Microscale culture of human liver cells for drug development.

Abstract:

:Tissue function depends on hierarchical structures extending from single cells ( approximately 10 microm) to functional subunits (100 microm-1 mm) that coordinate organ functions. Conventional cell culture disperses tissues into single cells while neglecting higher-order processes. The application of semiconductor-driven microtechnology in the biomedical arena now allows fabrication of microscale tissue subunits that may be functionally improved and have the advantages of miniaturization. Here we present a miniaturized, multiwell culture system for human liver cells with optimized microscale architecture that maintains phenotypic functions for several weeks. The need for such models is underscored by the high rate of pre-launch and post-market attrition of pharmaceuticals due to liver toxicity. We demonstrate utility through assessment of gene expression profiles, phase I/II metabolism, canalicular transport, secretion of liver-specific products and susceptibility to hepatotoxins. The combination of microtechnology and tissue engineering may enable development of integrated tissue models in the so-called 'human on a chip'.

journal_name

Nat Biotechnol

journal_title

Nature biotechnology

authors

Khetani SR,Bhatia SN

doi

10.1038/nbt1361

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

120-6

issue

1

eissn

1087-0156

issn

1546-1696

pii

nbt1361

journal_volume

26

pub_type

杂志文章
  • The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract.

    abstract::The exocrine pancreas, liver, and submandibular glands of the rat were used to express and secrete two exogenous, human protein hormones (growth hormone and insulin) into blood at physiological concentrations. Transfection, expression, and secretion were achieved by the in vivo retrograde injection of plasmid DNA into...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt1297-1378

    authors: Goldfine ID,German MS,Tseng HC,Wang J,Bolaffi JL,Chen JW,Olson DC,Rothman SS

    更新日期:1997-12-01 00:00:00

  • A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes.

    abstract::The ability to produce monoclonal antibodies (Mabs) in plants offers the opportunity for the development of an inexpensive method of mucosal immunoprotection against sexually transmitted diseases. To investigate the suitability of plant-expressed Mabs for vaginal preventive applications, we compared a humanized anti-h...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/4344

    authors: Zeitlin L,Olmsted SS,Moench TR,Co MS,Martinell BJ,Paradkar VM,Russell DR,Queen C,Cone RA,Whaley KJ

    更新日期:1998-12-01 00:00:00

  • RNA processing enables predictable programming of gene expression.

    abstract::Complex interactions among genetic components often result in variable systemic performance in designed multigene systems. Using the bacterial clustered regularly interspaced short palindromic repeat (CRISPR) pathway we develop a synthetic RNA-processing platform, and show that efficient and specific cleavage of precu...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.2355

    authors: Qi L,Haurwitz RE,Shao W,Doudna JA,Arkin AP

    更新日期:2012-10-01 00:00:00

  • The complete genome sequence of the meat-borne lactic acid bacterium Lactobacillus sakei 23K.

    abstract::Lactobacillus sakei is a psychotrophic lactic acid bacterium found naturally on fresh meat and fish. This microorganism is widely used in the manufacture of fermented meats and has biotechnological potential in biopreservation and food safety. We have explored the 1,884,661-base-pair (bp) circular chromosome of strain...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt1160

    authors: Chaillou S,Champomier-Vergès MC,Cornet M,Crutz-Le Coq AM,Dudez AM,Martin V,Beaufils S,Darbon-Rongère E,Bossy R,Loux V,Zagorec M

    更新日期:2005-12-01 00:00:00

  • Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease.

    abstract::RNA-guided genome editing with the CRISPR-Cas9 system has great potential for basic and clinical research, but the determinants of targeting specificity and the extent of off-target cleavage remain insufficiently understood. Using chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we mapped genom...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.2916

    authors: Kuscu C,Arslan S,Singh R,Thorpe J,Adli M

    更新日期:2014-07-01 00:00:00

  • Identification of co-regulated genes through Bayesian clustering of predicted regulatory binding sites.

    abstract::The identification of co-regulated genes and their transcription-factor binding sites (TFBS) are key steps toward understanding transcription regulation. In addition to effective laboratory assays, various computational approaches for the detection of TFBS in promoter regions of coexpressed genes have been developed. ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt802

    authors: Qin ZS,McCue LA,Thompson W,Mayerhofer L,Lawrence CE,Liu JS

    更新日期:2003-04-01 00:00:00

  • Engineered riboregulators enable post-transcriptional control of gene expression.

    abstract::Recent studies have demonstrated the important enzymatic, structural and regulatory roles of RNA in the cell. Here we present a post-transcriptional regulation system in Escherichia coli that uses RNA to both silence and activate gene expression. We inserted a complementary cis sequence directly upstream of the riboso...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt986

    authors: Isaacs FJ,Dwyer DJ,Ding C,Pervouchine DD,Cantor CR,Collins JJ

    更新日期:2004-07-01 00:00:00

  • Identification of a cyclohexylcarbonyl CoA biosynthetic gene cluster and application in the production of doramectin.

    abstract::The side chain of the antifungal antibiotic ansatrienin A from Streptomyces collinus contains a cyclohexanecarboxylic acid (CHC)-derived moiety. This moiety is also observed in trace amounts of omega-cyclohexyl fatty acids (typically less than 1% of total fatty acids) produced by S. collinus. Coenzyme A-activated CHC ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/79479

    authors: Cropp TA,Wilson DJ,Reynolds KA

    更新日期:2000-09-01 00:00:00

  • Improved properties of FLP recombinase evolved by cycling mutagenesis.

    abstract::The site-specific recombinases FLP and Cre are useful for genomic engineering in many living systems. Manipulation of their enzymatic properties offers a means to improve their applicability in different host organisms. We chose to manipulate the thermolability of FLP recombinase. A lacZ-based recombination assay in E...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0798-657

    authors: Buchholz F,Angrand PO,Stewart AF

    更新日期:1998-07-01 00:00:00

  • Extracellular secretion of polypeptides using a modified Escherichia coli flagellar secretion apparatus.

    abstract::We developed a modified flagellar type III secretion apparatus to secrete heterologous polypeptides into the growth medium of Escherichia coli. The secretion was facilitated by fusing the 173-bp untranslated DNA fragment upstream of the gene fliC (encoding flagellin) as well as a transcriptional terminator from fliC, ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt1077

    authors: Majander K,Anton L,Antikainen J,Lång H,Brummer M,Korhonen TK,Westerlund-Wikström B

    更新日期:2005-04-01 00:00:00

  • TagGraph reveals vast protein modification landscapes from large tandem mass spectrometry datasets.

    abstract::Although mass spectrometry is well suited to identifying thousands of potential protein post-translational modifications (PTMs), it has historically been biased towards just a few. To measure the entire set of PTMs across diverse proteomes, software must overcome the dual challenges of covering enormous search spaces ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/s41587-019-0067-5

    authors: Devabhaktuni A,Lin S,Zhang L,Swaminathan K,Gonzalez CG,Olsson N,Pearlman SM,Rawson K,Elias JE

    更新日期:2019-04-01 00:00:00

  • Author Correction: Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs.

    abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title:Nature biotechnology

    pub_type: 已发布勘误

    doi:10.1038/s41587-019-0292-y

    authors: Qu L,Yi Z,Zhu S,Wang C,Cao Z,Zhou Z,Yuan P,Yu Y,Tian F,Liu Z,Bao Y,Zhao Y,Wei W

    更新日期:2019-11-01 00:00:00

  • The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins.

    abstract::The green fluorescent protein (GFP) from the jellyfish Aequorea victoria and its fluorescent homologs from Anthozoa corals have become invaluable tools for in vivo imaging of cells and tissues. Despite spectral and chromophore diversity, about 100 cloned members of the GFP-like protein family possess common structural...

    journal_title:Nature biotechnology

    pub_type: 杂志文章,评审

    doi:10.1038/nbt943

    authors: Verkhusha VV,Lukyanov KA

    更新日期:2004-03-01 00:00:00

  • Author Correction: Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells.

    abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章,已发布勘误

    doi:10.1038/s41587-020-0427-1

    authors: Ramsköld D,Luo S,Wang YC,Li R,Deng Q,Faridani OR,Daniels GA,Khrebtukova I,Loring JF,Laurent LC,Schroth GP,Sandberg R

    更新日期:2020-03-01 00:00:00

  • A catalog of the mouse gut metagenome.

    abstract::We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing laboratories and fed either a ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.3353

    authors: Xiao L,Feng Q,Liang S,Sonne SB,Xia Z,Qiu X,Li X,Long H,Zhang J,Zhang D,Liu C,Fang Z,Chou J,Glanville J,Hao Q,Kotowska D,Colding C,Licht TR,Wu D,Yu J,Sung JJ,Liang Q,Li J,Jia H,Lan Z,Tremaroli V,Dworzyn

    更新日期:2015-10-01 00:00:00

  • Low-temperature resistance of higher plants is significantly enhanced by a nonspecific cyanobacterial desaturase.

    abstract::A broad-specificity delta 9 desaturase gene was cloned from the cyanobacterium Anacystis nidulans. The enzyme introduces a cis-double bond at the delta 9 position of both 16 and 18 carbon saturated fatty acids linked to many kinds of membrane lipids. The gene was stably introduced into tobacco plants under transcripti...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0896-1003

    authors: Ishizaki-Nishizawa O,Fujii T,Azuma M,Sekiguchi K,Murata N,Ohtani T,Toguri T

    更新日期:1996-08-01 00:00:00

  • Evolutionary molecular engineering by random elongation mutagenesis.

    abstract::We describe a new method of random mutagenesis that employs the addition of peptide tails with random sequences to the C-terminal of enzyme molecules. A mutant population of catalase I from Bacillus stearothermophilus prepared by this method has a diversity in thermostability and enzyme activity equal to that obtained...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/5232

    authors: Matsuura T,Miyai K,Trakulnaleamsai S,Yomo T,Shima Y,Miki S,Yamamoto K,Urabe I

    更新日期:1999-01-01 00:00:00

  • De novo assembly of soybean wild relatives for pan-genome analysis of diversity and agronomic traits.

    abstract::Wild relatives of crops are an important source of genetic diversity for agriculture, but their gene repertoire remains largely unexplored. We report the establishment and analysis of a pan-genome of Glycine soja, the wild relative of cultivated soybean Glycine max, by sequencing and de novo assembly of seven phylogen...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.2979

    authors: Li YH,Zhou G,Ma J,Jiang W,Jin LG,Zhang Z,Guo Y,Zhang J,Sui Y,Zheng L,Zhang SS,Zuo Q,Shi XH,Li YF,Zhang WK,Hu Y,Kong G,Hong HL,Tan B,Song J,Liu ZX,Wang Y,Ruan H,Yeung CK,Liu J,Wang H,Zhang LJ,Guan RX

    更新日期:2014-10-01 00:00:00

  • Large multiple sequence alignments with a root-to-leaf regressive method.

    abstract::Multiple sequence alignments (MSAs) are used for structural1,2 and evolutionary predictions1,2, but the complexity of aligning large datasets requires the use of approximate solutions3, including the progressive algorithm4. Progressive MSA methods start by aligning the most similar sequences and subsequently incorpora...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/s41587-019-0333-6

    authors: Garriga E,Di Tommaso P,Magis C,Erb I,Mansouri L,Baltzis A,Laayouni H,Kondrashov F,Floden E,Notredame C

    更新日期:2019-12-01 00:00:00

  • Lineage conversion induced by pluripotency factors involves transient passage through an iPSC stage.

    abstract::Brief expression of pluripotency-associated factors such as Oct4, Klf4, Sox2 and c-Myc (OKSM), in combination with differentiation-inducing signals, has been reported to trigger transdifferentiation of fibroblasts into other cell types. Here we show that OKSM expression in mouse fibroblasts gives rise to both induced ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.3247

    authors: Bar-Nur O,Verheul C,Sommer AG,Brumbaugh J,Schwarz BA,Lipchina I,Huebner AJ,Mostoslavsky G,Hochedlinger K

    更新日期:2015-07-01 00:00:00

  • Preventing gene silencing with human replicators.

    abstract::Transcriptional silencing, one of the major impediments to gene therapy in humans, is often accompanied by replication during late S-phase. We report that transcriptional silencing and late replication were prevented by DNA sequences that can initiate DNA replication (replicators). When replicators were included in si...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt1202

    authors: Fu H,Wang L,Lin CM,Singhania S,Bouhassira EE,Aladjem MI

    更新日期:2006-05-01 00:00:00

  • Publisher Correction: Death by inflammation: drug makers chase the master controller.

    abstract::In the version of this article initially published, a GlaxoSmithKline compound referred to as GSK298559 was listed in Table 1 as a RIPK1 inhibitor in phase 1 trials for inflammatory bowel disease. The correct designation is GSK2983559; however, this compound is a RIPK2 inhibitor and thus should not have been included ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章,已发布勘误

    doi:10.1038/s41587-019-0082-6

    authors: Sheridan C

    更新日期:2019-04-01 00:00:00

  • Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape.

    abstract::We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.2798

    authors: Sherwood RI,Hashimoto T,O'Donnell CW,Lewis S,Barkal AA,van Hoff JP,Karun V,Jaakkola T,Gifford DK

    更新日期:2014-02-01 00:00:00

  • Generation of Rhizobium strains with improved symbiotic properties by random DNA amplification (RDA)

    abstract::To select for bacterial strains with enhanced phenotypes, random fragments of a whole genome, or a defined region of the genome, are cloned in a nonreplicating vector. The resulting plasmids are integrated by recombination into the homologous DNA region of the original strain. Integration gives rise to a nontandem dir...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0697-564

    authors: Mavingui P,Flores M,Romero D,Martínez-Romero E,Palacios R

    更新日期:1997-06-01 00:00:00

  • Detecting and characterizing circular RNAs.

    abstract::Circular RNA transcripts were first identified in the early 1990s but knowledge of these species has remained limited, as their study through traditional methods of RNA analysis has been difficult. Now, novel bioinformatic approaches coupled with biochemical enrichment strategies and deep sequencing have allowed compr...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.2890

    authors: Jeck WR,Sharpless NE

    更新日期:2014-05-01 00:00:00

  • Author Correction: Plants with genetically encoded autoluminescence.

    abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title:Nature biotechnology

    pub_type: 已发布勘误

    doi:10.1038/s41587-020-0578-0

    authors: Mitiouchkina T,Mishin AS,Somermeyer LG,Markina NM,Chepurnyh TV,Guglya EB,Karataeva TA,Palkina KA,Shakhova ES,Fakhranurova LI,Chekova SV,Tsarkova AS,Golubev YV,Negrebetsky VV,Dolgushin SA,Shalaev PV,Shlykov D,Melnik OA,

    更新日期:2020-08-01 00:00:00

  • Recent Supreme Court decisions and licensing power.

    abstract::The recently decided eBay and MedImmune cases interject both reassurance and uncertainty into the present patent licensing landscape, affecting the strategic decisions to be considered during negotiations. ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0208-183

    authors: Giordano-Coltart J,Calkins CW

    更新日期:2008-02-01 00:00:00

  • Directed evolution of a para-nitrobenzyl esterase for aqueous-organic solvents.

    abstract::Through sequential generations of random mutagenesis and screening, we have directed the evolution of an esterase for deprotection of an antibiotic p-nitrobenzyl ester in aqueous-organic solvents. Because rapid screening directly on the desired antibiotic (loracarbef) nucleus p-nitrobenzyl ester was not feasible, the ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0496-458

    authors: Moore JC,Arnold FH

    更新日期:1996-04-01 00:00:00

  • A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes.

    abstract::In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt.4245

    authors: Kyrou K,Hammond AM,Galizi R,Kranjc N,Burt A,Beaghton AK,Nolan T,Crisanti A

    更新日期:2018-12-01 00:00:00

  • Almost in bloom.

    abstract::St. Louis wants to become a hub of agricultural biotechnology. All it needs is more start-ups and funds. ...

    journal_title:Nature biotechnology

    pub_type: 杂志文章

    doi:10.1038/nbt0408-471

    authors: Marris E

    更新日期:2008-04-01 00:00:00