization ability of mesenchymal stem cells(MSCs)and explore its influencing factors in aplastic anemia(AA) patients. Methods MSCs were isolated from the bone marrow of AA patients(AA MSCs) and normal controls(N MSCs) were cultured and then evaluated by flow cytometry and immunofluorescene staining technique.The expression level of vascular cell adhesion molecule-1(CD106) was detected by gene sequencing,and the content and fluorescene intensity of CD106 + MSCs was determined by fluorescence-activated cell sorting.The content of CD105 + CD106 + MSCs in fresh AA bone marrow was measured,followed by the determination of the capability of endothelial differentiation from AA MSCs and N MSCs with immunofluorescene analysis;finally,the capability of CD31 + cell differentiation from CD106-blocking N MSCs and its tubular structures formation in matrigel were tested.Results The expression of CD106 in AA patients was defective(decreased by 12.13 times when compared with N MSCs) and the concentration and fluorescene degree of CD106 + MSCs was also decreased in AA patients [(28.03±17.71)% vs.(59.61±12.26)%,P=0.000].The content of CD105 + CD106 + MSCs decreased significantly in the fresh bone marrow [(0.33±0.10)% vs.(2.98±0.46)%,P=0.0005].Besides, the capability of CD31 + cell differentiation from AA MSCs was significantly delayed [(13.67±1.50)% vs.(43.24±0.96)%,P=0.0004].Also,the capability of CD31 + cell differentiation and tubular structures formation of CD106-blocking N MSCs was also obviously decreased [(26.00±2.65)% vs.(91.78±2.44)%,P=0.000;(13.81±1.98)mm vs.(68.12±6.78)mm,P=0.0015].Conclusion The deficient or decreased expression of CD106 + MSCs accelerate the bone marrow vascularization failure in AA patients.

Mesenchymal stem cells (MSC) are able to differentiate into cells of multiple lineage, and additionally act to modulate the immune response. Interleukin (IL)-9 is primarily produced by cluster of differentiation (CD)4 + T cells to regulate the immune response. The present study aimed to investigate the effect of human umbilical cord derived-MSC (UC-MSC) on IL-9 production of human CD4 + T cells. It was demonstrated that the addition of UC-MSC to the culture of CD4 + T cells significantly enhanced IL-9 production by CD4 + T cells. Transwell experiments suggested that UC-MSC promotion of IL-9 production by CD4 + T cells was dependent on cell-cell contact. Upregulated expression of CD106 was observed in UC-MSC co-cultured with CD4 + T cells, and the addition of a blocking antibody of CD106 significantly impaired the ability of UC-MSC to promote IL-9 production by CD4 + T cells. Therefore, the results of the present study demonstrated that UC-MSC promoted the generation of IL-9 producing cells, which may be mediated, in part by CD106. The findings may act to expand understanding and knowledge of the immune modulatory role of UC-MSC.

Mesenchymal stem cells (MSCs) have shown promise for use in cell therapy, and due to their tumor tropism can serve as vehicles for delivering therapeutic agents to tumor sites. Because interleukin-8 (IL-8) is known to mediate the protumor effect of MSCs, elimination of IL-8 secretion by MSCs may enhance their safety for use in cancer gene therapy. However, little is known concerning the effect of endogenously secreted IL-8 on MSCs. We performed studies using placenta-derived MSCs (PMSCs) to determine whether knockdown of IL-8 would influence their biological activity. We first verified that IL-8 and its membrane receptor CXCR2, but not CXCR1, were highly expressed in PMSCs. We then employed lentivirus-mediated small hairpin RNA interference to generate stable IL-8-silenced PMSCs, which displayed a variety of characteristic senescent phenotypes. We observed that at day 9 post-transfection, IL-8-silenced PMSCs had become larger and displayed a more flattened appearance when compared with their controls. Moreover, their proliferation, colony forming unit-fibroblast formation, adipogenic and osteogenic differentiation, and immunosuppressive potentials were significantly impaired. Enhanced senescence-associated β-galactosidase (SA-β-gal) activity and specific global gene expression profiles confirmed that IL-8 silencing evoked the senescence process in PMSCs. Increased levels of p-Akt and decreased levels of FOXO3a protein expression suggested that reactive oxygen species played a role in the initiation and maintenance of senescence in IL-8-silenced PMSCs. Notably, the majority of CXCR2 ligands were downregulated in presenescent IL-8-silenced PMSCs but upregulated in senescent cells, indicating an antagonistic pleiotropy of the IL-8/CXCR2 signaling pathway in PMSCs. This effect may promote the proliferation of young cells and accelerate senescence of old cells.

Neovasculogenesis induced by stem cell therapy is an innovative approach to improve critical limb ischemia (CLI) in diabetes. Mesenchymal stem cells (MSCs) are ideal candidates due to their angiogenic and immunomodulatory features. The aim of this study is to determine the therapeutic effects of human placenta-derived MSCs (P-MSCs) on diabetic CLI, with or without exogenous insulin administration, and the underlying mechanism of any effect. A series of in vitro experiments were performed to assess the stemness and vasculogenic activity of P-MSCs. P-MSCs were intramuscularly injected at two different doses with and without the administration of insulin. The efficacy of P-MSC transplantation was evaluated by ischemia damage score, ambulatory score, laser Doppler perfusion image (LDPI), capillary, and vascular density. In vivo imaging was applied to track the implanted P-MSCs. In vivo differentiation and in situ secretion of angiogenic cytokines were determined. In vitro experimental outcomes showed the differentiation potential and potent paracrine effect of P-MSCs. P-MSCs survived in vivo for at least 3 weeks and led to the acceleration of ischemia recovery, due to newly formed capillaries, increased arterioles, and secretion of various proangiogenic factors. P-MSCs participate in angiogenesis and vascularization directly through differentiation and cytokine expression.