Effect and mechanism of high glucose on apoptosis and cell cycle arrest of islet β cells via p27 pathway

Objective:To study the effect of mechanism of high glucose on apoptosis and cell cycle arrest of isletβcells via p27 pathway.Methods:Islet INS-1 cells were cultured and divided into groups.The control group was treated with ordinary medium,the high glucose group was treated with high glucose medium containing 25mmol/L glucose,the high glucose+si-NC group was treated with high glucose medium and transfected with NC siRNA,and the high glucose+si-P27 group was treated with high glucose medium and transfected with p27 siRNA.After 24 hours treatment,MTS assay was used to detect the cell viability A490,TUNEL assay was used to detect apoptosis rate,flow cytometry was used to detect the cell cycle distribution and western blot was used to detect the expression levels of P27,caspase-8 and cyclinD1.Results:Compared with those in the control group,the A490,the ratio of S phase and G2/M phase as well as the expression level of CyclinD1 decreased,while the apoptosis rate,the ratio of G0/G1 phase as well as the expression levels of P27 and caspase-8 increased in the high glucose group(P<0.05);compared with those in the high glucose group,the A490,cell cycle as well as the expression levels of P27,caspase-8 and cyclinD1 were not different from those in the high glucose+si-NC group(P>0.05);compared with those in the high glucose group and high glucose+si-NC group,the A490,the ratio of S phase and G2/M phase as well as the expression levels of cyclinD1 increased,while the apoptosis rate,the ratio of G0/G1 phase as well as the expression levels of p27 and caspase-8 decreased in the high glucose+si-P27 group(P<0.05).Conclusion:The apoptosis and cell cycle arrest induced by high glucose are related to P27 pathway activation.

Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation

During the pathogenesis of type 1 diabetes(T1D) and type 2 diabetes(T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet(HFD) and streptozotocin(STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of isletβ cells. Cre-LoxP systems were used to generate islet cell type-specific(α, β, or δ) green fluorescent protein(GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing(scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into α or δ cells in both youth-and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice(both youthand adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these “α or δ” cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.

The combined application of stem cells and three-dimensional bioprinting scaffolds for the repair of spinal cord injury

Spinal cord injury is considered one of the most difficult injuries to repair and has one of the worst prognoses for injuries to the nervous system.Following surgery,the poor regenerative capacity of nerve cells and the generation of new scars can make it very difficult for the impaired nervous system to restore its neural functionality.Traditional treatments can only alleviate secondary injuries but cannot fundamentally repair the spinal cord.Consequently,there is a critical need to develop new treatments to promote functional repair after spinal cord injury.Over recent years,there have been seve ral developments in the use of stem cell therapy for the treatment of spinal cord injury.Alongside significant developments in the field of tissue engineering,three-dimensional bioprinting technology has become a hot research topic due to its ability to accurately print complex structures.This led to the loading of three-dimensional bioprinting scaffolds which provided precise cell localization.These three-dimensional bioprinting scaffolds co uld repair damaged neural circuits and had the potential to repair the damaged spinal cord.In this review,we discuss the mechanisms underlying simple stem cell therapy,the application of different types of stem cells for the treatment of spinal cord injury,and the different manufa cturing methods for three-dimensional bioprinting scaffolds.In particular,we focus on the development of three-dimensional bioprinting scaffolds for the treatment of spinal cord injury.

Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke:current evidence and future perspectives

Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

Priming mesenchymal stem cells to develop “super stem cells”

The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment,genetic manipulation,and chemical and pharmacological treatment,each strategy having advantages and limitations.Most of these pre-treatment protocols are non-combinative.This editorial is a continuum of Li et al’s published article and Wan et al’s editorial focusing on the significance of pre-treatment strategies to enhance their stemness,immunoregulatory,and immunosuppressive properties.They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia.Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells(MSCs),pre-treatment based on the mechanistic understanding is expected to develop“Super MSCs”,which will create a transformative shift in MSC-based therapies in clinical settings,potentially revolutionizing the field.Once optimized,the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop“super stem cells”with augmented stemness,functionality,and reparability for diverse clinical applications with better outcomes.

Metabolic and proteostatic differences in quiescent and active neural stem cells

Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis.Therefore,neural regeneration may be a promising target for treatment of many neurological illnesses.The regenerative capacity of adult neural stem cells can be chara cterized by two states:quiescent and active.Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool.Active adult neural stem cells are chara cterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits.This review focuses on diffe rences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis.Furthermore,we discuss the physiological significance and underlying advantages of these diffe rences.Due to the limited number of adult neural stem cells studies,we refe rred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.

Autophagy in neural stem cells and glia for brain health and diseases

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation,maturation,and survival.Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells.Autophagy arbitrates structural and functional remodeling during the cell differentiation process.Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases.Only recently,studies have begun to shed light on autophagy regulation in glia(microglia,astrocyte,and oligodendrocyte)in the brain.Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development,synaptic function,brain metabolism,cellular debris clearing,and restoration of damaged or injured tissues.Thus,this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions,neurodevelopmental disorders,and neurodegenerative diseases.This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

High quality repair of osteochondral defects in rats using the extracellular matrix of antler stem cells

BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown that decellularized extracellular matrix(ECM)derived from autologous,allogenic,or xenogeneic mesenchymal stromal cells(MSCs)can effectively restore osteochondral integrity.AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells(RMCs),a xenogeneic material from antler stem cells,is superior to the currently available treatments for osteochondral defects.METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70%confluence;50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition.Decellularized sheets of adipocyte-derived MSCs(aMSCs)and antlerogenic periosteal cells(another type of antler stem cells)were used as the controls.Three weeks after ascorbic acid stimulation,the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints.RESULTS The defects were successfully repaired by applying the ECM-sheets.The highest quality of repair was achieved in the RMC-ECM group both in vitro(including cell attachment and proliferation),and in vivo(including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues).Notably,the antler-stem-cell-derived ECM(xenogeneic)performed better than the aMSC-ECM(allogenic),while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells.CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell,particularly the active form(RMC-ECM),can achieve high quality repair/reconstruction of osteochondral defects,suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.

Ginsenoside Rk3 modulates gut microbiota and regulates immune response of group 3 innate lymphoid cells to against colorectal tumorigenesis

The gut microbiota plays a pivotal role in the immunomodulatory and protumorigenic microenvironment of colorectal cancer(CRC).However,the effect of ginsenoside Rk3(Rk3)on CRC and gut microbiota remains unclear.Therefore,the purpose of this study is to explore the potential effect of Rk3 on CRC from the perspective of gut microbiota and immune regulation.Our results reveal that treatment with Rk3 significantly suppresses the formation of colon tumors,repairs intestinal barrier damage,and regulates the gut microbiota imbalance caused by CRC,including enrichment of probiotics such as Akkermansia muciniphila and Barnesiella intestinihominis,and clearance of pathogenic Desulfovibrio.Subsequent metabolomics data demonstrate that Rk3 can modulate the metabolism of amino acids and bile acids,particularly by upregulating glutamine,which has the potential to regulate the immune response.Furthermore,we elucidate the regulatory effects of Rk3 on chemokines and inflammatory factors associated with group 3 innate lymphoid cells(ILC3s)and T helper 17(Th17)signaling pathways,which inhibits the hyperactivation of the Janus kinase-signal transducer and activator of transcription 3(JAK-STAT3)signaling pathway.These results indicate that Rk3 modulates gut microbiota,regulates ILC3s immune response,and inhibits the JAK-STAT3 signaling pathway to suppress the development of colon tumors.More importantly,the results of fecal microbiota transplantation suggest that the inhibitory effect of Rk3 on colon tumors and its regulation of ILC3 immune responses are mediated by the gut microbiota.In summary,these findings emphasize that Rk3 can be utilized as a regulator of the gut microbiota for the prevention and treatment of CRC.

Mesenchymal stem cells’“garbage bags”at work:Treating radial nerve injury with mesenchymal stem cell-derived exosomes

Unlike central nervous system injuries,peripheral nerve injuries(PNIs)are often characterized by more or less successful axonal regeneration.However,structural and functional recovery is a senile process involving multifaceted cellular and molecular processes.The contemporary treatment options are limited,with surgical intervention as the gold-standard method;however,each treatment option has its associated limitations,especially when the injury is severe with a large gap.Recent advancements in cell-based therapy and cell-free therapy approaches using stem cell-derived soluble and insoluble components of the cell secretome are fast-emerging therapeutic approaches to treating acute and chronic PNI.The recent pilot study is a leap forward in the field,which is expected to pave the way for more enormous,systematic,and well-designed clinical trials to assess the therapeutic efficacy of mesenchymal stem cell-derived exosomes as a bio-drug either alone or as part of a combinatorial approach,in an attempt synergize the best of novel treatment approaches to address the complexity of the neural repair and regeneration.

Unlocking the versatile potential:Adipose-derived mesenchymal stem cells in ocular surface reconstruction and oculoplastics

This review comprehensively explores the versatile potential of mesenchymal stem cells(MSCs)with a specific focus on adipose-derived MSCs.Ophthalmic and oculoplastic surgery,encompassing diverse procedures for ocular and periocular enhancement,demands advanced solutions for tissue restoration,functional and aesthetic refinement,and aging.Investigating immunomodulatory,regenerative,and healing capacities of MSCs,this review underscores the potential use of adipose-derived MSCs as a cost-effective alternative from bench to bedside,addressing common unmet needs in the field of reconstructive and regenerative surgery.

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.

Evaluation of the intracellular lipid-lowering effect of polyphenols extract from highland barley in HepG2 cells

Active ingredients from highland barley have received considerable attention as natural products for developing treatments and dietary supplements against obesity.In practical application,the research of food combinations is more significant than a specific food component.This study investigated the lipid-lowering effect of highland barley polyphenols via lipase assay in vitro and HepG2 cells induced by oleic acid(OA).Five indexes,triglyceride(TG),total cholesterol(T-CHO),low density lipoprotein-cholesterol(LDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),were used to evaluate the lipidlowering effect of highland barley extract.We also preliminary studied the lipid-lowering mechanism by Realtime fluorescent quantitative polymerase chain reaction(q PCR).The results indicated that highland barley extract contains many components with lipid-lowering effects,such as hyperoside and scoparone.In vitro,the lipase assay showed an 18.4%lipase inhibition rate when the additive contents of highland barley extract were 100μg/m L.The intracellular lipid-lowering effect of highland barley extract was examined using 0.25 mmol/L OA-induced HepG2 cells.The results showed that intracellular TG,LDL-C,and T-CHO content decreased by 34.4%,51.2%,and 18.4%,respectively.ALT and AST decreased by 51.6%and 20.7%compared with the untreated hyperlipidemic HepG2 cells.q PCR results showed that highland barley polyphenols could up-regulation the expression of lipid metabolism-related genes such as PPARγand Fabp4.

Therapeutic utility of human umbilical cord-derived mesenchymal stem cells-based approaches in pulmonary diseases:Recent advancements and prospects

Pulmonary diseases across all ages threaten millions of people and have emerged as one of the major public health issues worldwide.For diverse disease con-ditions,the currently available approaches are focused on alleviating clinical symptoms and delaying disease progression but have not shown significant therapeutic effects in patients with lung diseases.Human umbilical cord-derived mesenchymal stem cells(UC-MSCs)isolated from the human UC have the capacity for self-renewal and multilineage differentiation.Moreover,in recent years,these cells have been demonstrated to have unique advantages in the treatment of lung diseases.We searched the Public Clinical Trial Database and found 55 clinical trials involving UC-MSC therapy for pulmonary diseases,including coronavirus disease 2019,acute respiratory distress syndrome,bron-chopulmonary dysplasia,chronic obstructive pulmonary disease,and pulmonary fibrosis.In this review,we summarize the characteristics of these registered clinical trials and relevant published results and explore in depth the challenges and opportunitiesfaced in clinical application.Moreover,the underlying mole-cular mechanisms involved in UC-MSC-based therapy for pulmonary diseases are also analyzed in depth.In brief,this comprehensive review and detailed analysis of these clinical trials can be expected to provide a scientific reference for future large-scale clinical application.

Multiple pretreatments can effectively improve the functionality of mesenchymal stem cells

In this editorial,we offer our perspective on the groundbreaking study entitled“Hypoxia and inflammatory factor preconditioning enhances the immunosup-pressive properties of human umbilical cord mesenchymal stem cells”,recently published in World Journal of Stem Cells.Despite over three decades of research on the clinical application of mesenchymal stem cells(MSCs),only a few therapeutic products have made it to clinical use,due to multiple preclinical and clinical challenges yet to be addressed.The study proved the hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics,which revealed the combination of inflammatory factors and hypoxic preconditioning offers a promising approach to enhance the function of MSCs.As we delve deeper into the intricacies of pretreat-ment methodologies,we anticipate a transformative shift in the landscape of MSC-based therapies,ultimately contributing to improved patient outcomes and advancing the field as a whole.

Wharton’s jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury

Wharton’s jelly mesenchymal stem cells(WJ-MSCs)are gaining significant attention in regenerative medicine for their potential to treat degenerative diseases and mitigate radiation injuries.WJ-MSCs are more naïve and have a better safety profile,making them suitable for both autologous and allogeneic transplantations.This review highlights the regenerative potential of WJ-MSCs and their clinical applications in mitigating various types of radiation injuries.In this review,we will also describe why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine along with a balanced view on their strengths and weaknesses.Finally,the most updated literature related to both preclinical and clinical usage of WJ-MSCs for their potential application in the regeneration of tissues and organs will also be compiled.

Recent progresses in the development of tubular segmented-in-series solid oxide fuel cells:Experimental and numerical study

Solid oxide fuel cells(SOFCs)have attracted a great deal of interest because they have the highest efficiency without using any noble metal as catalysts among all the fuel cell technologies.However,traditional SOFCs suffer from having a higher volume,current leakage,complex connections,and difficulty in gas sealing.To solve these problems,Rolls-Royce has fabricated a simple design by stacking cells in series on an insulating porous support,resulting in the tubular segmented-in-series solid oxide fuel cells(SIS-SOFCs),which achieved higher output voltage.This work systematically reviews recent advances in the structures,preparation methods,perform-ances,and stability of tubular SIS-SOFCs in experimental and numerical studies.Finally,the challenges and future development of tubular SIS-SOFCs are also discussed.The findings of this work can help guide the direction and inspire innovation of future development in this field.

Tissue-source effect on mesenchymal stem cells as living biodrugs for heart failure:Systematic review and meta-analysis

BACKGROUND Mesenchymal stem cells(MSCs),as living biodrugs,have entered advanced phases of clinical assessment for cardiac function restoration in patients with myocardial infarction and heart failure.While MSCs are available from diverse tissue sources,bone-marrow-derived MSCs(BM-MSCs)remain the most wellstudied cell type,besides umbilical-cord-derived MSCs(UC-MSCs).The latter offers advantages,including noninvasive availability without ethical considerations.AIM To compare the safety and efficacy of BM-MSCs and UC-MSCs in terms of left ventricular ejection fraction(LVEF),6-min walking distance(6MWD),and major adverse cardiac events(MACEs).METHODS Five databases were systematically searched to identify randomized controlled trials(RCTs).Thirteen RCTs(693 patients)were included using predefined eligibility criteria.Weighted mean differences and odds ratio(OR)for the changes in the estimated treatment effects.RESULTS UC-MSCs significantly improved LVEF vs controls by 5.08%[95%confidence interval(CI):2.20%-7.95%]at 6 mo and 2.78%(95%CI:0.86%-4.70%)at 12 mo.However,no significant effect was observed for BM-MSCs vs controls.No significant changes were observed in the 6MWD with either of the two cell types.Also,no differences were observed for MACEs,except rehospitalization rates,which were lower only with BM-MSCs(odds ratio 0.48,95%CI:0.24-0.97)vs controls.CONCLUSION UC-MSCs significantly improved LVEF compared with BM-MSCs.Their advant-Safwan M et al.Tissue-source and MSCs as living biodrugs ageous characteristics position them as a promising alternative to MSC-based therapy.