Sertoli and granulosa cells,the initial differentiated somatic cells in bipotential gonads,play crucial roles in directing male and female gonad development,respectively.The transcription factor Foxo1 is involved in d...Sertoli and granulosa cells,the initial differentiated somatic cells in bipotential gonads,play crucial roles in directing male and female gonad development,respectively.The transcription factor Foxo1 is involved in diverse cellular processes,and its expression in gonadal somatic cells is sex-dependent.While Foxo1 is abundantly expressed in ovarian granulosa cells,it is notably absent in testicular Sertoli cells.Nevertheless,its function in gonadal somatic cell differentiation remains elusive.In this study,we find that ectopic expression of Foxo1 in Sertoli cells leads to defects in testes development.Further study uncovers that the ectopic expression of Foxo1 induces the abundant expression of Foxl2 in Sertoli cells,along with the upregulation of other female-specific genes.In contrast,the expression of male-specific genes is reduced.Mechanistic studies indicate that Foxo1 directly binds to the promoter region of Foxl2,inducing its expression.Our findings highlight that Foxo1 serves as a key regulator for the lineage maintenance of ovarian granulosa cells.This study contributes valuable insights into understanding the regulatory mechanisms governing the lineage maintenance of gonadal somatic cells.展开更多
Objective To study the role of insulin-like growth factor II receptor in free silica-induced transdifferentiation of primary rat lung fibroblasts Methods Rat lung fibroblasts and rat alveolar macrophages were cultured...Objective To study the role of insulin-like growth factor II receptor in free silica-induced transdifferentiation of primary rat lung fibroblasts Methods Rat lung fibroblasts and rat alveolar macrophages were cultured. A transdifferentiation model of primary rat lung fibroblasts was induced by free silica. Levels of a-SMA protein, IGF-liR protein and mRNA were measured by immunocytochemistry, Western blot and RT-PCR, respectively. Lung fibroblasts were treated with Wortmannin. Results The expression levels of a-SMA concentration and decreased after Wortmann and IGF-IIR increased with the increasing free silica n was used. Conclusion The IGF-IIR plays an important role in free silica-induced transdifferentiation of primary rat lung fibroblasts.展开更多
The damage of human corneal cells encounter with the problem of availability of corneal cells for replacement. Limitation of the source of corneal cells has been realized. An attempt of development of corneal epitheli...The damage of human corneal cells encounter with the problem of availability of corneal cells for replacement. Limitation of the source of corneal cells has been realized. An attempt of development of corneal epithelial-like cells from the human skin-derived precursor (hSKPs) has been made in this study. Combination of three essential growth factors: epidermal growth factor (EGF), keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) could demonstrate successfully induction of hSKPs to differentiation into corneal cells.The induced cells expressed the appearance of markers of corneal epithelial cells as shown by the presence of keratin 3 (K3) by antibody label and Western blot assay. The K3 gene expression of induced hSKPs cells as shown by reverse transcription-polymerase chain reaction (RT-PCR) technology was also demonstrated. The presence of these markers at both gene and protein levels could lead to our conclusion that the directional transdifferentiation of hSKPs cells into corneal epithelial cells was successfully done under this cell induction protocol. The finding shows a newly available stem cell source can be obtained from easily available skin. Cells from autologous human skin might be used for corneal disorder treatment in future clinical application.展开更多
To investigate the role of connective tissue growth factor (CTGF) in transdifferentiation of human renal tubular epithelial cell (HKC), in vitro cultured HKC cells were divided into 3 groups: negtive control, low dose...To investigate the role of connective tissue growth factor (CTGF) in transdifferentiation of human renal tubular epithelial cell (HKC), in vitro cultured HKC cells were divided into 3 groups: negtive control, low dose CTGF-treated group (rh CTGF, 2.5 ng/ml) and high dose CTGF-treated (rhCTGF, 5.0 ng/ml). Then the expression of α-smooth muscle actin (α-SMA) were assessed by indirect immuno-fluorescence, and the percentage of α-SMA positive cells were assessed by flow cytometry. RT-PCR were also performed to examine the mRNA level of α-SMA. Upon the stimulation of different concentrations of rhCTGF, the expression of α-SMA were markedly stronger than that in negative controls. The percentages of α-SMA positive cells were significantly higher in the stimulated groups than that of negative controls (38.9 %, 65.5 % vs 2.4 %, P<0.01) .α-SMA mRNA levels were also up-regulated by the stimulation of rhCTGF (P<0.01). These results suggest that CTGF can promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblast (Myo-F).展开更多
Background:Myogenic transdifferentiation can be accomplished through ectopic MYOD1 expression,which is facilitated by various signaling pathways associated with myogenesis.In this study,we attempted to transdifferenti...Background:Myogenic transdifferentiation can be accomplished through ectopic MYOD1 expression,which is facilitated by various signaling pathways associated with myogenesis.In this study,we attempted to transdifferentiate pig embryonic fibroblasts(PEFs)myogenically into skeletal muscle through overexpression of the pig MYOD1 gene and modulation of the FGF,TGF-β,WNT,and cAMP signaling pathways.Results:The MYOD1 overexpression vector was constructed based on comparative sequence analysis,demonstrating that pig MYOD1 has evolutionarily conserved domains across various species.Although forced MYOD1 expression through these vectors triggered the expression of endogenous muscle markers,transdifferentiated muscle cells from fibroblasts were not observed.Therefore,various signaling molecules,including FGF2,SB431542,CHIR99021,and forskolin,along with MYOD1 overexpression were applied to enhance the myogenic reprogramming.The modified conditions led to the derivation of myotubes and activation of muscle markers in PEFs,as determined by qPCR and immunostaining.Notably,a sarcomere-like structure was observed,indicating that terminally differentiated skeletal muscle could be obtained from transdifferentiated cells.Conclusions:In summary,we established a protocol for reprogramming MYOD1-overexpressing PEFs into the mature skeletal muscle using signaling molecules.Our myogenic reprogramming can be used as a cell source for muscle disease models in regenerative medicine and the production of cultured meat in cellular agriculture.展开更多
Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the ...Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.展开更多
BACKGROUND Senescence is characterized by a decline in hepatocyte function,with impairment of metabolism and regenerative capacity.Several models that duplicate liver functions in vitro are essential tools for studyin...BACKGROUND Senescence is characterized by a decline in hepatocyte function,with impairment of metabolism and regenerative capacity.Several models that duplicate liver functions in vitro are essential tools for studying drug metabolism,liver diseases,and organ regeneration.The human HepaRG cell line represents an effective model for the study of liver metabolism and hepatic progenitors.However,the impact of senescence on HepaRG cells is not yet known.AIM To characterize the effects of senescence on the transdifferentiation capacity and mitochondrial metabolism of human HepaRG cells.METHODS We compared the transdifferentiation capacity of cells over 10(passage 10[P10])vs P20.Aging was evaluated by senescence-associated(SA)beta-galactosidase activity and the comet assay.HepaRG transdifferentiation was analyzed by confocal microscopy and flow cytometry(expression of cluster of differentiation 49a[CD49a],CD49f,CD184,epithelial cell adhesion molecule[EpCAM],and cytokeratin 19[CK19]),quantitative PCR analysis(expression of albumin,cytochrome P4503A4[CYP3A4],γ-glutamyl transpeptidase[γ-GT],and carcinoembryonic antigen[CEA]),and functional analyses(albumin secretion,CYP3A4,andγ-GT).Mitochondrial respiration and the ATP and nicotinamide adenine dinucleotide(NAD^(+))/NAD with hydrogen(NADH)content were also measured.RESULTS SAβ-galactosidase staining was higher in P20 than P10 HepaRG cells;in parallel,the comet assay showed consistent DNA damage in P20 HepaRG cells.With respect to P10,P20 HepaRG cells exhibited a reduction of CD49a,CD49f,CD184,EpCAM,and CK19 after the induction of transdifferentiation.Furthermore,lower gene expression of albumin,CYP3A4,andγ-GT,as well as reduced albumin secretion capacity,CYP3A4,andγ-GT activity were reported in transdifferentiated P20 compared to P10 cells.By contrast,the gene expression level of CEA was not reduced by transdifferentiation in P20 cells.Of note,both cellular and mitochondrial oxygen consumption was lower in P20 than in P10 transdifferentiated cells.Finally,both ATP and NAD^(+)/NADH were depleted in P20 cells with respect to P10 cells.CONCLUSION SA mitochondrial dysfunction may limit the transdifferentiation potential of HepaRG cells,with consequent impairment of metabolic and regenerative properties,which may alter applications in basic studies.展开更多
Objective： The effects of hydraulic pressure on renal tubular epithelial-myofibroblast transdifferentiation （TEMT） were investigated. Methods： We applied hydraulic pressure （50 cmH2O） to normal rat kidney tubula...Objective： The effects of hydraulic pressure on renal tubular epithelial-myofibroblast transdifferentiation （TEMT） were investigated. Methods： We applied hydraulic pressure （50 cmH2O） to normal rat kidney tubular epithelial cells （NRK52E） for different durations. Furthermore, different pressure magnitudes were applied to cells. The morphology, cytoskeleton, and expression ofmyofibroblastic marker protein and transforming growth factor-β1 （TGF-β1） of NRK52E cells were examined. Results Disorganized actin filaments and formation of curling clusters in actin were seen in the cytoplasm of pressurized cells. We verified that de novo expression α-smooth muscle actin induced by pressure, which indicated TEMT, was dependent on both the magnitude and duration of pressure. TGF-β1 expression was significantly upregulated under certain conditions, which implies that the induction of TEMT by hydraulic pressure is related with TGF-β1. Conclusion： We illustrate for the first time that hydraulic pressure can induce TEMT in a pressure magnitude- and duration-dependent manner, and that this TEMT is accompanied by TGF-β1 secretion.展开更多
Peripheral nerve injuries are clinical conditions that often result in functional deficits,compromising patient quality of life.Given the relevance of these injuries,new treatment strategies are constantly being inves...Peripheral nerve injuries are clinical conditions that often result in functional deficits,compromising patient quality of life.Given the relevance of these injuries,new treatment strategies are constantly being investigated.Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action,the transdifferentiation of these cells into Schwann-like cells(SLCs)represents a significant advancement in nerve injury therapy.Recent studies indicate that SLCs can mimic the functions of Schwann cells,with promising results in animal models.However,challenges remain,such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications.A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries.Therefore,we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.展开更多
Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various ne...Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.展开更多
Background Tubulointerstitial renal fibrosis is the common end point of progressive kidney diseases, and tubular epithelial-myofibroblast transdifferentiation （TEMT） plays a key role in the progress of tubulointerst...Background Tubulointerstitial renal fibrosis is the common end point of progressive kidney diseases, and tubular epithelial-myofibroblast transdifferentiation （TEMT） plays a key role in the progress of tubulointerstitial renal fibrosis. Anaphylatoxin C3a and C5a are identified as novel profibrotic factors in renal disease and as potential new therapeutic targets. The aim of this study was to investigate whether C3a, C5a can regulate TEMT by transforming growth factor-β1 （TGF-β1）/connective tissue growth factor （CTGF） signaling pathway and the effects of C3a and C5a receptor antagonists （C3aRA and C5aRA） on C3α- and C5α-induced TEMT. Methods HK-2 cells were divided into C3a and C5a groups which were subdivided into four subgroups： control group, 10 ng/ml TGF-I31 group, 50 nmol/L C3a group, 50 nmol/L C3a plus 1 pmol/L C3aRA group; control group, 10 ng/ml TGF-I^I group, 50 nmol/L C5a group, 50 nmol/L C5a plus 2.5 pmol/L C5aRA group. TGF-β1 receptor antagonist （TGF-β1 RA） 10 IJg/ml was used to investigate the mechanism of C3α- and C5α-induced TEMT. Electron microscopy was used to observe the morphological changes. Immunocytochemistry staining, real-time PCR and Western blotting were used to detect the expressions of a smooth muscle actin （α-SMA）, E-cadherin, Col-I, C3a receptor （C3aR）, C5aR, CTGF and TGF-β1. Results HK-2 cells cultured with C3a and C5a for 72 hours exhibited strong staining of α-SMA, lost the positive staining of E-cadherin, and showed a slightly spindle-like shape and loss of microvilli on the cell surface. The expressions of α-SMA, E-cadherin, Col-I, C3aR, C5aR, TGF-β1 and CTGF in C3α- and C5α-treated groups were higher than normal control group （P 〈0.05）. C3aRA and C5aRA inhibited the expressions of α-SMA, Col-I, C3aR, C5aR, and up-regulated the expression of E-cadherin （P 〈0.05）. TGF-β1 and CTGF mRNA expressions induced by C3a and C5a were partly blocked by TGF-β1 RA （P 〈0.05）. Conclusion C3a and C5a can induce TEMT via the up-regulations of C3aR and C5aR mRNA and the activation of TGF-β1/CTGF signaling pathway in vitro.展开更多
Objective: To observe the imbalance of anatomical and functional innervation factors of sympathetic nerves, nerve growth factor(NGF) and leukemia inhibitory factor(LIF), in salt-sensitive hypertensive heart failure ra...Objective: To observe the imbalance of anatomical and functional innervation factors of sympathetic nerves, nerve growth factor(NGF) and leukemia inhibitory factor(LIF), in salt-sensitive hypertensive heart failure rats and to explore the effects of treatment with Guizhi Decoction(桂枝汤) on sympathetic remodeling by inhibiting cholinergic transdifferentiation. Methods: SS-13 BN and Dahl salt-sensitive(DS) rats were divided into 3 groups: SS-13 BN group(control group, n=9), DS group(model group, n=9) and GS group(Guizhi Decoction, n=9). After 10 weeks of a high-salt diet, the GS group rats were given Guizhi Decoction and other two groups were given saline at an equal volume as a vehicle. After 4 weeks’ intragastric administration, rats were executed to detect the relevant indicators. Echocardiography and plasma n-terminal pro-B type natriuretic peptide(NT-proBNP) levels were used to assess cardiac function. Noradrenaline(NA) levels in the plasma and myocardium were detected to evaluate the sympathetic function. NGF and LIF expression were detected in the myocardium by Western blot or quantitative real-time PCR. Double immunofluorescence or Western blot was used to detect tyrosine hydroxylase(TH), choline acetyltransferase(CHAT) and growth associated protein 43(GAP43) in order to reflect anatomical and functional changes of sympathetic nerves. Results: DS group had anatomical and functional deterioration of sympathetic nerves in the decompensation period of heart failure compared with SS-13 BN group. Compared with the DS group, Guizhi Decoction significantly decreased the expression of LIF mRNA/protein(P<0.01), increased the expression of NGF(P<0.05 or P<0.01), enhanced the levels of TH^+/GAP43^+ and TH^+/CHAT^+ positive nerve fibers(P<0.01), and improved the protein expression of TH and GAP43 in left ventricle, but had no effect on CHAT(P>0.05). Guizhi Decoction inhibited inflammatory infiltration and collagen deposition of myocardial injury, increased the content of myocardial NA(P<0.05), reduced the plasma NA level(P<0.01), improved cardiac function(P<0.01), and improved weight and blood pressure to some extent(P<0.05), compared with DS group. Conclusions: Guizhi Decoction could inhibit cholinergic transdifferentiation of sympathetic nerves, improve the anatomical and functional denervation of sympathetic nerves, and delay the progression of decompensated heart failure. The mechanism may be associated with the correction of the imbalance of NGF and LIF.展开更多
Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functi...Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functional cells. This process is crucial in regenerative medicine. However, the cell-converting strategies, which mainly depend on the virus-mediated expression of exogenous genes, have clinical safety concerns. Small molecules with compelling advantages are a potential alternative in manipulating cell fate conversion. In this review, we briefly retrospect the nature of cell transdifferentiation and summarize the current developments in the research of small molecules in promoting cell conversion. Particularly, we focus on the complete chemical compound-induced cell transdifferentiation, which is closer to the clinical translation in cell therapy. Despite these achievements, the mechanisms underpinning chemical transdifferentiation remain largely unknown. More importantly, identifying drugs that induce resident cell conversion in vivo to repair damaged tissue remains to be the end-goal in current regenerative medicine.展开更多
Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s di...Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal loss.Unfo rtunately,the neurons of most mammals including humans do not possess the ability to self-regenerate.Replenishment of lost neurons becomes an appealing therapeutic strategy to reve rse the disease phenotype.Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain edema.Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell therapy.Thus far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous system.However,some recent papers did not obtain expected results,and discrepancies exist.Therefore,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future studies.It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.展开更多
Atherosclerosis(AS)is characterized by impairment and apoptosis of endothelial cells,continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells,which is documented as the traditional ce...Atherosclerosis(AS)is characterized by impairment and apoptosis of endothelial cells,continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells,which is documented as the traditional cellular paradigm.However,the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis,transdifferentiation and novel cell death forms such as ferroptosis,pyroptosis,and extracellular trap were reported.Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets.On the other side,the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden.Stem cell-or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects.Given the complexity of pathological changes of AS,attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging.In this review,the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation.The future challenges and improvements were also discussed.展开更多
In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been sho...In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.展开更多
As with all tissues of the central nervous system,the low regeneration ability of spinal cord tissue after injury decreases the potential for repair and recovery.Initially,in spinal cord injuries(SCI),often the surgeo...As with all tissues of the central nervous system,the low regeneration ability of spinal cord tissue after injury decreases the potential for repair and recovery.Initially,in spinal cord injuries(SCI),often the surgeon can only limit further damage by early surgical decompression.However,with the development of basic science,especially the development of genetic engineering,molecular biology,tissue engineering,and materials science,some promising progress has been made in promoting the repair of central nervous system injuries.For example,transplantation of neural stem cells(NSCs),olfactory ensheathing cells(OECs),and gene-mediated transdifferentiation to repair central nervous system injury.This paper summarizes the progress and prospects of SCI repair with tissue engineering scaffold and cell transdifferentiation from an extensive literatures.展开更多
AIM： To investigate and compare the hepatogenic transdifferentiation of adipose tissue-derived stem cells （ADSC） and bone marrow-derived mesenchymal stem cells （BMSC） in vitro. Transdifferentiation of BMSC into h...AIM： To investigate and compare the hepatogenic transdifferentiation of adipose tissue-derived stem cells （ADSC） and bone marrow-derived mesenchymal stem cells （BMSC） in vitro. Transdifferentiation of BMSC into hepatic cells in vivo has been described. Adipose tissue represents an accessible source of ADSC, with similar characteristics to BMSC. METHODS： BMSCs were obtained from patients undergoing total hip arthroplasty and ADSC from human adipose tissue obtained from lipectomy. Cells were grown in medium containing 15% human serum. Cultures were serum deprived for 2 d before cultivating under similar pro-hepatogenic conditions to those of liver development using a 2-step protocol with sequential addition of growth factors, cytokines and hormones. Hepatic differentiation was RT-PCR-assessed and liver-marker genes were immunohistochemically analysed.RESULTS： BMSC and ADSC exhibited a fibroblastic morphology that changed to a polygonal shape when cells differentiated. Expression of stem cell marker Thyl decreased in differentiated ADSC and BMSC. However, the expression of the hepatic markers, albumin and CYPs increased to a similar extent in differentiated BMSC and ADSC. Hepatic gene activation could be attributed to increased liver-enriched transcription factors （C/EBPβ and HNF4α）, as demonstrated by adenoviral expression vectors.CONCLUSION： Mesenchymal stem cells can be induced to hepatogenic transdifferentiation in vitro. ADSCs have a similar hepatogenic differentiation potential to BMSC, but a longer culture period and higher proliferation capacity. Therefore, adipose tissue may be an ideal source of large amounts of autologous stem cells, and may become an alternative for hepatocyte regeneration, liver cell transplantation or preclinical drug testing.展开更多
Barrett's esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esoph-ageal adenocarcinoma. Whilst it is well accepted that...Barrett's esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esoph-ageal adenocarcinoma. Whilst it is well accepted that Barrett's esophagus is caused by gastroesophageal reflux, the molecular mechanisms of its pathogenesis and progression to cancer remain unclear. MicroRNAs (miRNAs) are short segments of RNA that have been shown to control the expression of many human genes. They have been implicated in most cellular processes, and the role of miRNAs in disease development is be-coming increasingly evident. Understanding altered miRNA expression is likely to help unravel the molecular mechanisms that underpin the development of Barrett's esophagus and its progression to cancer.展开更多
Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surge...Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0820000)the National Natural Science Foundation of China(82421003,32270902,32170855)+1 种基金the Faculty Resources Project of the College of Life Sciences,Inner Mongolia University(2022-104)Initiative Scientific Research Program,Institute of Zoology,Chinese Academy of Sciences(20231OZ0102).
文摘Sertoli and granulosa cells,the initial differentiated somatic cells in bipotential gonads,play crucial roles in directing male and female gonad development,respectively.The transcription factor Foxo1 is involved in diverse cellular processes,and its expression in gonadal somatic cells is sex-dependent.While Foxo1 is abundantly expressed in ovarian granulosa cells,it is notably absent in testicular Sertoli cells.Nevertheless,its function in gonadal somatic cell differentiation remains elusive.In this study,we find that ectopic expression of Foxo1 in Sertoli cells leads to defects in testes development.Further study uncovers that the ectopic expression of Foxo1 induces the abundant expression of Foxl2 in Sertoli cells,along with the upregulation of other female-specific genes.In contrast,the expression of male-specific genes is reduced.Mechanistic studies indicate that Foxo1 directly binds to the promoter region of Foxl2,inducing its expression.Our findings highlight that Foxo1 serves as a key regulator for the lineage maintenance of ovarian granulosa cells.This study contributes valuable insights into understanding the regulatory mechanisms governing the lineage maintenance of gonadal somatic cells.
基金supported by the Research Fund from theNational Natural Science Foundation of China(#81102109)
文摘Objective To study the role of insulin-like growth factor II receptor in free silica-induced transdifferentiation of primary rat lung fibroblasts Methods Rat lung fibroblasts and rat alveolar macrophages were cultured. A transdifferentiation model of primary rat lung fibroblasts was induced by free silica. Levels of a-SMA protein, IGF-liR protein and mRNA were measured by immunocytochemistry, Western blot and RT-PCR, respectively. Lung fibroblasts were treated with Wortmannin. Results The expression levels of a-SMA concentration and decreased after Wortmann and IGF-IIR increased with the increasing free silica n was used. Conclusion The IGF-IIR plays an important role in free silica-induced transdifferentiation of primary rat lung fibroblasts.
基金Supported by Stem Cell Project,National Research Council of Thailand (NRCT),Cell Engineering and Tissue Growth, Institute of Molecular Biosciences and Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Thailand
文摘The damage of human corneal cells encounter with the problem of availability of corneal cells for replacement. Limitation of the source of corneal cells has been realized. An attempt of development of corneal epithelial-like cells from the human skin-derived precursor (hSKPs) has been made in this study. Combination of three essential growth factors: epidermal growth factor (EGF), keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) could demonstrate successfully induction of hSKPs to differentiation into corneal cells.The induced cells expressed the appearance of markers of corneal epithelial cells as shown by the presence of keratin 3 (K3) by antibody label and Western blot assay. The K3 gene expression of induced hSKPs cells as shown by reverse transcription-polymerase chain reaction (RT-PCR) technology was also demonstrated. The presence of these markers at both gene and protein levels could lead to our conclusion that the directional transdifferentiation of hSKPs cells into corneal epithelial cells was successfully done under this cell induction protocol. The finding shows a newly available stem cell source can be obtained from easily available skin. Cells from autologous human skin might be used for corneal disorder treatment in future clinical application.
基金ThisworkwassupportedbyagrantfromtheScience&TechnologyFoundationofHubeiProvince (No .2 0 0 3AA30 1C14 )
文摘To investigate the role of connective tissue growth factor (CTGF) in transdifferentiation of human renal tubular epithelial cell (HKC), in vitro cultured HKC cells were divided into 3 groups: negtive control, low dose CTGF-treated group (rh CTGF, 2.5 ng/ml) and high dose CTGF-treated (rhCTGF, 5.0 ng/ml). Then the expression of α-smooth muscle actin (α-SMA) were assessed by indirect immuno-fluorescence, and the percentage of α-SMA positive cells were assessed by flow cytometry. RT-PCR were also performed to examine the mRNA level of α-SMA. Upon the stimulation of different concentrations of rhCTGF, the expression of α-SMA were markedly stronger than that in negative controls. The percentages of α-SMA positive cells were significantly higher in the stimulated groups than that of negative controls (38.9 %, 65.5 % vs 2.4 %, P<0.01) .α-SMA mRNA levels were also up-regulated by the stimulation of rhCTGF (P<0.01). These results suggest that CTGF can promote the transdifferentiation of human renal tubular epithelial cells towards myofibroblast (Myo-F).
基金supported by the BK21 Four program,the Korea Evaluation Institute of Industrial Technology(KEIT,20012411)the National Research Foundation of Korea(NRF)grant(2021R1A2C4001837).
文摘Background:Myogenic transdifferentiation can be accomplished through ectopic MYOD1 expression,which is facilitated by various signaling pathways associated with myogenesis.In this study,we attempted to transdifferentiate pig embryonic fibroblasts(PEFs)myogenically into skeletal muscle through overexpression of the pig MYOD1 gene and modulation of the FGF,TGF-β,WNT,and cAMP signaling pathways.Results:The MYOD1 overexpression vector was constructed based on comparative sequence analysis,demonstrating that pig MYOD1 has evolutionarily conserved domains across various species.Although forced MYOD1 expression through these vectors triggered the expression of endogenous muscle markers,transdifferentiated muscle cells from fibroblasts were not observed.Therefore,various signaling molecules,including FGF2,SB431542,CHIR99021,and forskolin,along with MYOD1 overexpression were applied to enhance the myogenic reprogramming.The modified conditions led to the derivation of myotubes and activation of muscle markers in PEFs,as determined by qPCR and immunostaining.Notably,a sarcomere-like structure was observed,indicating that terminally differentiated skeletal muscle could be obtained from transdifferentiated cells.Conclusions:In summary,we established a protocol for reprogramming MYOD1-overexpressing PEFs into the mature skeletal muscle using signaling molecules.Our myogenic reprogramming can be used as a cell source for muscle disease models in regenerative medicine and the production of cultured meat in cellular agriculture.
基金Supported by The Agence National de Recherche(ANR 2010 BLAN 1240 01)the Ligue contre le Cancer du Rh ne and de la Loire+3 种基金the CMIRA program of Region Rh?ne-Alpes,No.12004959-01the Fondation ARC pour la Recherche sur le Cancer,France,No.SFI20101201530National Nature Science Foundation of China,No.NSFC81170719,No.81370960Shanghai New Excellent Youth Program,No.XYQ2011009
文摘Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.
文摘BACKGROUND Senescence is characterized by a decline in hepatocyte function,with impairment of metabolism and regenerative capacity.Several models that duplicate liver functions in vitro are essential tools for studying drug metabolism,liver diseases,and organ regeneration.The human HepaRG cell line represents an effective model for the study of liver metabolism and hepatic progenitors.However,the impact of senescence on HepaRG cells is not yet known.AIM To characterize the effects of senescence on the transdifferentiation capacity and mitochondrial metabolism of human HepaRG cells.METHODS We compared the transdifferentiation capacity of cells over 10(passage 10[P10])vs P20.Aging was evaluated by senescence-associated(SA)beta-galactosidase activity and the comet assay.HepaRG transdifferentiation was analyzed by confocal microscopy and flow cytometry(expression of cluster of differentiation 49a[CD49a],CD49f,CD184,epithelial cell adhesion molecule[EpCAM],and cytokeratin 19[CK19]),quantitative PCR analysis(expression of albumin,cytochrome P4503A4[CYP3A4],γ-glutamyl transpeptidase[γ-GT],and carcinoembryonic antigen[CEA]),and functional analyses(albumin secretion,CYP3A4,andγ-GT).Mitochondrial respiration and the ATP and nicotinamide adenine dinucleotide(NAD^(+))/NAD with hydrogen(NADH)content were also measured.RESULTS SAβ-galactosidase staining was higher in P20 than P10 HepaRG cells;in parallel,the comet assay showed consistent DNA damage in P20 HepaRG cells.With respect to P10,P20 HepaRG cells exhibited a reduction of CD49a,CD49f,CD184,EpCAM,and CK19 after the induction of transdifferentiation.Furthermore,lower gene expression of albumin,CYP3A4,andγ-GT,as well as reduced albumin secretion capacity,CYP3A4,andγ-GT activity were reported in transdifferentiated P20 compared to P10 cells.By contrast,the gene expression level of CEA was not reduced by transdifferentiation in P20 cells.Of note,both cellular and mitochondrial oxygen consumption was lower in P20 than in P10 transdifferentiated cells.Finally,both ATP and NAD^(+)/NADH were depleted in P20 cells with respect to P10 cells.CONCLUSION SA mitochondrial dysfunction may limit the transdifferentiation potential of HepaRG cells,with consequent impairment of metabolic and regenerative properties,which may alter applications in basic studies.
基金Project (No. 2007CB947802) supported by National Basic Research Program of China
文摘Objective： The effects of hydraulic pressure on renal tubular epithelial-myofibroblast transdifferentiation （TEMT） were investigated. Methods： We applied hydraulic pressure （50 cmH2O） to normal rat kidney tubular epithelial cells （NRK52E） for different durations. Furthermore, different pressure magnitudes were applied to cells. The morphology, cytoskeleton, and expression ofmyofibroblastic marker protein and transforming growth factor-β1 （TGF-β1） of NRK52E cells were examined. Results Disorganized actin filaments and formation of curling clusters in actin were seen in the cytoplasm of pressurized cells. We verified that de novo expression α-smooth muscle actin induced by pressure, which indicated TEMT, was dependent on both the magnitude and duration of pressure. TGF-β1 expression was significantly upregulated under certain conditions, which implies that the induction of TEMT by hydraulic pressure is related with TGF-β1. Conclusion： We illustrate for the first time that hydraulic pressure can induce TEMT in a pressure magnitude- and duration-dependent manner, and that this TEMT is accompanied by TGF-β1 secretion.
文摘Peripheral nerve injuries are clinical conditions that often result in functional deficits,compromising patient quality of life.Given the relevance of these injuries,new treatment strategies are constantly being investigated.Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action,the transdifferentiation of these cells into Schwann-like cells(SLCs)represents a significant advancement in nerve injury therapy.Recent studies indicate that SLCs can mimic the functions of Schwann cells,with promising results in animal models.However,challenges remain,such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications.A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries.Therefore,we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.
基金supported by the National Natural Science Foundation of China,Nos.82471471(to WJ),82471485(to FY)Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation,No.tzjhjw(to WJ)+1 种基金Shaanxi Key Research and Development Plan Project,No.2023-YBSF-353(to XW)the Joint Fund Project of Innovation Research Institute of Xijing Hospital,No.LHJJ24JH13(to ZS)。
文摘Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.
基金This research was supported by the grants from the National Natural Science Foundation of China，the Science and Technology Research Projects of Sichuan Province
文摘Background Tubulointerstitial renal fibrosis is the common end point of progressive kidney diseases, and tubular epithelial-myofibroblast transdifferentiation （TEMT） plays a key role in the progress of tubulointerstitial renal fibrosis. Anaphylatoxin C3a and C5a are identified as novel profibrotic factors in renal disease and as potential new therapeutic targets. The aim of this study was to investigate whether C3a, C5a can regulate TEMT by transforming growth factor-β1 （TGF-β1）/connective tissue growth factor （CTGF） signaling pathway and the effects of C3a and C5a receptor antagonists （C3aRA and C5aRA） on C3α- and C5α-induced TEMT. Methods HK-2 cells were divided into C3a and C5a groups which were subdivided into four subgroups： control group, 10 ng/ml TGF-I31 group, 50 nmol/L C3a group, 50 nmol/L C3a plus 1 pmol/L C3aRA group; control group, 10 ng/ml TGF-I^I group, 50 nmol/L C5a group, 50 nmol/L C5a plus 2.5 pmol/L C5aRA group. TGF-β1 receptor antagonist （TGF-β1 RA） 10 IJg/ml was used to investigate the mechanism of C3α- and C5α-induced TEMT. Electron microscopy was used to observe the morphological changes. Immunocytochemistry staining, real-time PCR and Western blotting were used to detect the expressions of a smooth muscle actin （α-SMA）, E-cadherin, Col-I, C3a receptor （C3aR）, C5aR, CTGF and TGF-β1. Results HK-2 cells cultured with C3a and C5a for 72 hours exhibited strong staining of α-SMA, lost the positive staining of E-cadherin, and showed a slightly spindle-like shape and loss of microvilli on the cell surface. The expressions of α-SMA, E-cadherin, Col-I, C3aR, C5aR, TGF-β1 and CTGF in C3α- and C5α-treated groups were higher than normal control group （P 〈0.05）. C3aRA and C5aRA inhibited the expressions of α-SMA, Col-I, C3aR, C5aR, and up-regulated the expression of E-cadherin （P 〈0.05）. TGF-β1 and CTGF mRNA expressions induced by C3a and C5a were partly blocked by TGF-β1 RA （P 〈0.05）. Conclusion C3a and C5a can induce TEMT via the up-regulations of C3aR and C5aR mRNA and the activation of TGF-β1/CTGF signaling pathway in vitro.
基金Supported by the National Natural Science Foundation of China(No.81673970)
文摘Objective: To observe the imbalance of anatomical and functional innervation factors of sympathetic nerves, nerve growth factor(NGF) and leukemia inhibitory factor(LIF), in salt-sensitive hypertensive heart failure rats and to explore the effects of treatment with Guizhi Decoction(桂枝汤) on sympathetic remodeling by inhibiting cholinergic transdifferentiation. Methods: SS-13 BN and Dahl salt-sensitive(DS) rats were divided into 3 groups: SS-13 BN group(control group, n=9), DS group(model group, n=9) and GS group(Guizhi Decoction, n=9). After 10 weeks of a high-salt diet, the GS group rats were given Guizhi Decoction and other two groups were given saline at an equal volume as a vehicle. After 4 weeks’ intragastric administration, rats were executed to detect the relevant indicators. Echocardiography and plasma n-terminal pro-B type natriuretic peptide(NT-proBNP) levels were used to assess cardiac function. Noradrenaline(NA) levels in the plasma and myocardium were detected to evaluate the sympathetic function. NGF and LIF expression were detected in the myocardium by Western blot or quantitative real-time PCR. Double immunofluorescence or Western blot was used to detect tyrosine hydroxylase(TH), choline acetyltransferase(CHAT) and growth associated protein 43(GAP43) in order to reflect anatomical and functional changes of sympathetic nerves. Results: DS group had anatomical and functional deterioration of sympathetic nerves in the decompensation period of heart failure compared with SS-13 BN group. Compared with the DS group, Guizhi Decoction significantly decreased the expression of LIF mRNA/protein(P<0.01), increased the expression of NGF(P<0.05 or P<0.01), enhanced the levels of TH^+/GAP43^+ and TH^+/CHAT^+ positive nerve fibers(P<0.01), and improved the protein expression of TH and GAP43 in left ventricle, but had no effect on CHAT(P>0.05). Guizhi Decoction inhibited inflammatory infiltration and collagen deposition of myocardial injury, increased the content of myocardial NA(P<0.05), reduced the plasma NA level(P<0.01), improved cardiac function(P<0.01), and improved weight and blood pressure to some extent(P<0.05), compared with DS group. Conclusions: Guizhi Decoction could inhibit cholinergic transdifferentiation of sympathetic nerves, improve the anatomical and functional denervation of sympathetic nerves, and delay the progression of decompensated heart failure. The mechanism may be associated with the correction of the imbalance of NGF and LIF.
文摘Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functional cells. This process is crucial in regenerative medicine. However, the cell-converting strategies, which mainly depend on the virus-mediated expression of exogenous genes, have clinical safety concerns. Small molecules with compelling advantages are a potential alternative in manipulating cell fate conversion. In this review, we briefly retrospect the nature of cell transdifferentiation and summarize the current developments in the research of small molecules in promoting cell conversion. Particularly, we focus on the complete chemical compound-induced cell transdifferentiation, which is closer to the clinical translation in cell therapy. Despite these achievements, the mechanisms underpinning chemical transdifferentiation remain largely unknown. More importantly, identifying drugs that induce resident cell conversion in vivo to repair damaged tissue remains to be the end-goal in current regenerative medicine.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences,No.XDB39050600(to RL)the National Natural Science Foundation of China,No.81971610(to RL)Beijing Rehabilitation Hospital Introduction of Talent Research Start-up Fund,No.2021R-008(to JZ)。
文摘Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal loss.Unfo rtunately,the neurons of most mammals including humans do not possess the ability to self-regenerate.Replenishment of lost neurons becomes an appealing therapeutic strategy to reve rse the disease phenotype.Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain edema.Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell therapy.Thus far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous system.However,some recent papers did not obtain expected results,and discrepancies exist.Therefore,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future studies.It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.
基金supported by the National Natural Science Foundation of China(No.81573957,No.81874461 and No.82070307).
文摘Atherosclerosis(AS)is characterized by impairment and apoptosis of endothelial cells,continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells,which is documented as the traditional cellular paradigm.However,the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis,transdifferentiation and novel cell death forms such as ferroptosis,pyroptosis,and extracellular trap were reported.Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets.On the other side,the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden.Stem cell-or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects.Given the complexity of pathological changes of AS,attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging.In this review,the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation.The future challenges and improvements were also discussed.
基金supported by the National Natural Science Foundation of China,No.82071418the Natural Science Foundation of Fujian Province,No.2020J01612 (both to EH)。
文摘In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1(PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.e B-GFAP-sh PTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-sh PTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment.
文摘As with all tissues of the central nervous system,the low regeneration ability of spinal cord tissue after injury decreases the potential for repair and recovery.Initially,in spinal cord injuries(SCI),often the surgeon can only limit further damage by early surgical decompression.However,with the development of basic science,especially the development of genetic engineering,molecular biology,tissue engineering,and materials science,some promising progress has been made in promoting the repair of central nervous system injuries.For example,transplantation of neural stem cells(NSCs),olfactory ensheathing cells(OECs),and gene-mediated transdifferentiation to repair central nervous system injury.This paper summarizes the progress and prospects of SCI repair with tissue engineering scaffold and cell transdifferentiation from an extensive literatures.
基金Supported by the ALIVE Foundation, the FIS from Instituto de Salud Carlos III, Spain, No. 03/0339, and the European Commission, No. LSHB-CT-2004-504761
文摘AIM： To investigate and compare the hepatogenic transdifferentiation of adipose tissue-derived stem cells （ADSC） and bone marrow-derived mesenchymal stem cells （BMSC） in vitro. Transdifferentiation of BMSC into hepatic cells in vivo has been described. Adipose tissue represents an accessible source of ADSC, with similar characteristics to BMSC. METHODS： BMSCs were obtained from patients undergoing total hip arthroplasty and ADSC from human adipose tissue obtained from lipectomy. Cells were grown in medium containing 15% human serum. Cultures were serum deprived for 2 d before cultivating under similar pro-hepatogenic conditions to those of liver development using a 2-step protocol with sequential addition of growth factors, cytokines and hormones. Hepatic differentiation was RT-PCR-assessed and liver-marker genes were immunohistochemically analysed.RESULTS： BMSC and ADSC exhibited a fibroblastic morphology that changed to a polygonal shape when cells differentiated. Expression of stem cell marker Thyl decreased in differentiated ADSC and BMSC. However, the expression of the hepatic markers, albumin and CYPs increased to a similar extent in differentiated BMSC and ADSC. Hepatic gene activation could be attributed to increased liver-enriched transcription factors （C/EBPβ and HNF4α）, as demonstrated by adenoviral expression vectors.CONCLUSION： Mesenchymal stem cells can be induced to hepatogenic transdifferentiation in vitro. ADSCs have a similar hepatogenic differentiation potential to BMSC, but a longer culture period and higher proliferation capacity. Therefore, adipose tissue may be an ideal source of large amounts of autologous stem cells, and may become an alternative for hepatocyte regeneration, liver cell transplantation or preclinical drug testing.
文摘Barrett's esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esoph-ageal adenocarcinoma. Whilst it is well accepted that Barrett's esophagus is caused by gastroesophageal reflux, the molecular mechanisms of its pathogenesis and progression to cancer remain unclear. MicroRNAs (miRNAs) are short segments of RNA that have been shown to control the expression of many human genes. They have been implicated in most cellular processes, and the role of miRNAs in disease development is be-coming increasingly evident. Understanding altered miRNA expression is likely to help unravel the molecular mechanisms that underpin the development of Barrett's esophagus and its progression to cancer.
文摘Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.
