Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 den...Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 dengue hemorrhagic fever(DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system.Results: We observed a protective association of IL-10(-819 C/T) C allele(P = 0.028,OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T(P = 0.047, OR = 2.10,CI = 1.01–4.38) and T/T(P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA-308 GA + AA(P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG(+874 A/T) A/T genotype against DF(P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF(P = 0.034,OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA(P = 0.022, OR = 2.95,CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT(P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF.Conclusions: This research identifies the association of the IFNG(+874 A/T), TNFA(-308 G/A), IL-10(-819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.展开更多
Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated wit...Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells （iPSCs） from fibroblasts of familial ALS patients bearing SOD1＋1A27~c and FUS＋/GISe6A mutations, respectively. We further gener- ated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing （RNA-seq） analysis of motor neurons derived from SOD1＋~A272c and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.展开更多
Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the co...Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the course of normal aging.Unfortunately,the body does not fully repair itself from this type of degeneration,resulting in impaired movement.Microfracture,an articular cartilage repair surgical technique,has been commonly used in the clinic to induce the repair of tissue at damage sites.Mesenchymal stem cells(MSC)have also been used as cell therapy to repair degenerated cartilage.However,the therapeutic outcomes of all these techniques vary in different patients depending on their age,health,lesion size and the extent of damage to the cartilage.The repairing tissues either form fibrocartilage or go into a hypertrophic stage,both of which do not reproduce the equivalent functionality of endogenous hyaline cartilage.One of the reasons for this is inefficient chondrogenesis by endogenous and exogenous MSC.Drugs that promote chondrogenesis could be used to induce self-repair of damaged cartilage as a non-invasive approach alone,or combined with other techniques to greatly assist the therapeutic outcomes.The recent development of human induced pluripotent stem cell(iPSCs),which are able to self-renew and differentiate into multiple cell types,provides a potentially valuable cell resource for drug screening in a“more relevant”cell type.Here we report a screening platform using human iPSCs in a multi-well plate format to identify compounds that could promote chondrogenesis.展开更多
In this issue,Wang et al.report on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base editor.Base editing is an emerging novel genome editing technique for modifying a...In this issue,Wang et al.report on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base editor.Base editing is an emerging novel genome editing technique for modifying a single base pair at specific sites in the genome.Base editors(BEs)have two prin cipal comp orients,a catalytically in active or single strand cleaving Cas-variant,which binds to the guide RNA and a nucleobase deaminase domain to convert specific base pairs at the target loci(Komor et al.,2016;Nishida et al.,2016;Gaudelli et al.,2017).Cytosine base editor(CBE)and adenine base editor(ABE)are two baseeditors,which con vert Cytosi ne-Gua nine(C-G)to Thymine-Adenine(T-A)and A-T to G-C,respectively.展开更多
Dear Editor Human pluripotent stem cells including human embryonic stem cells （ESCs） and induced pluripotent stem cells （iPSCs） are cells displaying abilities of unlimited self-renewal and differentiation into any...Dear Editor Human pluripotent stem cells including human embryonic stem cells （ESCs） and induced pluripotent stem cells （iPSCs） are cells displaying abilities of unlimited self-renewal and differentiation into any somatic cell type. These unique properties make them increasingly attractive for novel applications in disease modeling, drug discovery, and cell therapy （Buganim et al., 2014; Liu et al., 2011; Liu et al., 2012; Sanchez Alvarado and Yamanaka, 2014）. Moreover, iPSCs hold great potential for personalized cell therapy as they avoid some of the ethical concerns as well as the immunological rejection issues ascribed to ESCs.展开更多
Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signa...Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.展开更多
Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent induc- ers of int...Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent induc- ers of interleukin （IL）-I~ and IL-18 during infammation, are large protein complexes typically consisting of a Nod-like receptor （NLR）, the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific con- text. Here we summarize the role of different inflamma- some complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro- inflammatory cytokines play in immunity.展开更多
Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells different...Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.展开更多
Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator ...Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator of gene expression, as well as being utilized for illuminating specific chromosomal structures or genomic regions.展开更多
Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underly...Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.展开更多
The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is ...The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene.WD affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages.Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B.Combining with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and neurons.Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells.Hence we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future.展开更多
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation.However,the underlying cellular and molecular...Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation.However,the underlying cellular and molecular mechanisms remain unidentified.Here,we generated non-integrative induced pluripotent stem cells(iPSCs)from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation(c.3226C>T,p.R1076C).Vascular smooth muscle cells(VSMCs)differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes,including activation of the NOTCH and NF-kB signaling pathway,cytoskeleton disorganization,and excessive cell proliferation.In comparison,these abnormalities were not observed in vascular endothelial cells(VECs)derived from the patients iPSCs.Importantly,the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor,providing a potential therapeutic strategy for CADASIL.Overall,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.展开更多
The generation of functional retinal pigment epithelium （RPE） is of great therapeutic interest to the field of regenerative medicine and may provide possible cures for retinal degenerative diseases, including age-re...The generation of functional retinal pigment epithelium （RPE） is of great therapeutic interest to the field of regenerative medicine and may provide possible cures for retinal degenerative diseases, including age-related macular degeneration （AMD）. Although RPE cells can be produced from either embryonic stem cells or induced pluripotent stem cells, direct cell reprogramming driven by lineage-determining transcription factors provides an immediate route to their generation. By monitoring a human RPE specific Bestl：：GFP reporter, we report the conversion of human fibroblasts into RPE lineage using defined sets of transcription factors. We found that Bestl：：GFP positive cells formed colonies and exhibited morphological and molecular features of early stage RPE cells. Moreover, they were able to obtain pigmen- tation upon activation of Retinoic acid （RA） and Sonic Hedgehog （SHH） signaling pathways. Our study not only established an ideal platform to investigate the tran- scriptional network regulating the RPE cell fate deter- mination, but also provided an alternative strategy to generate functional RPE cells that complement the useof pluripotent stem cells for disease modeling, drug screening, and cell therapy of retinal degeneration.展开更多
progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated...progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.展开更多
Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking....Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.展开更多
Dear Editor,Myocardial infarction(MI)is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply(ischemia),leading to contractile dysfunction and cardiac remodeli...Dear Editor,Myocardial infarction(MI)is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply(ischemia),leading to contractile dysfunction and cardiac remodeling.In recent decades,stem cell transplantation has been extensively investigated for the repair of injured heart in animal studies and clinical trials(Kanelidis et al.,2017;Gyongyosi et al.,2018).展开更多
The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases.Yet a systematic profiling of the aging ef...The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases.Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing.Here,we reported a variety of new aging-associated phenotypic changes of the primate hippocampus.These include,in particular,increased DNA damage and heterochromatin erosion with time,alongside loss of proteostasis and elevated inflammation.To understand their cellular and molecular causes,we established the first single-nucleus transcriptomic atlas of primate hippocampal aging.Among the 12 identified cell types,neural transiently amplifying progenitor cell(TAPC)and microglia were most affected by aging.In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory;additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte,as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis.This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.展开更多
Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered...Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.展开更多
Progressive functional deterioration in the cochlea is associated with age-related hearing loss(ARHL).However,the cellular and molecular basis underlying cochlear aging remains largely unknown.Here,we established a dy...Progressive functional deterioration in the cochlea is associated with age-related hearing loss(ARHL).However,the cellular and molecular basis underlying cochlear aging remains largely unknown.Here,we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging,in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points.Overall,our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging,highlights unexpected age-related transcriptional fluctuations in intermediate ceils localized in the stria vascularis(SV)and demonstrates that upregulation of endoplasmic reticulum(ER)chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging.Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related sVatrophyand hencedelay theprogressionofARHL.展开更多
Dear Editor,Homeostasis and repair are critical biological processes that allow for tissue and organ preservation and function in multicellular organisms.Their regulation and extension vary drastically across the anim...Dear Editor,Homeostasis and repair are critical biological processes that allow for tissue and organ preservation and function in multicellular organisms.Their regulation and extension vary drastically across the animal kingdom,and mammals show limited tissue-specific regenerative capacity that declines with age.During aging,articular cartilage is one of the tissues that undergo substantial changes in the matrix structure,molecular composition,metabolic activity,and mechanical properties(Loeser et al.2016).展开更多
基金supported by the Fundacao de Amparo a Pesquisa de Alagoas(FAPEAL)–Programa Primeiros Projetos(PPP/2011)
文摘Objective: To evaluate gene polymorphisms and their association with susceptibility to dengue.Methods: A retrospective case-control study was performed with 262 subjects,comprising 78 dengue fever(DF) patients, 49 dengue hemorrhagic fever(DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system.Results: We observed a protective association of IL-10(-819 C/T) C allele(P = 0.028,OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T(P = 0.047, OR = 2.10,CI = 1.01–4.38) and T/T(P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA-308 GA + AA(P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG(+874 A/T) A/T genotype against DF(P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF(P = 0.034,OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA(P = 0.022, OR = 2.95,CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT(P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF.Conclusions: This research identifies the association of the IFNG(+874 A/T), TNFA(-308 G/A), IL-10(-819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.
文摘Amyotrophic lateral sclerosis （ALS） is a complex neu- rodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells （iPSCs） from fibroblasts of familial ALS patients bearing SOD1＋1A27~c and FUS＋/GISe6A mutations, respectively. We further gener- ated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing （RNA-seq） analysis of motor neurons derived from SOD1＋~A272c and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.
文摘Articular cartilage,which is mainly composed of collagen Ⅱ,enables smooth skeletal movement.Degeneration of collagen Ⅱ can be caused by various events,such as injury,but degeneration especially increases over the course of normal aging.Unfortunately,the body does not fully repair itself from this type of degeneration,resulting in impaired movement.Microfracture,an articular cartilage repair surgical technique,has been commonly used in the clinic to induce the repair of tissue at damage sites.Mesenchymal stem cells(MSC)have also been used as cell therapy to repair degenerated cartilage.However,the therapeutic outcomes of all these techniques vary in different patients depending on their age,health,lesion size and the extent of damage to the cartilage.The repairing tissues either form fibrocartilage or go into a hypertrophic stage,both of which do not reproduce the equivalent functionality of endogenous hyaline cartilage.One of the reasons for this is inefficient chondrogenesis by endogenous and exogenous MSC.Drugs that promote chondrogenesis could be used to induce self-repair of damaged cartilage as a non-invasive approach alone,or combined with other techniques to greatly assist the therapeutic outcomes.The recent development of human induced pluripotent stem cell(iPSCs),which are able to self-renew and differentiate into multiple cell types,provides a potentially valuable cell resource for drug screening in a“more relevant”cell type.Here we report a screening platform using human iPSCs in a multi-well plate format to identify compounds that could promote chondrogenesis.
基金We thank M.Schwarz for administrative support.This work was supported by the Moxie Foundation,Department of Defense(grant number W81XWH-17-1-0552)The Progeria Research Foundation and UCAM.
文摘In this issue,Wang et al.report on the generation of a nonhuman primate model of Hutchinson-Gilford progeria syndrome(HGPS)using a base editor.Base editing is an emerging novel genome editing technique for modifying a single base pair at specific sites in the genome.Base editors(BEs)have two prin cipal comp orients,a catalytically in active or single strand cleaving Cas-variant,which binds to the guide RNA and a nucleobase deaminase domain to convert specific base pairs at the target loci(Komor et al.,2016;Nishida et al.,2016;Gaudelli et al.,2017).Cytosine base editor(CBE)and adenine base editor(ABE)are two baseeditors,which con vert Cytosi ne-Gua nine(C-G)to Thymine-Adenine(T-A)and A-T to G-C,respectively.
文摘Dear Editor Human pluripotent stem cells including human embryonic stem cells （ESCs） and induced pluripotent stem cells （iPSCs） are cells displaying abilities of unlimited self-renewal and differentiation into any somatic cell type. These unique properties make them increasingly attractive for novel applications in disease modeling, drug discovery, and cell therapy （Buganim et al., 2014; Liu et al., 2011; Liu et al., 2012; Sanchez Alvarado and Yamanaka, 2014）. Moreover, iPSCs hold great potential for personalized cell therapy as they avoid some of the ethical concerns as well as the immunological rejection issues ascribed to ESCs.
基金supported by CIRM fellowshipssupported by grants from the G.Harold and Leila Y.Mathers Charitable Foundation,The California Institute of Regenerative Medicine,Ellison Medical Foundation,and The Leona M.and Harry B.Helmsley Charitable Trust grant#2012-PG-MED002supported by the KAUST Office of Sponsored Research(OSR)under Award No.BAS/1/1080-01(ML),URF/1/4716-01(ML)and KAUST Center of Excellence for Smart Health(KCSH)award number 5932.
文摘Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.
文摘Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent induc- ers of interleukin （IL）-I~ and IL-18 during infammation, are large protein complexes typically consisting of a Nod-like receptor （NLR）, the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific con- text. Here we summarize the role of different inflamma- some complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro- inflammatory cytokines play in immunity.
基金supported by Sanofi-Aventis,The Helmsley Charitable Trust and The Ellison Medical Foundation.GHL was supported by 100 Talents Program of the Chinese Academy of Sciences.
文摘Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.
文摘Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator of gene expression, as well as being utilized for illuminating specific chromosomal structures or genomic regions.
基金This work was supported by National Basic Research Program （973 Program） （Nos. 2015CB964800 and 2014CB910503）, the Strategic Priority Research Program of the Chinese Academy of Sciences （XDA01020312）, National High Technology Research and Development Program of China （2015AA020307）, National Natural Science Foundation of China （Grant Nos. 81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, and 81401159）, Beijing Natural Science Foundation （7141005 5142016）, Program of Beijing Municipal Science and Technology Commission （Z151100003915072）, Key Research Program of the Chinese Academy of Sciences （KJZDEW-TZ-L05）, the Thousand Young Talents program of China, National Laboratory of Biomacromolecules （012kf02, 2013kf05, 2013kf11, 2014kf02, 2015kfl 0）. J.C.I.B. was supported by UCAM, the G. Harold and Leila Y. Mathers Charitable Foundation, the Leona M. and Harry B. Helmsley Charitable Trust （2012-PG-MED002） and the Moxie Foundation.
文摘Xeroderma pigmentosum （XP） is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patientspecific induced pluripotent stem cells （iPSCs） harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells （NSCs） or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clari the molecular mechanisms of neurological abnormalities in the XP patients.
基金supported by Sanofi-Aventis,The Helmsley Charitable Trust and The Ellison Medical Foundationsupported by"Thousand Young Talents"program of China+3 种基金National Laboratory of Biomacromolecules,Strategic Priority Research Program of the Chinese Academy of Sciencesa CIRM training grant fellowship(No.TG2-01158)a Glenn foundation grantpartially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship.
文摘The combination of disease-specific human induced pluripotent stem cells(iPSC)and directed cell differentiation offers an ideal platform for modeling and studying many inherited human diseases.Wilson’s disease(WD)is a monogenic disorder of toxic copper accumulation caused by pathologic mutations of the ATP7B gene.WD affects multiple organs with primary manifestations in the liver and central nervous system(CNS).In order to better investigate the cellular pathogenesis of WD and to develop novel therapies against various WD syndromes,we sought to establish a comprehensive platform to differentiate WD patient iPSC into both hepatic and neural lineages.Here we report the generation of patient iPSC bearing a Caucasian population hotspot mutation of ATP7B.Combining with directed cell differentiation strategies,we successfully differentiated WD iPSC into hepatocyte-like cells,neural stem cells and neurons.Gene expression analysis and cDNA sequencing confirmed the expression of the mutant ATP7B gene in all differentiated cells.Hence we established a platform for studying both hepatic and neural abnormalities of WD,which may provide a new tool for tissue-specific disease modeling and drug screening in the future.
文摘Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation.However,the underlying cellular and molecular mechanisms remain unidentified.Here,we generated non-integrative induced pluripotent stem cells(iPSCs)from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation(c.3226C>T,p.R1076C).Vascular smooth muscle cells(VSMCs)differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes,including activation of the NOTCH and NF-kB signaling pathway,cytoskeleton disorganization,and excessive cell proliferation.In comparison,these abnormalities were not observed in vascular endothelial cells(VECs)derived from the patients iPSCs.Importantly,the abnormal upregulation of NF-kB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor,providing a potential therapeutic strategy for CADASIL.Overall,using this iPSCbased disease model,our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
文摘The generation of functional retinal pigment epithelium （RPE） is of great therapeutic interest to the field of regenerative medicine and may provide possible cures for retinal degenerative diseases, including age-related macular degeneration （AMD）. Although RPE cells can be produced from either embryonic stem cells or induced pluripotent stem cells, direct cell reprogramming driven by lineage-determining transcription factors provides an immediate route to their generation. By monitoring a human RPE specific Bestl：：GFP reporter, we report the conversion of human fibroblasts into RPE lineage using defined sets of transcription factors. We found that Bestl：：GFP positive cells formed colonies and exhibited morphological and molecular features of early stage RPE cells. Moreover, they were able to obtain pigmen- tation upon activation of Retinoic acid （RA） and Sonic Hedgehog （SHH） signaling pathways. Our study not only established an ideal platform to investigate the tran- scriptional network regulating the RPE cell fate deter- mination, but also provided an alternative strategy to generate functional RPE cells that complement the useof pluripotent stem cells for disease modeling, drug screening, and cell therapy of retinal degeneration.
文摘progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
基金This work was supported by the National Key Research and Development Program of China(2017YFA0105804)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+8 种基金the National Key Research and Development Program of China(2018YFC2000100,2017YFA0103304,2017YFA0102802,2018YFA0107203)the National Natural Science Foundation of China(81670897,81625009,91749202.81861168034,81921006,31671429,91949209,91749123,81671377,81822018,81870228,81922027,81701388,81601233)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Bejing Natural Science Foun-dation(Z190019)Bejing Municipal Commission of Health and Family Planning(PXM2018026283_000002)Advanced Innovation Center for Human Brain Protection(3500-1192012)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08),Youth Innovation Promotion Association of CAS(2016093)the State Key Laboratory of Membrane Biology and the State Key Laboratory of Stem Cell and Reproductive Biology.
文摘Age-associated changes in immune cells have been linked to an increased risk for infection.However,a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking.Here,we combined scRNA-seq,mass cytometry and sCATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19.We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector,cytotoxic,exhausted and reg-ulatory cells,along with increased late natural killer cells,age-associated B cells,inflammatory monocytes and age-associated dendritic cells.In addition,the expression of genes,which were implicated in coron-avirus susceptibility,was upregulated in a cell subtype-specific manner with age.Notably,COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senes-cence.Therefore,these findings suggest that a dysreg-ulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
文摘Dear Editor,Myocardial infarction(MI)is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply(ischemia),leading to contractile dysfunction and cardiac remodeling.In recent decades,stem cell transplantation has been extensively investigated for the repair of injured heart in animal studies and clinical trials(Kanelidis et al.,2017;Gyongyosi et al.,2018).
基金This work was supported by the National Key Research and Development Program of China(2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+8 种基金the National Key Research and Development Program of China(2019YFA0110100,2020YFA0112201,2018 YFC2000100,2017YFA0103304,2017YFA0102802,2018Y FA0107203,2020YFA0803401,and 2019YFA0802202)the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,81861168034,91949209,92049304,81822018,82071588,92049116,31900523,32000500,31970597,82030037,and 81801534)the Program of the Beijing Municipal Science and Technology Commissi on(Z191100001519005)Beijing Natural Science Foundation(Z190019)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)the International Partnership Program of Chinese Academy of Sciences(152111KYSB20160004)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS-011)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,the Milky Way Research Foundation(MWRF),and the Moxie Foundation(for J.C.I.B.).
文摘The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases.Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing.Here,we reported a variety of new aging-associated phenotypic changes of the primate hippocampus.These include,in particular,increased DNA damage and heterochromatin erosion with time,alongside loss of proteostasis and elevated inflammation.To understand their cellular and molecular causes,we established the first single-nucleus transcriptomic atlas of primate hippocampal aging.Among the 12 identified cell types,neural transiently amplifying progenitor cell(TAPC)and microglia were most affected by aging.In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory;additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte,as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis.This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.
基金This work was supported by the National Key Research and Development Program of China(2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+9 种基金the National Key Research and Development Program of China(2018YFC2000100,2020YFA0112201,2017YFA0103304,2017YFA0102802,2018YFA0107203,2020YFA0803401,and 2019YFA0802202)the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,81861168034,91949209,92049304,81822018,82071588,92049116,81801370,31801010,31970597,31901058 and U20A20403)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Beijing Natural Science Foundation(Z190019)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)China Postdoctoral Science Foundation(2018M640154)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS011)the Youth Innovation Promotion Association of CAS(2021078,E1CAZW0401)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,and the Milky Way Research Foundation(MWRF).
文摘Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.
基金supported by the National Key Research and Development Program of China(No.2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16000000)+12 种基金the National Natural Science Foundation of China(Nos.82192863,81921006,92149301,92168201,91949209,92049304,82125011,82122024,82071588,92049116,32121001,32000500,82030029,81970882,31900523,82271600,32200610,and 81861168034)the National Key Research and Development Program of China(Nos.2018YFC2000100,2021ZD0202400,2020YFA0112200,2018YFA0107203,2021YFF1201005,and2019YFA0110100)the Program of the Beijing Natural Science Foundation(No.Z190019)CAS Project for Young Scientists in Basic Research(No.YSBR-076 and YSBR-012)the Key Research Program of the Chinese Academy of Sciences(No.KFZD-SW-221)K.C.Wong Education Foundation(Nos.GJTD-2019-06 and GJTD-2019-08)Youth Innovation Promotion Association of CAS(Nos.2021078,2022083,and E1CAZW0401)Young Elite Scientists Sponsorship Program by CAST(Nos.YESS20200012 and YESS20210002)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,the Tencent Foundation(No.2021-1045)the Informatization Plan of Chinese Academy of Sciences(Nos.CAS-WX2021SF-0301 and CASWX2022SDC-XK14)the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(No.11000022T000000461062)Natural Science Foundation from Jiangsu Province(No.BE2019711),Shenzhen Fundamental Research Program(No.JCYJ20190814093401920)Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(No.SKLGE-2109).
文摘Progressive functional deterioration in the cochlea is associated with age-related hearing loss(ARHL).However,the cellular and molecular basis underlying cochlear aging remains largely unknown.Here,we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging,in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points.Overall,our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging,highlights unexpected age-related transcriptional fluctuations in intermediate ceils localized in the stria vascularis(SV)and demonstrates that upregulation of endoplasmic reticulum(ER)chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging.Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related sVatrophyand hencedelay theprogressionofARHL.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone(ZJ2018-ZD-004)+2 种基金the National Natural Science Foundation of China(81625009,81330008,91749202)Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002)This study was supported by,Fundaci6n Dr.Pedro Guillen,Universidad Catolica San Antonio de Murcia(UCAM),Asociacion de Futbolistas Espanoles(AFE),Fundacion Telefonica,Fundacion MAPFRE,The Moxie Foundation and The G.Harold and Leila Y.Mathers Charitable Foundation.
文摘Dear Editor,Homeostasis and repair are critical biological processes that allow for tissue and organ preservation and function in multicellular organisms.Their regulation and extension vary drastically across the animal kingdom,and mammals show limited tissue-specific regenerative capacity that declines with age.During aging,articular cartilage is one of the tissues that undergo substantial changes in the matrix structure,molecular composition,metabolic activity,and mechanical properties(Loeser et al.2016).
