The technology of induced pluripotent stem cells(iPSCs)has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming.This approach provides possibilities for cell replacement ther...The technology of induced pluripotent stem cells(iPSCs)has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming.This approach provides possibilities for cell replacement therapies and drug screening,but the potential risk of tumorigenesis hampers its further development and in vivo application.How to generate differentiated cells such as valvular endothelial cells(VECs)has remained a major challenge.Utilizing a combinatorial strategy of selective soluble chemicals,cytokines and substrate stiffness modulation,mouse embryonic fibroblasts are directly and efficiently transdifferentiated into induced aortic endothelial cell-like cells(iAECs),or human primary adult fibroblasts are transdifferentiated into induced valvular endothelial cell-like cells(hiVECs),without expressing pluripotency stem cell markers.These iAECs and hiVECs express VEC-associated genes and proteins and VEC-specific marker NFATC1 and are functional in culture and on decellu-larized porcine aortic valves,like mouse aortic endothelial cells or human primary aortic valvular endothelial cells.The iAECs and hiVECs seeded on decellularized porcine aortic valves stay intact and express VEC-associated proteins for 60 days after grafting into abdominal aorta of immune-compromised rats.In contrast,induced pluripotent stem cells(iPSCs)are less efficient in differentiating into VEC-like cells and pluripotency marker Nanog is expressed in a small subpopulation of iPSC-derived VEC-like cells that generate teratomas in SCID mice whereas hiVECs derived from transdifferentiation do not generate teratomas in vivo.Our findings highlight an approach to efficiently convert fibroblasts into iAECs and hiVECs and seed them onto decellularized aortic valves for safely generating autologous tissue-engineered aortic valves without using viruses or first reprogramming the cells into pluripotent stem cells.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
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
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
Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all <span>postnatal organs and tissues in the perivascular region. These cells present</span> multiple characteristics that make them c...Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all <span>postnatal organs and tissues in the perivascular region. These cells present</span> multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high <span>capacity for mesodermal differentiation;however, numerous studies have</span> shown that MSCs can also differentiate into neurons. However, despite posi<span>tive results in multiple trials in which undifferentiated MSCs transplanted</span> into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are <span>several methods to induce <i>in vitro</i> reprogramming of MSCs towards the</span> neuronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRNAs, etc., and small molecules <span>stand out. Therefore, this article compares multiple experimental tests in </span>which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.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
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the can...Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells(liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.展开更多
Liver fibrosis is a wound-healing response to chronic injuries, characterized by the excessive accumulation of extracellular matrix or scar tissue within the liver;in addition, its formation is associated with multipl...Liver fibrosis is a wound-healing response to chronic injuries, characterized by the excessive accumulation of extracellular matrix or scar tissue within the liver;in addition, its formation is associated with multiple cytokines as well as several cell types and a variety of signaling pathways. When liver fibrosis is not well controlled, it can progress to liver cirrhosis, but it is reversible in principle. Thus far, no efficient therapy is available for treatment of liver fibrosis. Although liver transplantation is the preferred strategy, there are many challenges remaining in this approach, such as shortage of donor organs, immunological rejection, and surgical complications. Hence, there is a great need for an alternative therapeutic strategy. Currently, mesenchymal stem cell (MSC) therapy is considered a promising therapeutic strategy for the treatment of liver fibrosis;advantageously, the characteristics of MSCs are continuous self-renewal, proliferation, multipotent differentiation, and immunomodulatory activities. The human umbilical cord-derived (hUC)-MSCs possess not only the common attributes of MSCs but also more stable biological characteristics, relatively easy accessibility, abundant source, and no ethical issues (e.g., bone marrow being the adult source), making hUC-MSCs a good choice for treatment of liver fibrosis. In this review, we summarize the biological characteristics of hUC-MSCs and their paracrine effects, exerted by secretion of various cytokines, which ultimately promote liver repair through several signaling pathways. Additionally, we discuss the capacity of hUC-MSCs to differentiate into hepatocyte-like cells for compensating the function of existing hepatocytes, which may aid in amelioration of liver fibrosis. Finally, we discuss the current status of the research field and its future prospects.展开更多
Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and r...Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and remission.High plasticity is an important feature of pancreaticβ-cells.During T2D development,pancreaticβ-cells undergo dynamic adaptation.Althoughβ-cell death/apoptosis in later-stage T2D is the major cause ofβ-cell dysfunction,recent studies have revealed thatβ-cell dedifferentiation and reprogramming,which play critical roles inβ-cell functional regulation in the early and middle T2D progression stages,are characterized by(i)a loss of matureβ-cell-enriched genes;(ii)dedifferentiation to a progenitor-like state;and(iii)transdifferentiation into other cell types.The roles of transcription factors(TFs)in the establishment and maintenance ofβ-cell identity during pancreatic development have been extensively studied.Here,we summarize the roles and underlying mechanisms of TFs in the maintenance ofβ-cell identity under physiological and type 2 diabetic conditions.Several feasible approaches for restoring islet functions are also discussed.A better understanding of the transcriptional control ofβ-cell identity and plasticity will pave the way for developing more effective strategies,such asβ-cell regeneration therapy,to treat T2D and associated metabolic disorders.展开更多
Diabetes,one of the most common chronic diseases in the modern world,has pancreaticβcell deficiency as a major part of its pathophysiological mechanism.Pancreatic regeneration is a potential therapeutic strategy for ...Diabetes,one of the most common chronic diseases in the modern world,has pancreaticβcell deficiency as a major part of its pathophysiological mechanism.Pancreatic regeneration is a potential therapeutic strategy for the recovery ofβcell loss.However,endocrine islets have limited regenerative capacity,especially in adult humans.Almost all hypoglycemic drugs can protectβcells by inhibitingβcell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress.Several agents,including glucagon-like peptide-1 andγ-aminobutyric acid,have been shown to promoteβcell proliferation,which is considered the main source of the regeneratedβcells in adult rodents,but with less clarity in humans.Pancreatic progenitor cells might exist and be activated under particular circumstances.Artemisinins andγ-aminobutyric acid can induceα-to-βcell conversion,although some disputes exist.Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion,and pharmacological research into FoxO1 inhibition is ongoing.Other cells,including pancreatic acinar cells,can transdifferentiate intoβcells,and clinical and preclinical strategies are currently underway.In this review,we summarize the clinical and preclinical agents used in different approaches forβcell regeneration and make some suggestions regarding future perspectives for clinical application.展开更多
Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regenera...Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.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
Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence impli...Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.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
Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into sper...Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.展开更多
AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte pr...AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.展开更多
Summary: To explore the mechanism of Notch in hyperoxia-induced preterm rat lung injury, 2-days-old preterm SD rats were randomized into control and hyperoxia group (FiO 2≥0.85). On day 1, 7, 14 and 21, 8 rat pups o...Summary: To explore the mechanism of Notch in hyperoxia-induced preterm rat lung injury, 2-days-old preterm SD rats were randomized into control and hyperoxia group (FiO 2≥0.85). On day 1, 7, 14 and 21, 8 rat pups of each time point were used to assess histopathological changes of lung with HE staining and to evaluate the expression of Notch1 and Notch3 with immunohistochemistry. Notch1, Notch3, Aquaprin5 (AQP5) and surfactant protein C (SP-C) mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). The results showed that the lung injury in the hyperoxia group was characterized by retarded lung alveolization and differentiation of alveolar epithelial type Ⅱcells (AEC Ⅱ). Positive staining of Notch1 in hyperoxia group was weaker than controls at every time point (except for day 7), while positive staining of Notch3 was much stronger (P<0.05, P<0.01). Notch1, Notch3 mRNA level showed similar change as protein level. AQP5, SP-C mRNA decreased significantly as compared with that of the controls (P<0.01). We are led to conclude that hyperoxia results in abnormal expression of Notch, which is likely to contribute to the pathogenesis of lung injury through regulating proliferation and transdifferentiation of alveolar epithelial cells.展开更多
Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment,one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars...Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment,one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta.In addition,Parkinson’s disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost.In neurodegenerative disorders,some therapeutic strategies could be effective only at inhibiting further degeneration;on the other hand,cell replacement therapies aim at replacing lost neurons,an approach that would be ideal for the treatment of Parkinson’s disease.Many cell replacement therapies have been tested since the 1970s in the field of Parkinson’s disease;however,there are still significant limitations prohibiting a successful clinical application.From the first fetal midbrain intrastriatal graft to the most recent conversion of astrocytes into dopaminergic neurons,we have gained equally,significant insights and questions still looking for an answer.This review aims to summarize the main milestones in cell replacement approaches against Parkinson’s disease.By focusing on achievements and failures,as well as on the additional research steps needed,we aim to provide perspective on how future cell replacement therapies treats Parkinson’s disease.展开更多
基金supported by the Ministry of Science and Technology of China grants 2021YFA1101900(ND)National Natural Science Foundation of China grants(12422212,32071306,11902121)(JC)+1 种基金Huazhong University of Science and Technology Program for Academic Frontier Youth Team grant(2018QYTD01)(JC)the Fundamental Research Funds for the Central Universities(2024BRB004)(JC).
文摘The technology of induced pluripotent stem cells(iPSCs)has enabled the conversion of somatic cells into primitive undifferentiated cells via reprogramming.This approach provides possibilities for cell replacement therapies and drug screening,but the potential risk of tumorigenesis hampers its further development and in vivo application.How to generate differentiated cells such as valvular endothelial cells(VECs)has remained a major challenge.Utilizing a combinatorial strategy of selective soluble chemicals,cytokines and substrate stiffness modulation,mouse embryonic fibroblasts are directly and efficiently transdifferentiated into induced aortic endothelial cell-like cells(iAECs),or human primary adult fibroblasts are transdifferentiated into induced valvular endothelial cell-like cells(hiVECs),without expressing pluripotency stem cell markers.These iAECs and hiVECs express VEC-associated genes and proteins and VEC-specific marker NFATC1 and are functional in culture and on decellu-larized porcine aortic valves,like mouse aortic endothelial cells or human primary aortic valvular endothelial cells.The iAECs and hiVECs seeded on decellularized porcine aortic valves stay intact and express VEC-associated proteins for 60 days after grafting into abdominal aorta of immune-compromised rats.In contrast,induced pluripotent stem cells(iPSCs)are less efficient in differentiating into VEC-like cells and pluripotency marker Nanog is expressed in a small subpopulation of iPSC-derived VEC-like cells that generate teratomas in SCID mice whereas hiVECs derived from transdifferentiation do not generate teratomas in vivo.Our findings highlight an approach to efficiently convert fibroblasts into iAECs and hiVECs and seed them onto decellularized aortic valves for safely generating autologous tissue-engineered aortic valves without using viruses or first reprogramming the cells into pluripotent stem cells.
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.
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 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.
文摘Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all <span>postnatal organs and tissues in the perivascular region. These cells present</span> multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high <span>capacity for mesodermal differentiation;however, numerous studies have</span> shown that MSCs can also differentiate into neurons. However, despite posi<span>tive results in multiple trials in which undifferentiated MSCs transplanted</span> into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are <span>several methods to induce <i>in vitro</i> reprogramming of MSCs towards the</span> neuronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRNAs, etc., and small molecules <span>stand out. Therefore, this article compares multiple experimental tests in </span>which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.
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.
基金Supported by The Special Research Foundation of the National Natural Science Foundation of China,No.81172068
文摘Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells(liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.
基金Supported by the Natural Science Foundation of Jilin Province of China,No.20190201010JC
文摘Liver fibrosis is a wound-healing response to chronic injuries, characterized by the excessive accumulation of extracellular matrix or scar tissue within the liver;in addition, its formation is associated with multiple cytokines as well as several cell types and a variety of signaling pathways. When liver fibrosis is not well controlled, it can progress to liver cirrhosis, but it is reversible in principle. Thus far, no efficient therapy is available for treatment of liver fibrosis. Although liver transplantation is the preferred strategy, there are many challenges remaining in this approach, such as shortage of donor organs, immunological rejection, and surgical complications. Hence, there is a great need for an alternative therapeutic strategy. Currently, mesenchymal stem cell (MSC) therapy is considered a promising therapeutic strategy for the treatment of liver fibrosis;advantageously, the characteristics of MSCs are continuous self-renewal, proliferation, multipotent differentiation, and immunomodulatory activities. The human umbilical cord-derived (hUC)-MSCs possess not only the common attributes of MSCs but also more stable biological characteristics, relatively easy accessibility, abundant source, and no ethical issues (e.g., bone marrow being the adult source), making hUC-MSCs a good choice for treatment of liver fibrosis. In this review, we summarize the biological characteristics of hUC-MSCs and their paracrine effects, exerted by secretion of various cytokines, which ultimately promote liver repair through several signaling pathways. Additionally, we discuss the capacity of hUC-MSCs to differentiate into hepatocyte-like cells for compensating the function of existing hepatocytes, which may aid in amelioration of liver fibrosis. Finally, we discuss the current status of the research field and its future prospects.
基金supported by grants from the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91857110)the National Key Research and Development Programme of China (2018YFA0800403 and 2016YFC1305303)+5 种基金the National Natural Science Foundation of China (81670740)the National Natural Science Fund for Excellent Young Scholars of China (81722012)the Zhejiang Provincial Natural Science Foundation of China (LZ21H070001)the Innovative Institute of Basic Medical Sciences of Zhejiang University, and the Fundamental Research Funds for the Central Universities, the Construction Fund of Medical Key Disciplines of Hangzhou (No. OO20200055)the Hangzhou Science and Technology Bureau (20150733Q13 and ZD20200129)the support from K.C. Wong Education Foundation
文摘Type 2 diabetes(T2D)is caused by insulin resistance and insufficient insulin secretion.Evidence has increasingly indicated that pancreaticβ-cell dysfunction is the primary determinant of T2D disease progression and remission.High plasticity is an important feature of pancreaticβ-cells.During T2D development,pancreaticβ-cells undergo dynamic adaptation.Althoughβ-cell death/apoptosis in later-stage T2D is the major cause ofβ-cell dysfunction,recent studies have revealed thatβ-cell dedifferentiation and reprogramming,which play critical roles inβ-cell functional regulation in the early and middle T2D progression stages,are characterized by(i)a loss of matureβ-cell-enriched genes;(ii)dedifferentiation to a progenitor-like state;and(iii)transdifferentiation into other cell types.The roles of transcription factors(TFs)in the establishment and maintenance ofβ-cell identity during pancreatic development have been extensively studied.Here,we summarize the roles and underlying mechanisms of TFs in the maintenance ofβ-cell identity under physiological and type 2 diabetic conditions.Several feasible approaches for restoring islet functions are also discussed.A better understanding of the transcriptional control ofβ-cell identity and plasticity will pave the way for developing more effective strategies,such asβ-cell regeneration therapy,to treat T2D and associated metabolic disorders.
基金Supported by the National Key Research and Development Program of China,No.2016YFA0100501the National Natural Science Foundation of China,No.81770768 and No.81970671and the Natural Science Foundation of Beijing,No.7192225.
文摘Diabetes,one of the most common chronic diseases in the modern world,has pancreaticβcell deficiency as a major part of its pathophysiological mechanism.Pancreatic regeneration is a potential therapeutic strategy for the recovery ofβcell loss.However,endocrine islets have limited regenerative capacity,especially in adult humans.Almost all hypoglycemic drugs can protectβcells by inhibitingβcell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress.Several agents,including glucagon-like peptide-1 andγ-aminobutyric acid,have been shown to promoteβcell proliferation,which is considered the main source of the regeneratedβcells in adult rodents,but with less clarity in humans.Pancreatic progenitor cells might exist and be activated under particular circumstances.Artemisinins andγ-aminobutyric acid can induceα-to-βcell conversion,although some disputes exist.Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion,and pharmacological research into FoxO1 inhibition is ongoing.Other cells,including pancreatic acinar cells,can transdifferentiate intoβcells,and clinical and preclinical strategies are currently underway.In this review,we summarize the clinical and preclinical agents used in different approaches forβcell regeneration and make some suggestions regarding future perspectives for clinical application.
基金supported by the National Natural Science Foundation of China,No.81420108010,81271084,81200740,81371093
文摘Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.
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.
文摘Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.
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.
文摘Spermatogonial stem cells （SSCs）, also known as male germline stem cells, are a small subpopulation of type A spermatogonia with the potential of self-renewal to maintain stem cell pool and differentiation into spermatids in mammalian testis. SSCs are previously regarded as the unipotent stem cells since they can only give rise to sperm within the seminiferous tubules. However, this concept has recently been challenged because numerous studies have demonstrated that SSCs cultured with growth factors can acquire pluripotency to become embryonic stem-like cells. The in vivo and in vitro studies from peers and us have clearly revealed that SSCs can directly transdifferentiate into morphologic, phenotypic, and functional cells of other lineages. Direct conversion to the cells of other tissues has important significance for regenerative medicine. SSCs from azoospermia patients could be induced to differentiate into spermatids with fertilization and developmental potentials. As such, SSCs could have significant applications in both reproductive and regenerative medicine due to their unique and great potentials. In this review, we address the important plasticity of SSCs, with focuses on their self-renewal, differentiation, dedifferentiation, transdifferentiation, and translational medicine studies.
基金Supported by JSp S Grant-in-Aid for Scientific Research(C)No.16K09385 to Torimura T
文摘AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
基金This project was supported by the National Natural Science Foundation of China ( No. 30471824 ) and National Key Technologies Research and Development Program of Chinaduring the 10th Five Year Plan Period (No.2004BA720A).
文摘Summary: To explore the mechanism of Notch in hyperoxia-induced preterm rat lung injury, 2-days-old preterm SD rats were randomized into control and hyperoxia group (FiO 2≥0.85). On day 1, 7, 14 and 21, 8 rat pups of each time point were used to assess histopathological changes of lung with HE staining and to evaluate the expression of Notch1 and Notch3 with immunohistochemistry. Notch1, Notch3, Aquaprin5 (AQP5) and surfactant protein C (SP-C) mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). The results showed that the lung injury in the hyperoxia group was characterized by retarded lung alveolization and differentiation of alveolar epithelial type Ⅱcells (AEC Ⅱ). Positive staining of Notch1 in hyperoxia group was weaker than controls at every time point (except for day 7), while positive staining of Notch3 was much stronger (P<0.05, P<0.01). Notch1, Notch3 mRNA level showed similar change as protein level. AQP5, SP-C mRNA decreased significantly as compared with that of the controls (P<0.01). We are led to conclude that hyperoxia results in abnormal expression of Notch, which is likely to contribute to the pathogenesis of lung injury through regulating proliferation and transdifferentiation of alveolar epithelial cells.
文摘Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment,one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta.In addition,Parkinson’s disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost.In neurodegenerative disorders,some therapeutic strategies could be effective only at inhibiting further degeneration;on the other hand,cell replacement therapies aim at replacing lost neurons,an approach that would be ideal for the treatment of Parkinson’s disease.Many cell replacement therapies have been tested since the 1970s in the field of Parkinson’s disease;however,there are still significant limitations prohibiting a successful clinical application.From the first fetal midbrain intrastriatal graft to the most recent conversion of astrocytes into dopaminergic neurons,we have gained equally,significant insights and questions still looking for an answer.This review aims to summarize the main milestones in cell replacement approaches against Parkinson’s disease.By focusing on achievements and failures,as well as on the additional research steps needed,we aim to provide perspective on how future cell replacement therapies treats Parkinson’s disease.
