Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via ...Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition,also known as dedifferentiation.There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation,exerting vasoprotective functions;however,the precise mechanisms have not been fully characterized.Therefore,we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation.Ginger significantly inhibited neointimal hyperplasia and promoted lumen(L)opening in a 3-month VG,which was primarily achieved by reducing ferroptotic stress.Ferroptotic stress is a pro-ferroptotic state.Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type,forming neointima(NI)after vein transplantation.Ginger and its two main vasoprotective ingredients(6-gingerol and 6-shogaol)inhibit VSMC dedifferentiation by reducing ferroptotic stress.Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53,while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase(Alox5),both promoting ferroptosis.Furthermore,both ingredients co-target peroxisome proliferator-activated receptor gamma(PPARγ),decreasing PPARγ-mediated nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 1(Nox1)expression.Nox1 promotes intracellular reactive oxygen species(ROS)production and directly induces VSMC dedifferentiation.In addition,Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production,indirectly leading to VSMC dedifferentiation.Ginger,a natural multi-targeted ferroptotic stress inhibitor,finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.展开更多
Plant cells retain the ability for cellular reprogramming,including totipotency and pluripotency,enabling them to revert their cell fate from differentiated to dedifferentiated one and subsequently redifferentiate und...Plant cells retain the ability for cellular reprogramming,including totipotency and pluripotency,enabling them to revert their cell fate from differentiated to dedifferentiated one and subsequently redifferentiate under specific physiological and environmental cues.In response to these cues,endogenous phytohormones,genetic landscapes,and epigenetic remodeling play a significant role in initiating the reprogramming of somatic cells and re-establishment of an organized structure.Detailed studies on dedifferentiation have gradually unraveled the involvement of stem-like cells during early callus formation,along with the existence of QC-like transcriptional features in the middle cell layer of callus,which exhibits organ regeneration ability.Tracking natural variations and real-time regeneration dynamics across species,combined with single-cell RNA sequencing,will enable the identification of key developmental regulators and small peptides.These breakthroughs can be applied to enhance regeneration efficiency,improve transformation in recalcitrant species,and accelerate next-generation crop development.The current review summarizes the longstanding history and ongoing research progress in two pathways:dedifferentiation and redifferentiation.It also highlights how hormonal effects on the genetic factors and provides insights into how genetic signatures interact with epigenetic landscapes to drive these processes.It highlights the potential applications of developmental regulators for efficient gene transformation to enhance plant genetic engineering,while also addressing fundamental questions and identifying research gaps to guide future studies.展开更多
BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but th...BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.展开更多
In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedif...In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedifferentiation being key factors in insulin secretion loss.β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state,characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A,and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3.This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum(ER)stress and repression of the forkhead box protein O1(FoxO1)transcription factor.The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilizeβ-cell identity.Notably,evidence suggests that this process can be reversed under certain circumstances,with potential for therapies aiming to redifferentiateβ-cells or prevent identity loss.We also outline the therapeutic potential of modulating ER stress pathways,controlling FoxO1 activity,and developing biomarkers to trackβ-cell plasticity in patients.Overall,β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functionalβ-cell mass.展开更多
The ultracytochemical localization of ATPase in the secondary xylem cells during their differentiation and dedifferentiation in the girdled Eucommia ulmoides Oliv. was carried out using a lead phosphate precipitation ...The ultracytochemical localization of ATPase in the secondary xylem cells during their differentiation and dedifferentiation in the girdled Eucommia ulmoides Oliv. was carried out using a lead phosphate precipitation technique. Throughout the differentiation, which is a typical programmed cell death (PCD) process, ATPase deposits increased in the nucleus but decreased and progressively disappeared in the cell organelles. At the same time, the distribution of ATPase increased in the inner face of the cell wall and pits with cytoplasmic degeneration. The results demonstrated that the PCD was an energy dependent active process and was controlled by nuclear genes. On the other hand, the distribution of ATPase in the intercellular spaces increased with the formation of the new cambium resulted from the dedifferentiation of the secondary xylem cells after girdling. However, ATPase was not found in the nucleus of the dividing cells, suggesting that nutrients were transported through protoplast during differentiation, and through both protoplast and apoplast during dedifferentiation. Thus, the energy required in cell division was provided mainly by intercellular spaces. These findings indicate that the dynamic distribution of ATPase reflected which cell component was actively taking part in the cell metabolism at various stages of the plant development, and its distribution was associated with the physiological state of the cell. Based on the characteristic distributions of ATPase, the critical stage of cell differentiation and the relationship between the critical stage and dedifferentiation were discussed.展开更多
Based on selecting MS minimal medium, through changing the concentrations and additive amounts of two plant growth regulators of NAA and BA, the redifferentiation experiments of plant morphology on callus and embryos ...Based on selecting MS minimal medium, through changing the concentrations and additive amounts of two plant growth regulators of NAA and BA, the redifferentiation experiments of plant morphology on callus and embryos cell which got after the dedifferentiation of ＂Xianglin No.1＂ Camellia oleifera Abel. were carried out.The experimental results showed that callus lines with white, yellowish white or oyster colors, obvious uneven surface and loose texture were inoculated on the medium of MS ＋NAA（0.3 mg/L） ＋BA（2.0 mg/L） ＋saccharose（30 g/L） ＋agar（7 g/L）for 30 d,then multiple shoots were differentiated from the white protuberant part, moreover,the growth vigor was good. If inoculating using regeneration buds of C. oleifera, its multiplication coefficient was 6.50.展开更多
Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the levels of the growth factor receptor-bound protein 10(GRB10), a negative re...Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the levels of the growth factor receptor-bound protein 10(GRB10), a negative regulator of insulin and m TORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1 cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced m TORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting m TORC1 signaling.展开更多
Schwann cells are glial cells that are responsible for the synthesis and maintenance of the myelin sheath in the peripheral nerve system. Under pathological conditions, such as physical nerve injury and inflammatory n...Schwann cells are glial cells that are responsible for the synthesis and maintenance of the myelin sheath in the peripheral nerve system. Under pathological conditions, such as physical nerve injury and inflammatory neuropathies, Schwann cells undergo a substantial phenotype transformation that is not related to their intended function. For example, Schwann cells dedifferentiate into immature states and thereby cease to express myelin genes after nerve injury.展开更多
Objective Chronic atrial fibrillation （AF） results in dedifferentiation of atrial cardiomyocytes that plays an important role in the perpetuation of AF. In this study, we aimed to investigate the changes oftitin and...Objective Chronic atrial fibrillation （AF） results in dedifferentiation of atrial cardiomyocytes that plays an important role in the perpetuation of AF. In this study, we aimed to investigate the changes oftitin and a-smooth muscle actin （α-SMA） after long time of AF reversal. Methods Twenty-four goats were randomized into four groups： （1） sinus rhythm （SR）, （2） 3 months AF （3-too AF）, （3） 3 months SR after 3 months AF （3-mo post AF）, （4） 6 months SR after 3-mo AF （6-mo post AF）, with 6 in each group. By pacing on the anterior bottom of left atria appendage （LAA）, we established a goat model of chronic AF. Atria effective refractory period （AERP） was measured with electrophysiological methods. Ultra-structure was studied with echocardiography, light and electron microscopy. Titin and α-SMA protein expressions were determined by Western blot. Results The animals underwent high rate pacing on LAA for a mean of 42.23± 21.70 days before presenting AF. Electrophysiological analysis revealed that AERP completely resumed in 3-mo post AF goats. Echocardiography displayed that the size of left atrium resumed almost in 6-too post AF goats （P〈 0.01）. Pathological and electron microscopic examination revealed the disorder of myofibrils, augmentation of intercellular space, myolysis, accumulation of glycogen, and numerous bigger mitochondria among atrial cardiomyocytes in 3-mo AF goats. They recovered mostly in 6-mo post AF goats. Western blot showed that the band density oftitin significantly reduced in 3-mo AF goats compared to SR ones [1826 ± 319 vs 5012±854, P 〈 0.01]. In 3- and 6-mo post AF goats, titin increased gradually and it reversed completely in 6-mo post AF goats （3841 ± 601 and 4523 ±833 respectively, P 〈 0.01）. Conversely, the band density ofa-SMAwas significantly higher in 3-mo AF goats （5324 ± 948） than in SR ones （1619 ±271, P 〈 0.01）. In 3- and 6-mo post-AF goats, α-SMA decreased gradually, and it recovered mostly in 6- mo post AF goats （4437 ± 792 and 2205 ± 540 respectively, P〈 0.01,）. Conclusions These data indicate that the reversal of dedifferentiation of atrial cardiomyocyts is a very slow process, and it is definitely essential for normal cardiac function .展开更多
Primary hepatocytes(PHCs)are widely used in various fields,but the progressive deterioration of liverspecific features in vitro significantly limits their application.While the transcriptional regulation and whole cel...Primary hepatocytes(PHCs)are widely used in various fields,but the progressive deterioration of liverspecific features in vitro significantly limits their application.While the transcriptional regulation and whole cell proteome(WCP)of PHCs have been extensively studied,only a small number of studies have addressed the role of posttranslational modifications in this process.To elucidate the underlying mechanisms that induce dedifferentiation,we carried out parallel quantifications of the transcriptome,WCP,ubiquitinome,and phosphoproteome of rat PHCs after 0,6,12,24,and 48 h of in vitro culture.Our data constitute a detailed proteomic analysis of dedifferentiated PHCs including 2196 proteins,2056 ubiquitinated sites,and 4932 phosphorylated peptides.We revealed a low correlation between the transcriptome and WCP during dedifferentiation.A combined analysis of the ubiquitinome with the corresponding WCP indicated that the dedifferentiation of PHCs led to an increase in nondegradative K27 ubiquitination.Functional analysis of the altered phosphoproteins suggested a significant enrichment in ferroptosis.In all,404 proteins with both ubiquitination and phosphorylation were identified to be involved in critical metabolic events.Furthermore,Ptbph Hnqjd,Hnrnpu,and Srrm2 were identified as hub genes.Taken together,our data provide new insights into proteome dynamics during PHC dedifferentiation and potential targets to inhibit the dedifferentiation process.展开更多
Objective:To explore the effects of dopamine receptor D2(DRD2)on astrocytic dedifferentiation based on SOX2-regulated genes in neural stem cells(NSCs)and astrocytes.Methods:Immunofluorescence staining and SOX2-GFP mic...Objective:To explore the effects of dopamine receptor D2(DRD2)on astrocytic dedifferentiation based on SOX2-regulated genes in neural stem cells(NSCs)and astrocytes.Methods:Immunofluorescence staining and SOX2-GFP mice were used to examine the lineage differentiation of SOX2-positive cells during the development of cerebral cortex.Primary NSCs/astrocytes culture,ChIP-seq and Western Blot were adopted to analyze and verify the expression of candidate genes.Pharmacological manipulation,neurosphere formation,photochemical ischemia,immunofluorescence staining and behavior tests were adopted to evaluate the effects of activating DRD2 signaling on astrocytic dedifferentiation.Results:Immunofluorescence staining demonstrated the NSC-astrocyte switch of SOX2-expression in the normal development of cerebral cortex.ChIP-seq revealed enrichment of DRD2 signaling by SOX2-bound enhancers in NSCs and SOX2-bound promoters in astrocytes.Western Blot and immunofluorescence staining verified the expression of DRD2 in NSCs and reactive astrocytes.Application of quinagolide hydrocholoride(QH),an agonist of DRD2,significantly promoted astrocytic dedifferentiation both in vitro and in vivo following ischemia.In addition,quinagolide hydrocholoride treatment improved locomotion recovery.Conclusion:Activating DRD2 signaling facilitates astrocytic dedifferentiation and may be used to treat ischemic stroke.展开更多
AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferenti...AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferentiation,thus improving visual function and delaying retinal degenerative progression.METHODS:h ERO-RPCs were subretinally transplanted into Royal College of Surgeons(RCS)rats.Electroretinography(ERG)recording was performed at 4 and 8wk postoperation to assess retinal function.Using immunofluorescence,the changes in outer nuclear layer(ONL)thickness and retinal Müller glia were explored at 2,4,and 8wk postoperation.To verify the effect of h ERO-RPCs on Müller glia in vitro,we cocultured h ERO-RPCs with Müller glia with a Transwell system.After coculture,Ki67 staining and quantitative polymerase chain reaction(q PCR)were performed to measure the proliferation and m RNA levels of Müller glia respectively.Cell migration experiment was used to detect the effect of h ERO-RPCs on Müller glial migration.Comparisons between two groups were performed by the unpaired Student’s t-test,and comparisons among multiple groups were made with one-way ANOVA followed by Tukey’s multiple comparison test.RESULTS:The visual function and ONL thickness of RCS rats were significantly improved by transplantation of h ERO-RPCs at 4 and 8wk postoperation.In addition to inhibiting gliosis at 4 and 8wk postoperation,h ERO-RPCs significantly increased the expression of dedifferentiation-associated transcriptional factor in Müller glia and promoted the migration at 2,4 and 8wk postoperation,but not the transdifferentiation of these cells in RCS rats.In vitro,using the Transwell system,we found that h ERO-RPCs promoted the proliferation and migration of primary rat Müller glia and induced their dedifferentiation at the m RNA level.CONCLUSION:These results show that h ERO-RPCs might promote early dedifferentiation of Müller glia,which may provide novel insights into the mechanisms of stem cell therapy and Müller glial reprogramming,contributing to the development of novel therapies for retinal degeneration disorders.展开更多
Objective:To observe the effect of Qishen decoction on dedifferentiation and autophagy of liver sinusoid endothelial cells(LSEC);Methods:LSEC were randomly divided into the control group,model group,Qishen Decoction l...Objective:To observe the effect of Qishen decoction on dedifferentiation and autophagy of liver sinusoid endothelial cells(LSEC);Methods:LSEC were randomly divided into the control group,model group,Qishen Decoction low,medium,high dose group,and inhibitor group.The model was induced by 100μg/ml oxidized low-density lipoprotein(oxLDL)for 24 hours,and the corresponding drugs or medicated serum were given for intervention.The expression levels of VEGFR2 and ET1 were detected by RT-qPCR and immunofluorescence staining,the ultrastructure of LSEC was detected by transmission electron microscopy,the content of NO was detected by ELISA,the expression levels of autophagy related proteins(LC3BI,LC3BⅡand p62)and endothelial function related proteins(eNOS and p-eNOS)were detected by western blot;Results:The results of transmission electron microscopy showed that Qishen decoction medicated serum could increase the number of fenestra and autophagy in LSEC cells,and inhibit the formation of basement membrane under endothelium.Compared with the model group,Qishen decoction medicated serum could significantly up-regulate the expression level of VEGFR2 mRNA and protein in LSEC,down regulate the expression level of ET1 mRNA and protein,the difference was statistically significant(P<0.05).In addition,Qishen decoction medicated serum could significantly increase the expression of LC3BII,p-eNOS,eNOS protein and the ratio of LC3BII/LC3BI,p-eNOS/eNOS,and reduce the expression of LC3BI and p62 protein in LSEC,which is statistically significant compared with the model group(P<0.05).Conclusion:Qishen decoction can inhibit the dedifferentiation of LSEC by promoting the autophagy level of LSEC,and then play an anti-fibrosis role.展开更多
Cancer tissues contain cancer stem cells (CSCs), which play important roles in cancer metastasis. However, the mechanisms through which cancer cells dedifferentiate into stem cells have not yet been elucidated. In thi...Cancer tissues contain cancer stem cells (CSCs), which play important roles in cancer metastasis. However, the mechanisms through which cancer cells dedifferentiate into stem cells have not yet been elucidated. In this study, the effects of high concentrations of polyamines produced in cancer cells on dedifferentiation were examined. The results showed that when normal human fibroblasts were cultured with high concentrations of spermine, the obtained polyamine-induced cells expressed alkaline phosphatase and marker proteins of pluripotent stem cells, although apoptosis occurred in most cells. In contrast, another polyamine-induced stem (PIS) cell line (Spe-2 PIS cells), obtained by culture in medium containing Rock, p53, and Bax inhibitors plus spermine, did not show signs of apoptosis. These Spe-2 PIS cells expressed marker proteins of pluripotent stem cells and differentiated into cardiomyocytes, brown adipocytes, and nerve cells. These results suggest that a high concentration of spermine, which often induces apoptosis in normal cells, has the capacity to dedifferentiate somatic cells into pluripotent stem cells and may be associated with the dedifferentiation of cancer cells, which continuously produce high concentrations of spermine. Moreover, the procedure to obtain Spe-2 PIS cells, which is simple and efficient, may have potential applications in regenerative medicine.展开更多
Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis;however,the mechanisms by which this occurs remain poorly understood.Our previou...Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis;however,the mechanisms by which this occurs remain poorly understood.Our previous study demonstrated that elevation of microRNA-24(miR-24)in a diabetic setting caused beta cell dysfunction and replicative deficiency.In this study,we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum(ER)stress conditions.We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucosestimulated insulin secretion(GSIS)and enhancing the presence of dedifferentiation markers.Ingenuity?Pathway Analysis(IPA)revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4,which are downstream effectors of two key branches of ER stress,by inhibiting its direct target,Irela.Notably,elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells,thus guiding their dedifferentiation under ER stress conditions.Our results demonstrated that the elevated miR-24,to the utmost extent,preserves beta cell mass by inhibiting apoptosis and inducing dedifFerentiation.This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.展开更多
The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages.The renewal and regenerative processes are driven by intestinal stem cells(ISCs...The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages.The renewal and regenerative processes are driven by intestinal stem cells(ISCs),which reside at the base of crypts and are marked by Lgr5.As Lgr5^(+)ISCs undergo fast cycling and are vulnerable to damages,there must be other types of cells that can replenish the lost Lgr5^(+)ISCs and then regenerate the damage epithelium.In addition to Lgr5^(+)ISCs,quiescent ISCs at the+4 position in the crypt have been proposed to convert to Lgr5^(+)ISCs during regeneration.However,this“reserve stem cell”model still remains controversial.Different from the traditional view of a hierarchical organization of the intestinal epithelium,recent works support the dynamic“dedifferentiation”model,in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury.Here,we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.展开更多
Spathoglottis plicata Blume. is a horticulturally important vulnerable ground orchid with beautiful flowers blooming round the year. Highfrequency protocorm-like body(PLB) formation was established via callus culture ...Spathoglottis plicata Blume. is a horticulturally important vulnerable ground orchid with beautiful flowers blooming round the year. Highfrequency protocorm-like body(PLB) formation was established via callus culture from vegetative tissues of in vitro germinated seedlings of S.plicata. Media containing MS salts and Gamborg's B5 vitamins supplemented with 1.0 mg·L^(-1) 2,4-dichlorophenoxyacetic acid(2,4-D), 3.0 mg·L^(-1) α-naphthaleneacetic acid(NAA), 1.0 mg·L^(-1) kinetin(KIN), and 10%(v/v) ‘Aloe vera gel'(Av G) were effective in fragile calli induction. A maximum of(22.3 ± 0.52) PLBs were induced from about 250 mg callus within 45–55 days in the presence of 2.0 mg·L^(-1) NAA and 3.0 mg·L^(-1) 6-benzylaminopurine(BAP). Briefly, 3.0% sodium alginate was found to be most suitable for the formation of an appropriate shape and good germination rates(86.7%)of artificial seeds. Out of three different temperatures(4, 15, and 24 °C), the best result was achieved at 4 °C with 66.7% germinability even after90 days of storage. Plantlets were acclimatized with 86.6% survival rate and 76.3% of these plants produced flowers within 12–15 months of field transfer. Chromosomal studies revealed cytological stability of all regenerants containing 2 n = 40 chromosomes as in the parental plants.The present protocol can be applied reliably for the purposes of large-scale commercial propagation and short-term conservation of this orchid.展开更多
Dedifferentiation of chondrocyte greatly restricts its function and application,however,it is poorly understood except a small number of canonical markers.The non-cell-adhesive property endows polysaccharide hydrogel ...Dedifferentiation of chondrocyte greatly restricts its function and application,however,it is poorly understood except a small number of canonical markers.The non-cell-adhesive property endows polysaccharide hydrogel with the ability to maintain chondrocyte phenotype,which can serve as a platform to identify new molecular markers and therapeutic targets of chondrocyte dedifferentiation.In this study,the high-throughput RNA sequencing(RNA-seq)was first performed on articular chondrocytes at primary(P0)and passage 1(P1)stages to explore the global alteration of gene expression along with chondrocyte dedifferentiation.Significantly,several potential marker genes,such as PFKFB3,KDM6B,had been identified via comparatively analyzing their expression in P0 and P1 chondrocytes as well as in 3D constructs(i.e.chondrocyte-laden alginate hydrogel and HA-MA hydrogel)at both mRNA and protein level.Besides,the changes in cellular morphology and enriched pathway of differentially expressed genes during chondrocyte dedifferentiation was studied in detail.This study developed the use of hydrogel as a platform to investigate chondrocyte dedifferentiation;the results provided new molecular markers and potential therapeutic targets of chondrocyte dedifferentiation.展开更多
Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery...Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.展开更多
INTRODUCTION.According to the widely accepted‘endosymbiotic theory’,mitochondria are originated from bacteria when the eukaryotic cell evolved from the capture of alphaproteobacteria,within primitive archaea around ...INTRODUCTION.According to the widely accepted‘endosymbiotic theory’,mitochondria are originated from bacteria when the eukaryotic cell evolved from the capture of alphaproteobacteria,within primitive archaea around 2 billion years ago,which set a symbiotic relationship between the captured bacterium and its archaeal host.Mitochondria are double membrane-bound organelles that have unique sub-compartments:outer mitochondrial membrane,inner mitochondrial membrane,inter-mitochondrial membrane space and mitochondrial matrix.Mitochondria are not only the‘powerhouses’for generation of ATP for cellular functions and survival but also are critical for lipid and glucose metabolism,calcium buffering,phospholipid synthesis,programmed cell death and innate immune response.Given their crucial roles in maintaining cellular functions,cells have developed intricate mechanisms to regulate mitochondrial morphology,quality and numbers1-5.展开更多
基金supported by grants from the Natural Science Foundation of Shandong Province,China(Grant Nos.:ZR2019ZD28 and ZR2022QH008)the National Natural Science Foundation of China(Grant Nos.:82270301 and 82200465)+1 种基金China Postdoctoral Science Foundation(Grant No.:2023M731842)Shandong Postdoctoral Science Foundation,China(Grant No.:SDCX-ZG-202203013).
文摘Vein graft(VG)failure(VGF)is associated with VG intimal hyperplasia,which is characterized by abnormal accumulation of vascular smooth muscle cells(VSMCs).Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition,also known as dedifferentiation.There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation,exerting vasoprotective functions;however,the precise mechanisms have not been fully characterized.Therefore,we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation.Ginger significantly inhibited neointimal hyperplasia and promoted lumen(L)opening in a 3-month VG,which was primarily achieved by reducing ferroptotic stress.Ferroptotic stress is a pro-ferroptotic state.Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type,forming neointima(NI)after vein transplantation.Ginger and its two main vasoprotective ingredients(6-gingerol and 6-shogaol)inhibit VSMC dedifferentiation by reducing ferroptotic stress.Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53,while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase(Alox5),both promoting ferroptosis.Furthermore,both ingredients co-target peroxisome proliferator-activated receptor gamma(PPARγ),decreasing PPARγ-mediated nicotinamide adenine dinucleotide phosphate(NADPH)oxidase 1(Nox1)expression.Nox1 promotes intracellular reactive oxygen species(ROS)production and directly induces VSMC dedifferentiation.In addition,Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production,indirectly leading to VSMC dedifferentiation.Ginger,a natural multi-targeted ferroptotic stress inhibitor,finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.
基金funded by National Key R&D Program of China(Grant No.2024YFD2200600)Science and Technology Project of Hebei Education Department(Grant No.QN2022017)+3 种基金Natural Science Foundation of Hebei Province(Grant No.C2023204062)Fundamental Scientific Research Fund of Universities in Hebei Province(KY2021059)China Agriculture Research System(Grant No.CARS-30-2-07)Hebei Agriculture Research System(Grant Nos.HBCT2024190201,HBCT2024190203).
文摘Plant cells retain the ability for cellular reprogramming,including totipotency and pluripotency,enabling them to revert their cell fate from differentiated to dedifferentiated one and subsequently redifferentiate under specific physiological and environmental cues.In response to these cues,endogenous phytohormones,genetic landscapes,and epigenetic remodeling play a significant role in initiating the reprogramming of somatic cells and re-establishment of an organized structure.Detailed studies on dedifferentiation have gradually unraveled the involvement of stem-like cells during early callus formation,along with the existence of QC-like transcriptional features in the middle cell layer of callus,which exhibits organ regeneration ability.Tracking natural variations and real-time regeneration dynamics across species,combined with single-cell RNA sequencing,will enable the identification of key developmental regulators and small peptides.These breakthroughs can be applied to enhance regeneration efficiency,improve transformation in recalcitrant species,and accelerate next-generation crop development.The current review summarizes the longstanding history and ongoing research progress in two pathways:dedifferentiation and redifferentiation.It also highlights how hormonal effects on the genetic factors and provides insights into how genetic signatures interact with epigenetic landscapes to drive these processes.It highlights the potential applications of developmental regulators for efficient gene transformation to enhance plant genetic engineering,while also addressing fundamental questions and identifying research gaps to guide future studies.
基金Supported by the Natural Science Foundation of China,No.81471081the Natural Science Foundation of Fujian Province,No.2023D009+1 种基金the Natural Science Foundation of Xiamen City,No.3502Z202373104 and No.3502Z20227162Scientific Research Foundation for Advanced Talents,Xiang’an Hospital of Xiamen University,No.PM201809170005。
文摘BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.
基金Supported by Kuwait Foundation for the Advancement of Sciences,No.RACB-2021-007.
文摘In this editorial,we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes.Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder,with apoptosis and dedifferentiation being key factors in insulin secretion loss.β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state,characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A,and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3.This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum(ER)stress and repression of the forkhead box protein O1(FoxO1)transcription factor.The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilizeβ-cell identity.Notably,evidence suggests that this process can be reversed under certain circumstances,with potential for therapies aiming to redifferentiateβ-cells or prevent identity loss.We also outline the therapeutic potential of modulating ER stress pathways,controlling FoxO1 activity,and developing biomarkers to trackβ-cell plasticity in patients.Overall,β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functionalβ-cell mass.
文摘The ultracytochemical localization of ATPase in the secondary xylem cells during their differentiation and dedifferentiation in the girdled Eucommia ulmoides Oliv. was carried out using a lead phosphate precipitation technique. Throughout the differentiation, which is a typical programmed cell death (PCD) process, ATPase deposits increased in the nucleus but decreased and progressively disappeared in the cell organelles. At the same time, the distribution of ATPase increased in the inner face of the cell wall and pits with cytoplasmic degeneration. The results demonstrated that the PCD was an energy dependent active process and was controlled by nuclear genes. On the other hand, the distribution of ATPase in the intercellular spaces increased with the formation of the new cambium resulted from the dedifferentiation of the secondary xylem cells after girdling. However, ATPase was not found in the nucleus of the dividing cells, suggesting that nutrients were transported through protoplast during differentiation, and through both protoplast and apoplast during dedifferentiation. Thus, the energy required in cell division was provided mainly by intercellular spaces. These findings indicate that the dynamic distribution of ATPase reflected which cell component was actively taking part in the cell metabolism at various stages of the plant development, and its distribution was associated with the physiological state of the cell. Based on the characteristic distributions of ATPase, the critical stage of cell differentiation and the relationship between the critical stage and dedifferentiation were discussed.
基金Supported by China Hunan Provincial Science&Technology Department(2012NK3118)~~
文摘Based on selecting MS minimal medium, through changing the concentrations and additive amounts of two plant growth regulators of NAA and BA, the redifferentiation experiments of plant morphology on callus and embryos cell which got after the dedifferentiation of ＂Xianglin No.1＂ Camellia oleifera Abel. were carried out.The experimental results showed that callus lines with white, yellowish white or oyster colors, obvious uneven surface and loose texture were inoculated on the medium of MS ＋NAA（0.3 mg/L） ＋BA（2.0 mg/L） ＋saccharose（30 g/L） ＋agar（7 g/L）for 30 d,then multiple shoots were differentiated from the white protuberant part, moreover,the growth vigor was good. If inoculating using regeneration buds of C. oleifera, its multiplication coefficient was 6.50.
基金supported by grants from the National Natural Science Foundation of China (91749118, 82070807, 81770775, 81730022)Natural Science Foundation of Hunan Province, China (2021JJ30976)National Key Research and Development Program (2019YFA0801903, 2018YFC2000100)。
文摘Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the levels of the growth factor receptor-bound protein 10(GRB10), a negative regulator of insulin and m TORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1 cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced m TORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting m TORC1 signaling.
基金supported by research funds from Dong-A University
文摘Schwann cells are glial cells that are responsible for the synthesis and maintenance of the myelin sheath in the peripheral nerve system. Under pathological conditions, such as physical nerve injury and inflammatory neuropathies, Schwann cells undergo a substantial phenotype transformation that is not related to their intended function. For example, Schwann cells dedifferentiate into immature states and thereby cease to express myelin genes after nerve injury.
基金Acknowledgement This work supported by the National Basic Research Program of China （973 Program, 2008CB517303）, a grant from National Natural Science Foundation of China （30800464）, a grant of pivot talents of medicine of Jiangsu Province （RC2007040）, and a grant from Provincial Natu- ral Science of Jiangsu, China （BK2005218）
文摘Objective Chronic atrial fibrillation （AF） results in dedifferentiation of atrial cardiomyocytes that plays an important role in the perpetuation of AF. In this study, we aimed to investigate the changes oftitin and a-smooth muscle actin （α-SMA） after long time of AF reversal. Methods Twenty-four goats were randomized into four groups： （1） sinus rhythm （SR）, （2） 3 months AF （3-too AF）, （3） 3 months SR after 3 months AF （3-mo post AF）, （4） 6 months SR after 3-mo AF （6-mo post AF）, with 6 in each group. By pacing on the anterior bottom of left atria appendage （LAA）, we established a goat model of chronic AF. Atria effective refractory period （AERP） was measured with electrophysiological methods. Ultra-structure was studied with echocardiography, light and electron microscopy. Titin and α-SMA protein expressions were determined by Western blot. Results The animals underwent high rate pacing on LAA for a mean of 42.23± 21.70 days before presenting AF. Electrophysiological analysis revealed that AERP completely resumed in 3-mo post AF goats. Echocardiography displayed that the size of left atrium resumed almost in 6-too post AF goats （P〈 0.01）. Pathological and electron microscopic examination revealed the disorder of myofibrils, augmentation of intercellular space, myolysis, accumulation of glycogen, and numerous bigger mitochondria among atrial cardiomyocytes in 3-mo AF goats. They recovered mostly in 6-mo post AF goats. Western blot showed that the band density oftitin significantly reduced in 3-mo AF goats compared to SR ones [1826 ± 319 vs 5012±854, P 〈 0.01]. In 3- and 6-mo post AF goats, titin increased gradually and it reversed completely in 6-mo post AF goats （3841 ± 601 and 4523 ±833 respectively, P 〈 0.01）. Conversely, the band density ofa-SMAwas significantly higher in 3-mo AF goats （5324 ± 948） than in SR ones （1619 ±271, P 〈 0.01）. In 3- and 6-mo post-AF goats, α-SMA decreased gradually, and it recovered mostly in 6- mo post AF goats （4437 ± 792 and 2205 ± 540 respectively, P〈 0.01,）. Conclusions These data indicate that the reversal of dedifferentiation of atrial cardiomyocyts is a very slow process, and it is definitely essential for normal cardiac function .
基金This work was supported by the National Key Research and Development Program of China(2016YFC1101304/3)the National Natural Science Foundation of China(81400589,81790630,and 81790633)Research Unit of Infectious Diseases and Microecology,Chinese Academy of Medical Sciences(2019RU021).
文摘Primary hepatocytes(PHCs)are widely used in various fields,but the progressive deterioration of liverspecific features in vitro significantly limits their application.While the transcriptional regulation and whole cell proteome(WCP)of PHCs have been extensively studied,only a small number of studies have addressed the role of posttranslational modifications in this process.To elucidate the underlying mechanisms that induce dedifferentiation,we carried out parallel quantifications of the transcriptome,WCP,ubiquitinome,and phosphoproteome of rat PHCs after 0,6,12,24,and 48 h of in vitro culture.Our data constitute a detailed proteomic analysis of dedifferentiated PHCs including 2196 proteins,2056 ubiquitinated sites,and 4932 phosphorylated peptides.We revealed a low correlation between the transcriptome and WCP during dedifferentiation.A combined analysis of the ubiquitinome with the corresponding WCP indicated that the dedifferentiation of PHCs led to an increase in nondegradative K27 ubiquitination.Functional analysis of the altered phosphoproteins suggested a significant enrichment in ferroptosis.In all,404 proteins with both ubiquitination and phosphorylation were identified to be involved in critical metabolic events.Furthermore,Ptbph Hnqjd,Hnrnpu,and Srrm2 were identified as hub genes.Taken together,our data provide new insights into proteome dynamics during PHC dedifferentiation and potential targets to inhibit the dedifferentiation process.
文摘Objective:To explore the effects of dopamine receptor D2(DRD2)on astrocytic dedifferentiation based on SOX2-regulated genes in neural stem cells(NSCs)and astrocytes.Methods:Immunofluorescence staining and SOX2-GFP mice were used to examine the lineage differentiation of SOX2-positive cells during the development of cerebral cortex.Primary NSCs/astrocytes culture,ChIP-seq and Western Blot were adopted to analyze and verify the expression of candidate genes.Pharmacological manipulation,neurosphere formation,photochemical ischemia,immunofluorescence staining and behavior tests were adopted to evaluate the effects of activating DRD2 signaling on astrocytic dedifferentiation.Results:Immunofluorescence staining demonstrated the NSC-astrocyte switch of SOX2-expression in the normal development of cerebral cortex.ChIP-seq revealed enrichment of DRD2 signaling by SOX2-bound enhancers in NSCs and SOX2-bound promoters in astrocytes.Western Blot and immunofluorescence staining verified the expression of DRD2 in NSCs and reactive astrocytes.Application of quinagolide hydrocholoride(QH),an agonist of DRD2,significantly promoted astrocytic dedifferentiation both in vitro and in vivo following ischemia.In addition,quinagolide hydrocholoride treatment improved locomotion recovery.Conclusion:Activating DRD2 signaling facilitates astrocytic dedifferentiation and may be used to treat ischemic stroke.
基金Supported by the National Key Research and Development Program of China(No.2018YFA0107302)the Natural Science Foundation of Chongqing,China(No.cstc2021jcyj-msxm X0437)。
文摘AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferentiation,thus improving visual function and delaying retinal degenerative progression.METHODS:h ERO-RPCs were subretinally transplanted into Royal College of Surgeons(RCS)rats.Electroretinography(ERG)recording was performed at 4 and 8wk postoperation to assess retinal function.Using immunofluorescence,the changes in outer nuclear layer(ONL)thickness and retinal Müller glia were explored at 2,4,and 8wk postoperation.To verify the effect of h ERO-RPCs on Müller glia in vitro,we cocultured h ERO-RPCs with Müller glia with a Transwell system.After coculture,Ki67 staining and quantitative polymerase chain reaction(q PCR)were performed to measure the proliferation and m RNA levels of Müller glia respectively.Cell migration experiment was used to detect the effect of h ERO-RPCs on Müller glial migration.Comparisons between two groups were performed by the unpaired Student’s t-test,and comparisons among multiple groups were made with one-way ANOVA followed by Tukey’s multiple comparison test.RESULTS:The visual function and ONL thickness of RCS rats were significantly improved by transplantation of h ERO-RPCs at 4 and 8wk postoperation.In addition to inhibiting gliosis at 4 and 8wk postoperation,h ERO-RPCs significantly increased the expression of dedifferentiation-associated transcriptional factor in Müller glia and promoted the migration at 2,4 and 8wk postoperation,but not the transdifferentiation of these cells in RCS rats.In vitro,using the Transwell system,we found that h ERO-RPCs promoted the proliferation and migration of primary rat Müller glia and induced their dedifferentiation at the m RNA level.CONCLUSION:These results show that h ERO-RPCs might promote early dedifferentiation of Müller glia,which may provide novel insights into the mechanisms of stem cell therapy and Müller glial reprogramming,contributing to the development of novel therapies for retinal degeneration disorders.
基金Heilongjiang Traditional Chinese Medicine Research Project(No.ZHY18-029, ZHY19-061, ZHY19-062)Heilongjiang Natural Science FoundationJoint Guiding Project(No.LH2019H095)National Administration of TraditionalChinese Medicine(No.2016ZX05)
文摘Objective:To observe the effect of Qishen decoction on dedifferentiation and autophagy of liver sinusoid endothelial cells(LSEC);Methods:LSEC were randomly divided into the control group,model group,Qishen Decoction low,medium,high dose group,and inhibitor group.The model was induced by 100μg/ml oxidized low-density lipoprotein(oxLDL)for 24 hours,and the corresponding drugs or medicated serum were given for intervention.The expression levels of VEGFR2 and ET1 were detected by RT-qPCR and immunofluorescence staining,the ultrastructure of LSEC was detected by transmission electron microscopy,the content of NO was detected by ELISA,the expression levels of autophagy related proteins(LC3BI,LC3BⅡand p62)and endothelial function related proteins(eNOS and p-eNOS)were detected by western blot;Results:The results of transmission electron microscopy showed that Qishen decoction medicated serum could increase the number of fenestra and autophagy in LSEC cells,and inhibit the formation of basement membrane under endothelium.Compared with the model group,Qishen decoction medicated serum could significantly up-regulate the expression level of VEGFR2 mRNA and protein in LSEC,down regulate the expression level of ET1 mRNA and protein,the difference was statistically significant(P<0.05).In addition,Qishen decoction medicated serum could significantly increase the expression of LC3BII,p-eNOS,eNOS protein and the ratio of LC3BII/LC3BI,p-eNOS/eNOS,and reduce the expression of LC3BI and p62 protein in LSEC,which is statistically significant compared with the model group(P<0.05).Conclusion:Qishen decoction can inhibit the dedifferentiation of LSEC by promoting the autophagy level of LSEC,and then play an anti-fibrosis role.
文摘Cancer tissues contain cancer stem cells (CSCs), which play important roles in cancer metastasis. However, the mechanisms through which cancer cells dedifferentiate into stem cells have not yet been elucidated. In this study, the effects of high concentrations of polyamines produced in cancer cells on dedifferentiation were examined. The results showed that when normal human fibroblasts were cultured with high concentrations of spermine, the obtained polyamine-induced cells expressed alkaline phosphatase and marker proteins of pluripotent stem cells, although apoptosis occurred in most cells. In contrast, another polyamine-induced stem (PIS) cell line (Spe-2 PIS cells), obtained by culture in medium containing Rock, p53, and Bax inhibitors plus spermine, did not show signs of apoptosis. These Spe-2 PIS cells expressed marker proteins of pluripotent stem cells and differentiated into cardiomyocytes, brown adipocytes, and nerve cells. These results suggest that a high concentration of spermine, which often induces apoptosis in normal cells, has the capacity to dedifferentiate somatic cells into pluripotent stem cells and may be associated with the dedifferentiation of cancer cells, which continuously produce high concentrations of spermine. Moreover, the procedure to obtain Spe-2 PIS cells, which is simple and efficient, may have potential applications in regenerative medicine.
基金the National Key Research and Development Program of China(2016YFC1304804)the National Natural Science Foundation of China(81420108007)to X.H.+1 种基金the National Natural Science Found ation of China(81670703)China Postdoctoral Science Foundation(2016M590479)to Y.Z.
文摘Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis;however,the mechanisms by which this occurs remain poorly understood.Our previous study demonstrated that elevation of microRNA-24(miR-24)in a diabetic setting caused beta cell dysfunction and replicative deficiency.In this study,we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum(ER)stress conditions.We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucosestimulated insulin secretion(GSIS)and enhancing the presence of dedifferentiation markers.Ingenuity?Pathway Analysis(IPA)revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4,which are downstream effectors of two key branches of ER stress,by inhibiting its direct target,Irela.Notably,elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells,thus guiding their dedifferentiation under ER stress conditions.Our results demonstrated that the elevated miR-24,to the utmost extent,preserves beta cell mass by inhibiting apoptosis and inducing dedifFerentiation.This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.
基金The research in the Chen’s lab is supported by the grants from the National Natural Science Foundation of China(31988101 and 31730056)the National Key Research and Development Program of China(2017YFA0103601).
文摘The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages.The renewal and regenerative processes are driven by intestinal stem cells(ISCs),which reside at the base of crypts and are marked by Lgr5.As Lgr5^(+)ISCs undergo fast cycling and are vulnerable to damages,there must be other types of cells that can replenish the lost Lgr5^(+)ISCs and then regenerate the damage epithelium.In addition to Lgr5^(+)ISCs,quiescent ISCs at the+4 position in the crypt have been proposed to convert to Lgr5^(+)ISCs during regeneration.However,this“reserve stem cell”model still remains controversial.Different from the traditional view of a hierarchical organization of the intestinal epithelium,recent works support the dynamic“dedifferentiation”model,in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury.Here,we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.
文摘Spathoglottis plicata Blume. is a horticulturally important vulnerable ground orchid with beautiful flowers blooming round the year. Highfrequency protocorm-like body(PLB) formation was established via callus culture from vegetative tissues of in vitro germinated seedlings of S.plicata. Media containing MS salts and Gamborg's B5 vitamins supplemented with 1.0 mg·L^(-1) 2,4-dichlorophenoxyacetic acid(2,4-D), 3.0 mg·L^(-1) α-naphthaleneacetic acid(NAA), 1.0 mg·L^(-1) kinetin(KIN), and 10%(v/v) ‘Aloe vera gel'(Av G) were effective in fragile calli induction. A maximum of(22.3 ± 0.52) PLBs were induced from about 250 mg callus within 45–55 days in the presence of 2.0 mg·L^(-1) NAA and 3.0 mg·L^(-1) 6-benzylaminopurine(BAP). Briefly, 3.0% sodium alginate was found to be most suitable for the formation of an appropriate shape and good germination rates(86.7%)of artificial seeds. Out of three different temperatures(4, 15, and 24 °C), the best result was achieved at 4 °C with 66.7% germinability even after90 days of storage. Plantlets were acclimatized with 86.6% survival rate and 76.3% of these plants produced flowers within 12–15 months of field transfer. Chromosomal studies revealed cytological stability of all regenerants containing 2 n = 40 chromosomes as in the parental plants.The present protocol can be applied reliably for the purposes of large-scale commercial propagation and short-term conservation of this orchid.
基金The work is financially supported by the China Postdoctoral Science Foundation(Grant No.2020M671993)Start-Up Grant for Professor(SGP 9380099 to D.-A.W.)City University of Hong Kong,and the National Natural Science Foundation of China,China(Grant No.51973180 and 21604045).
文摘Dedifferentiation of chondrocyte greatly restricts its function and application,however,it is poorly understood except a small number of canonical markers.The non-cell-adhesive property endows polysaccharide hydrogel with the ability to maintain chondrocyte phenotype,which can serve as a platform to identify new molecular markers and therapeutic targets of chondrocyte dedifferentiation.In this study,the high-throughput RNA sequencing(RNA-seq)was first performed on articular chondrocytes at primary(P0)and passage 1(P1)stages to explore the global alteration of gene expression along with chondrocyte dedifferentiation.Significantly,several potential marker genes,such as PFKFB3,KDM6B,had been identified via comparatively analyzing their expression in P0 and P1 chondrocytes as well as in 3D constructs(i.e.chondrocyte-laden alginate hydrogel and HA-MA hydrogel)at both mRNA and protein level.Besides,the changes in cellular morphology and enriched pathway of differentially expressed genes during chondrocyte dedifferentiation was studied in detail.This study developed the use of hydrogel as a platform to investigate chondrocyte dedifferentiation;the results provided new molecular markers and potential therapeutic targets of chondrocyte dedifferentiation.
基金This work was supported by the Swedish Cancer Society(Junior Clinical Investigator Award).
文摘Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.
基金partially supported by NIH grants:R37 AA020518,R01 DK102142 and R01 AG072895(W-XD).
文摘INTRODUCTION.According to the widely accepted‘endosymbiotic theory’,mitochondria are originated from bacteria when the eukaryotic cell evolved from the capture of alphaproteobacteria,within primitive archaea around 2 billion years ago,which set a symbiotic relationship between the captured bacterium and its archaeal host.Mitochondria are double membrane-bound organelles that have unique sub-compartments:outer mitochondrial membrane,inner mitochondrial membrane,inter-mitochondrial membrane space and mitochondrial matrix.Mitochondria are not only the‘powerhouses’for generation of ATP for cellular functions and survival but also are critical for lipid and glucose metabolism,calcium buffering,phospholipid synthesis,programmed cell death and innate immune response.Given their crucial roles in maintaining cellular functions,cells have developed intricate mechanisms to regulate mitochondrial morphology,quality and numbers1-5.
