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
Owing to a unique set of attributes, human pluripotent stem cells （hPSCs） have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over l...Owing to a unique set of attributes, human pluripotent stem cells （hPSCs） have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure （particularly of chromosomes 1, 12, 17 and 20）, remi- niscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving for- ces behind the genome evolution that may eventually lead to cancerous transformation.展开更多
Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other c...Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other connective tissues and expresses both tryptase and chymase, while the second, termed MCT, which only expresses tryptase, is found primarily in the mucosa. MCs induced from human adult-type CD34+ cells are reported to be of the MCT type, but the development of MCs during embryonic/fetal stages is largely unknown. Using an efficient coculture system, we identified that a CD34+c-kit+ cell population, which appeared prior to the emergence of CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), stimulated robust production of pure Tryptase+Chymase+ MCs (MCTCs). Single-cell analysis revealed dual development directions of CD34+c-kit+ progenitors, with one lineage developing into erythro-myeloid progenitors (EMP) and the other lineage developing into HSPC. Interestingly, MCTCs derived from early CD34+c-kit+ cells exhibited strong histamine release and immune response functions. Particularly, robust release of IL-17 suggested that these early developing tissue-type MCTCs could play a central role in tumor immunity. These findings could help elucidate the mechanisms controlling early development of MCTCs and have significant therapeutic implications.展开更多
In this paper, a novel structure of a high-precision synchronization circuit, HPSC, using interleaved delay units and a dynamic compensation circuit is proposed. HPSCs are designed for synchronization of clock distrib...In this paper, a novel structure of a high-precision synchronization circuit, HPSC, using interleaved delay units and a dynamic compensation circuit is proposed. HPSCs are designed for synchronization of clock distribution networks in large-scale integrated circuits, where high-quality clocks are required. The application of a hybrid structure of a coarse delay line and dynamic compensation circuit performs roughly the alignment of the clock signal in two clock cycles, and finishes the fine tuning in the next three clock cycles with the phase error suppressed under 3.8 ps. The proposed circuit is implemented and fabricated using a SMIC 0.13 μm 1P6M process with a supply voltage at 1.2 V. The allowed operation frequency ranges from 200 to 800 MHz, and the duty cycle ranges between [20%, 80%]. The active area of the core circuits is 245 × 134 μm2, and the power consumption is 1.64 mW at 500 MHz.展开更多
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Owing to a unique set of attributes, human pluripotent stem cells （hPSCs） have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure （particularly of chromosomes 1, 12, 17 and 20）, remi- niscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving for- ces behind the genome evolution that may eventually lead to cancerous transformation.
基金This work was supported by the National Basic Research Program(973 Program2015CB96A902)+4 种基金the National Natural Science Foundation of China(H81170466 and H81370597)and the CAMS Initiatives for Innovative Medicine(2016-I2M-1-018)awarded to F.M.the CAMS Initiatives for Innovative Medicine(2017-12M-2005)the Union Youth Fund of Chinese Academy of Medical Sciences(81572089)to G.B.and the National Nature Science Foundation of China Youth Fund(81700107)to B.M.
文摘Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other connective tissues and expresses both tryptase and chymase, while the second, termed MCT, which only expresses tryptase, is found primarily in the mucosa. MCs induced from human adult-type CD34+ cells are reported to be of the MCT type, but the development of MCs during embryonic/fetal stages is largely unknown. Using an efficient coculture system, we identified that a CD34+c-kit+ cell population, which appeared prior to the emergence of CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), stimulated robust production of pure Tryptase+Chymase+ MCs (MCTCs). Single-cell analysis revealed dual development directions of CD34+c-kit+ progenitors, with one lineage developing into erythro-myeloid progenitors (EMP) and the other lineage developing into HSPC. Interestingly, MCTCs derived from early CD34+c-kit+ cells exhibited strong histamine release and immune response functions. Particularly, robust release of IL-17 suggested that these early developing tissue-type MCTCs could play a central role in tumor immunity. These findings could help elucidate the mechanisms controlling early development of MCTCs and have significant therapeutic implications.
文摘In this paper, a novel structure of a high-precision synchronization circuit, HPSC, using interleaved delay units and a dynamic compensation circuit is proposed. HPSCs are designed for synchronization of clock distribution networks in large-scale integrated circuits, where high-quality clocks are required. The application of a hybrid structure of a coarse delay line and dynamic compensation circuit performs roughly the alignment of the clock signal in two clock cycles, and finishes the fine tuning in the next three clock cycles with the phase error suppressed under 3.8 ps. The proposed circuit is implemented and fabricated using a SMIC 0.13 μm 1P6M process with a supply voltage at 1.2 V. The allowed operation frequency ranges from 200 to 800 MHz, and the duty cycle ranges between [20%, 80%]. The active area of the core circuits is 245 × 134 μm2, and the power consumption is 1.64 mW at 500 MHz.
