Search

Biliary fibrosis is an important pathological indicator of hepatobiliary damage. Cholangiocyte is the key cell type involved in this process. To reveal the pathogenesis of biliary fibrosis, it is essential to understand the normal development as well as the aberrant generation and proliferation of cholangiocytes. Numerous reports suggest that the Wnt signaling pathway is implicated in the physiological and pathological processes of cholangiocyte development and ductular reaction. In this review, we summarize the effects of Wnt pathway in cholangiocyte development from embryonic stem cells, as well as the underlying mechanisms of cholangiocyte responses to adult ductal damage. Wnt signaling pathway is regulated in a step-wise manner during each of the liver differentiation stages from embryonic stem cells to functional mature cholangiocytes. With the modulation of Wnt pathway, cholangiocytes can also be generated from adult liver progenitor cells and mature hepatocytes to repair liver damage. Non-canonical Wnt signaling is triggered in the active ductal cells during biliary fibrosis. Targeted control of the Wnt signaling may hold the great potential to reduce and/or reverse the biliary fibrogenic process.

Neonatal thyrotoxicosis is rare and most of the cases are secondary to maternal Graves’ disease. It is usually transient, but can be associated with significant morbidity and mortality if not recognized promptly and treated adequately. Neonates born to mothers treated with antithyroid drugs or those who receive maternal thyroid blocking antibodies may exhibit normal thyroid function or even hypothyroidism at birth. Since there may not be any obvious symptoms of hyperthyroidism at birth, it may be overlooked. Therefore, such neonates should be evaluated properly and monitored regularly to prevent serious complications of hyperthyroidism. We report a case of a 21-day-old male infant who developed thyrotoxicosis with dyspnea, irritability, tachycardia, and cardiac insufficiency. He was born to a mother who was treated for Graves’ disease with antithyroid drugs during pregnancy. We have also discussed the importance of careful examination and monitoring to prevent the development of clinical hyperthyroidism.

Background: Croup is a respiratory illness usually caused by acute viral infection of the larynx, trachea, and bronchi, and characterized by the abrupt onset of a barking cough, inspiratory stridor, hoarseness, and respiratory distress due to upper airway obstruction. Croup commonly affects children younger than 6 years of age, with peak incidence between 7 and 36 months. Although the disease is usually self-limited, it may occasionally become life threatening, and can, on rare occasion, lead to respiratory failure.Current Concepts: Treatment of viral croup depends on the severity of symptoms as denoted by Westley croup score (i.e., mild, moderate, or severe). A single dose of oral or intramuscular dexamethasone (0.15-0.6 mg/kg) is the mainstay of treatment for viral croup, irrespective of severity. A single dose of nebulized budesonide (2 mg) is equally effective as systemically administered dexamethasone, and is considered when a patient is unable to take a medicine orally. Nebulized L-epinephrine (1:1,000, 3-5 mL) causes vasoconstriction in the mucosa, rapidly reducing airway edema. Addition of nebulized L-epinephrine is indicated in the patients with croup of at least moderate severity, displaying chest retraction and signs of labored breathing.Discussion and Conclusion: The most effective pharmacological treatments for patients with viral croup are oral or intramuscular dexamethasone, and nebulized L-epinephrine. Especially, corticosteroids can significantly decrease the intensity of croup symptoms and reduce hospital admissions, return visits to emergency department and length of stay in the hospital.

Purpose This study analyzed the clinical and genetic characteristics of young children with fragile X syndrome (FXS) and evaluated the significance of FXS genetic (FX) testing for children with global developmental delay (GDD). Methods FX testing was performed in 324 children aged

Background: Bronchial hyperresponsiveness (BHR), an important physiological feature of asthma, is a prognostic marker of childhood asthma.Purpose: We aimed to investigate the factors associated with BHR in adolescents with childhood asthma.Methods: Two hundred and fifteen adolescents (≥13 years of age; 149 males, 66 females) who were diagnosed with asthma during childhood were enrolled, underwent methacholine challenge tests, and were divided into the BHR group (1] [PC20], n=113) or non-BHR group (≥25 mg/mL of PC20, n=102). We examined longitudinal changes in BHR and the risk factors for its persistence in the 108 adolescents for whom baseline data, including methacholine PC20 at age 6 years, were available. Multivariate logistic regression analyses were performed to assess the factors associated with BHR in adolescents.Results: Mold sensitization (adjusted odds ratio [aOR], 5.569; P=0.005) and increased blood eosinophil count (aOR, 1.002; P=0.026) were independently associated with BHR in boys but not girls. The odds of BHR decreased by 32% with each 1-year increase in age in boys (aOR, 0.683; P=0.010) but not girls. A reduced FEV1/forced vital capacity ratio (P=0.007). BHR decreased with age throughout childhood. A low methacholine PC20 at age 6 years was independently associated with persistent BHR throughout childhood in male and female patients, whereas early mold sensitization was a risk factor for persistent BHR in male patients only (aOR, 7.718; P=0.028).Conclusion: Our study revealed sex-specific differences in the factors associated with BHR in adolescents with childhood asthma. Our findings suggest the risk factors that might affect asthma transition from childhood to adolescence and adulthood.

Background Respiratory infection in children is a major disease that ranks high in outpatient and inpatient cases. In particular, the causes of community acquired pneumonia (CAP) vary depending on the individual susceptibility, epidemiological characteristics of the community, and season, and it is difficult to obtain samples for microbiological diagnosis. This study analysis that laboratory surveillance network of pathogen for pediatric CAP by linking the national community-based hospital and clinics and the Centers for Disease Control and Prevention (KCDC) to identify the distribution trend and prevalence of causative pathogens and to prevent antibiotic resistance of bacterial pathogens. Method The monitoring network was composed of the 28 secondary and tertiary medical institutions based on the national community, and the 24-month prospective study operated a community monitoring network for CAP in children. Results A total of 1023 cases were registered for nasopharyngeal aspirate or sputum in patients with CAP, and 711 cases (69.5%) were isolated by culture, S. aureus 131 cases (12.8%), S. pneumonia 92 cases (9%), H. influenzae 20 cases (2%). PCR of atypical pneumonia revealed 422 cases of M. pneumoniae (41.3%), 5 cases of C. pneumonia (0.5%), and 5 case (0.5%) of B. pertussis. Respiratory virus multiplex PCR test showed positive rates in 65.7%, human rhinovirus 312 (30.5%), RSV(A+B) 212 (20.7%), Adenovirus 123 (12%), Influenza (A+B) 53 (7.8%), CoV (OC43+NL63+229E) 69 (6.7%), HMPV 81 (7.9%), HBoV 51 (5%), PIV (1+2+3+4) 65 (6.4%) and HEV 30 (2.9%) Conclusion It will identify the pathogens that cause respiratory infections, and analyze the current status of antibiotic resistance to provide scientific evidence for management policies of domestic respiratory infection. Also, in preparation for the new epidemic, including COVID19, monitoring of respiratory infections in children and adolescents, especially community pneumonia, has become more important, and research should be continuously conducted in the future. The location and extent of involvement in the medulla were the most important factors associated with the severity of dysphagia after LMI.

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A, OMIM 264700) is a rare autosomal recessive inherited disorder. Pathogenic variants in the CYP27B1 gene lead to loss of 1α-hydroxylase activity. We report the case of a 22-month-old toddler who presented with growth retardation and delayed development. The patient exhibited the typical laboratory findings of VDDR1A, including hypocalcemia (calcium: 5.2 mg/dL), elevated serum level of alkaline phosphatase (2,600 U/L), elevated serum level of intact-parathyroid hormone (238 pg/mL), low 1,25(OH)2D3 level (11.2 pg/mL), and normal 25(OH)D3 level (40.7 ng/mL). His height and weight were 76.5 cm and 9.5 kg, respectively (both

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A, OMIM 264700) is a rare autosomal recessive inherited disorder. Pathogenic variants in the CYP27B1 gene lead to loss of 1α-hydroxylase activity. We report the case of a 22-month-old toddler who presented with growth retardation and delayed development. The patient exhibited the typical laboratory findings of VDDR1A, including hypocalcemia (calcium: 5.2 mg/dL), elevated serum level of alkaline phosphatase (2,600 U/L), elevated serum level of intact-parathyroid hormone (238 pg/mL), low 1,25(OH)2D3 level (11.2 pg/mL), and normal 25(OH)D3 level (40.7 ng/mL). His height and weight were 76.5 cm and 9.5 kg, respectively (both

Directed differentiation of human induced pluripotent stem cells (iPSCs) toward hepatobiliary lineages has been increasingly used as models of human liver development/diseases. As protein kinases are important components of signaling pathways regulating cell fate changes, we sought to define the key molecular mediators regulating human liver development using inhibitors targeting tyrosine kinases during hepatic differentiation of human iPSCs. A library of tyrosine kinase inhibitors was used for initial screening during the multistage differentiation of human iPSCs to hepatic lineage. Among the 80 kinase inhibitors tested, only Src inhibitors suppressed endoderm formation while none had significant effect on later stages of hepatic differentiation. Transient inhibition of c-Src during endodermal induction of human iPSCs reduced endodermal commitment and expression of endodermal markers, including SOX17 and FOXA2, in a dose-dependent manner. Interestingly, the transiently treated cells later developed into profibrogenic cholangiocyte-like cells expressing both cholangiocyte markers, such as CK7 and CK19, and fibrosis markers, including Collagen1 and smooth muscle actin. Further analysis of these cells revealed colocalized expression of collagen and yes-associated protein (YAP; a marker associated with bile duct proliferation/fibrosis) and an increased production of interleukin-6 and tumor necrosis factor-α. Moreover, treatment with verteporfin, a YAP inhibitor, significantly reduced expression of fibrosis markers. In summary, these results suggest that c-Src has a critical role in cell fate determination during endodermal commitment of human iPSCs, and its alteration in early liver development in human may lead to increased production of abnormal YAP expressing profibrogenic proinflammatory cholangiocytes, similar to those seen in livers of patients with biliary fibrosis. Stem Cells 2019;37:306–317

The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.

Regenerative medicine promises a bright future where damaged body parts can be restored, rejuvenated, and replaced. The application of regenerative medicine is interdisciplinary and covers nearly all fields of medical sciences and molecular engineering. This review provides a roadmap on how regenerative medicine is applied on the levels of cell, tissue, and organ, and summarizes the advantages and limitation of human pluripotent stem cells in disease modeling and regenerative application.

Mycoplasma pneumoniae is a major causative pathogen of community-acquired pneumonia in children, and the treatment of choice is macrolides. There is an increasing trend in reports of refractory clinical responses despite macrolide treatment due to the emergence of macrolide-resistant M. pneumoniae. Early discrimination of macrolide-refractory M. pneumoniae pneumonia (MrMP) from macrolide-sensitive M. pneumoniae pneumonia (MSMP) is vital; however, testing for macrolide susceptibility at the time of admission is not feasible. This study aimed to identify the characteristics of MrMP in Korean children, in comparison with those of MSMP. In this multicenter study, board-certified pediatric pulmonologists at 22 tertiary hospitals reviewed the medical records from 2010 to 2015 of 5294 children who were hospitalized with M. pneumoniae pneumonia and administered macrolides as the initial treatment. One-way analysis of variance and the Kruskal-Wallis test were used to compare differences between groups. Of 5294 patients (mean age, 5.6 years) included in this analysis, 240 (4.5%), 925 (17.5%), and 4129 (78.0%) had MrMP, macrolide-less effective M. pneumoniae pneumonia, and MSMP, respectively. Compared with the MSMP group, the MrMP group had a longer fever duration, overall (13.0 days) and after macrolide use (8.0 days). A higher proportion of MrMP patients had respiratory distress, pleural effusion, and lobar pneumonia. The mean aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and C-reactive protein levels were the highest in the MrMP group, along with higher incidences of extrapulmonary manifestations and atelectasis (during and post infection). Pre-existing conditions were present in 17.4% (n = 725/4159) of patients, with asthma being the most common (n = 334/4811, 6.9%). This study verified that MrMP patients show more severe initial radiographic findings and clinical courses than MSMP patients. MrMP should be promptly managed by agents other than macrolides.

In vitro studies of drug toxicity and drug-drug interactions are crucial for drug development efforts. Currently, the utilization of primary human hepatocytes (PHHs) is the de facto standard for this purpose, due to their functional xenobiotic response and drug metabolizing CYP450 enzyme metabolism. However, PHHs are scarce, expensive, require laborious maintenance, and exhibit lot-to-lot heterogeneity. Alternative human in vitro platforms include hepatic cell lines, which are easy to access and maintain, and induced pluripotent stem cell (iPSC) derived hepatocytes. In this study, we provide a direct comparison of drug induced CYP3A4 and PXR expression levels of PHHs, hepatic cell lines Huh7 and HepG2, and iPSC derived hepatocyte like cells. Confluently cultured Huh7s exhibited an improved CYP3A4 expression and were inducible by up to 4.9-fold, and hepatocytes differentiated from human iPSCs displayed a 3.3-fold CYP3A4 induction. In addition, an increase in PXR expression levels was observed in both hepatic cell lines and iPSC derived hepatocytes upon rifampicin treatment, whereas a reproducible increase in PXR expression was not achieved in PHHs. Our results indicate that both hepatoma originated cell lines and iPSCs may provide alternative sources to primary hepatocytes, providing reliable and reproducible results for CYP3A4/PXR metabolism, upon in vitro maturation. This study may serve as a guide for the selection of suitable and feasible in vitro platforms for drug-drug interaction and toxicology studies.

Background: Community–acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality and its disease burden is affected by age and etiologies with time-dependent changes. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. Methods: We conducted a retrospective study in 30,994 children (0-18 years old) with CAP between 2010 and 2015 at 23 nationwide hospitals in Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified into macrolide-sensitive MP, macrolide-less effective MP (MLEP) and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. Results: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.36% of the total MP pneumonia. In children less than 2 years of age, RSV (34.01%) was the most common cause of CAP, followed by MP (9.44%), whereas MP was the most common cause of CAP in children 2-18 years of age. Systemic corticosteroid was most commonly administered in MP pneumonia. The rate of hospitalization in intensive care unit was highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. Conclusions: The present study provides fundamental data for establishment of public health policies to decrease disease burden due to CAP as well as for improvement of pediatric health.

Biliary atresia (BA) is a common cause of pediatric end-stage liver disease. While its etiology is not yet clear, evidence has suggested that BA results from interactions between genetic susceptibility and environmental factors. Disease relevant human cellular models of BA will facilitate identification of both genetic and environmental factors that are important for disease prevention and treatment. Here we report the generation of a human induced pluripotent stem cell line from a BA patient using episomal vectors. Patient-specific BA iPSC lines provide valuable tools for disease mechanism study and drug development.

Children with post-infectious bronchiolitis obliterans (PIBO) are frequently hospitalized with acute exacerbation, but clinical differentiation of PIBO exacerbation from acute bronchiolitis is often challenging, which may result in treatment delay and chronic lung function impairment. We aimed to examine whether serum YKL-40 and growth factors could be markers for PIBO exacerbation. Thirty-seven children admitted with acute exacerbation of PIBO were enrolled and studied retrospectively. Diagnosis of PIBO was based on clinical history of acute respiratory infection followed by persistent airway obstruction and characteristic findings in high-resolution computed tomography. Serum levels of YKL-40, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-BB were measured on admission. The biomarkers were also examined in children admitted with acute bronchiolitis serving as positive controls (N = 30) and in age-matched controls (N = 20). Only YKL-40 levels were found to be significantly higher in PIBO patients with exacerbation compared with that in bronchiolitis patients and showed a positive correlation with the severity of disease before diagnosis of PIBO. Conclusion: Our results suggest that measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children. What is Known: • The children with post-infectious BO (PIBO) usually have recurrent wheezing and need frequent hospitalization due to acute exacerbation during the first disease years. • Clinical differentiation of PIBO exacerbation from acute bronchiolitis in young children is often challenging, which may result in treatment delay and chronic lung function impairment. What is New: • Measuring serum YKL-40 levels might help distinguish exacerbation of PIBO from acute bronchiolitis in young children.

DNA base editors have enabled genome editing without generating DNA double strand breaks. The applications of this technology have been reported in a variety of animal and plant systems, however, their editing specificity in human stem cells has not been studied by unbiased genome-wide analysis. Here we investigate the fidelity of cytidine deaminase-mediated base editing in human induced pluripotent stem cells (iPSCs) by whole genome sequencing after sustained or transient base editor expression. While base-edited iPSC clones without significant off-target modifications are identified, this study also reveals the potential of APOBEC-based base editors in inducing unintended point mutations outside of likely in silico-predicted CRISPR-Cas9 off-targets. The majority of the off-target mutations are C:G->T:A transitions or C:G->G:C transversions enriched for the APOBEC mutagenesis signature. These results demonstrate that cytosine base editor-mediated editing may result in unintended genetic modifications with distinct patterns from that of the conventional CRISPR-Cas nucleases., Cytidine base editors are powerful tools for making subtle genome alterations. Here the authors analyse edited human iPSCs with whole genome sequencing and reveal the spectrum of off-target effects.

Pharmaceutical drug development and clinical testing is associated with billions of dollars, and often the time and money spent does not result in a viable drug formulation. The pharmaceutical industry has long relied on animal models for testing efficacy, toxicity and specificity of novel drugs. However, the studies cannot be fully relied upon, as animal models are not reflective of human pathophysiology and drug response, which results in drugs being pulled from development as late as at stage IV, after billions of dollars have already been invested in such an effort. With the advent of adult-induced pluripotent stem cell technology, came an era which offered the potential of pursing human relevant developmental and pathogenesis research and drug testing on patient-induced pluripotent stem cell-derived differentiated cells, consciously reflecting human responses with regard to drug safety, toxicity, efficacy, and side effects. Specifically, human-induced pluripotent stem cell-derived hepatobiliary cells and tissues may be a more human-relevant model system to address the biggest barrier to drug safety and approval: hepatotoxicity. In this review, we address the potential of human-induced pluripotent stem cell-based hepatobiliary differentiation technology as a means to study human liver development and hepatic cell fate determination, and to model liver diseases in an effort to develop a new human-relevant preclinical platform for drug development. Impact statement In this review, we address the potential of human-induced pluripotent stem cell-based hepatobiliary differentiation technology as a means to study human liver development and cell fate determination, and to model liver diseases in an effort to develop a new human-relevant preclinical platform for drug development.

Background Bronchiectasis is a chronic pulmonary disease characterized by progressive and irreversible bronchial dilatation. The aim of the present study was to investigate the etiologies and clinical features of bronchiectasis in Korean children. Methods We performed a retrospective review of the medical records for children diagnosed with bronchiectasis between 2000 and 2017 at 28 secondary or tertiary hospitals in South Korea. Results A total of 387 cases were enrolled. The mean age at diagnosis was 9.2 ± 5.1 years and 53.5% of the patients were boys. The most common underlying cause of bronchiectasis was preexisting respiratory infection (55.3%), post-infectious bronchiolitis obliterans (14.3%), pulmonary tuberculosis (12.3%), and heart diseases (5.6%). Common initial presenting symptoms included chronic cough (68.0%), recurrent pneumonia (36.4%), fever (31.1%), and dyspnea (19.7%). The most predominantly involved lesions were left lower lobe (53.9%), right lower lobe (47.1%) and right middle lobe (40.2%). No significant difference was observed in the distribution of these involved lesions by etiology. The forced expiratory volume in 1 s (FEV1) levels were lowest in cases with interstitial lung disease-associated bronchiectasis, followed by those with recurrent aspiration and primary immunodeficiency. Conclusions Bronchiectasis should be strongly considered in children with chronic cough and recurrent pneumonia. Long-term follow-up studies on pediatric bronchiectasis are needed to further clarify the prognosis and reduce the disease burden in these patients.

Background Residential greenness has been reported to be positively associated with health benefits for children, including improved cognitive function. We investigated the association between the intelligence quotient (IQ) of 6-year-old children in Seoul, South Korea and surrounding greenness currently and during the mothers' pregnancy. We also analyzed whether these effects differed by the type of greenness, such as natural or built greenness. Methods This study considered 189 mother-child dyads from the Environment and Development of Children Cohort study, who lived in Seoul during the prenatal period and when the child was 6 years old. We defined surrounding greenness using Landsat image data from Korean Arirang satellite images with buffers within 100 m – 2000 m of the radius of each participant's residential address. We separately analyzed two types of greenness, namely natural and built greenness. The children's IQ (total, verbal, and performance IQ) was measured using the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children. Results Prenatal exposure to built greenness in 500 m and 1000 m buffers was associated with children's total IQ in a full model [difference in IQ (95% CI): 3.46(0.68, 6.24) and 3.42 (0.53, 6.31) per interquartile increase in proportion of greenness]. However, postnatal exposure to built greenness in all buffers was associated in children's total IQ. We found a stronger association between children's total IQ and built greenness rather than natural greenness. Conclusions We found that 6-year-old children tended to score higher on total IQ if they lived in greener neighborhoods. The results provide further evidence of the health benefits of greenness and provide support for urban planning and public health to build healthy urban cities for children and pregnant women.

Purpose: Survivors of preterm birth are at high risk of chronic pulmonary disease. We examined lung function in the school-age children born preterm and investigated the relationship between lung function and clinical parameters. Methods: Thirty children born preterm were enrolled and divided into 2 groups: 14 very preterm (

Purpose: Cluster analysis on pediatric asthma identifying a cluster characterized by obesity, females, and puberty showed that obe-sity is an independent risk factor for severe asthma in this cluster. In the present study, we aimed to investigate the effect of over-weight/obesity on lung function and asthma severity in prepubertal asthmatic children. Methods: One hundred fifty-five prepubertal children (aged 6-10) with asthma were enrolled and divided into 2 groups: the over-weight/obese group (body mass index [BMI] ≥85th percentile, n=44) and the normal BMI group (

Due to the limitations of research using human embryos and the lack of a biological model of human liver development, the roles of the various markers associated with liver stem or progenitor cell potential in humans are largely speculative, and based on studies utilizing animal models and certain patient tissues. Human pluripotent stem cell-based in vitro multistage hepatic differentiation systems may serve as good surrogate models for mimicking normal human liver development, pathogenesis and injury/regeneration studies. Here, we describe the implications of various liver stem or progenitor cell markers and their bipotency (i.e. hepatocytic- and biliary-epithelial cell differentiation), based on the pluripotent stem cell-derived model of human liver development. Future studies using the human cellular model(s) of liver and biliary development will provide more human relevant biological and/or pathological roles of distinct markers expressed in heterogeneous liver stem/progenitor cell populations.

Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults.

Significance: Stem cells are characterized by the properties of self-renewal and the ability to differentiate into multiple cell types, and thus maintain tissue homeostasis. Reactive oxygen species (ROS) are a natural byproduct of aerobic metabolism and have roles in cell signaling. Regulation of ROS has a vital role in maintaining “stemness” and differentiation of the stem cells, as well as in progression of stem-cell-associated diseases. Recent Advances: As of late, much research has been done on the adverse effects of ROS in stem cells. However, recently it has become apparent that in some cases redox status of the stem cell does have a role in maintaining its identity as such. Both pluripotent and multipotent stem cell types have been reported to possess enzymatic and nonenzymatic mechanisms for detoxification of ROS and to correct oxidative damage to the genome as well as the proteome. Critical Issues: Although context dependent and somewhat varied among different stem cell types, the correlation seems to exist between antioxidant defense level and stem cell fate change (i.e., proliferation, differentiation, and death). Changes in stem cell redox regulation may affect the pathogenesis of various human diseases. Future Directions: Dissecting the defined roles of ROS in distinct stem cell types will greatly enhance their basic and translational applications. Here, we discuss the various roles of ROS in adult, embryonic, and induced pluripotent stem cells. Antioxid. Redox Signal. 20, 1881–1890.