Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells.

Abstract:

:Reduced serum testosterone (T), or hypogonadism, affects millions of men and is associated with many pathologies, including infertility, cardiovascular diseases, metabolic syndrome, and decreased libido and sexual function. Administering T-replacement therapy (TRT) reverses many of the symptoms associated with low T levels. However, TRT is linked to side effects such as infertility and increased risk of prostate cancer and cardiovascular diseases. Thus, there is a need to obtain T-producing cells that could be used to treat hypogonadism via transplantation and reestablishment of T-producing cell lineages in the body. T is synthesized by Leydig cells (LCs), proposed to derive from mesenchymal cells of mesonephric origin. Although mesenchymal cells have been successfully induced into LCs, the limited source and possible trauma to donors hinders their application to clinical therapies. Alternatively, human induced pluripotent stem cells (hiPSCs), which are expandable in culture and have the potential to differentiate into all somatic cell types, have become the emerging source of autologous cell therapies. We have successfully induced the differentiation of hiPSCs into either human Leydig-like (hLLCs) or adrenal-like cells (hALCs) using chemically defined culture conditions. Factors critical for the development of LCs were added to both culture systems. hLLCs expressed all steroidogenic genes and proteins important for T biosynthesis, synthesized T rather than cortisol, secreted steroid hormones in response to dibutyryl-cAMP and 22(R)-hydroxycholesterol, and displayed ultrastructural features resembling LCs. By contrast, hALCs synthesized cortisol rather than T. The success in generating hiPSC-derived hLLCs with broad human LC (hLC) features supports the potential for hiPSC-based hLC regeneration.

authors

Li L,Li Y,Sottas C,Culty M,Fan J,Hu Y,Cheung G,Chemes HE,Papadopoulos V

doi

10.1073/pnas.1908207116

subject

Has Abstract

pub_date

2019-11-12 00:00:00

pages

23274-23283

issue

46

eissn

0027-8424

issn

1091-6490

pii

1908207116

journal_volume

116

pub_type

杂志文章
  • Isolation and visualization of large compact ribonucleoprotein particles of specific nuclear RNAs.

    abstract::We have previously shown that nuclear transcripts of the multifunctional enzyme, carbamoyl-phosphate synthetase, aspartate transcarbamylase, dihydroorotase RNA can be released from nuclei of Syrian hamster cells as compact ribonucleoprotein (RNP) particles that sediment at the 200S region in a sucrose gradient. The 20...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.2.466

    authors: Spann P,Feinerman M,Sperling J,Sperling R

    更新日期:1989-01-01 00:00:00

  • 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway.

    abstract::Prostaglandin J(2) (PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of prostaglandin D(2) that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator-activated rec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.97.9.4844

    authors: Straus DS,Pascual G,Li M,Welch JS,Ricote M,Hsiang CH,Sengchanthalangsy LL,Ghosh G,Glass CK

    更新日期:2000-04-25 00:00:00

  • Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates.

    abstract::A hallmark of most neurodegenerative diseases, including those caused by polyglutamine expansion, is the formation of ubiquitin (Ub)-positive protein aggregates in affected neurons. This finding suggests that the Ub system may be involved in common mechanisms underlying these otherwise unrelated diseases. Here we repo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1530212100

    authors: Donaldson KM,Li W,Ching KA,Batalov S,Tsai CC,Joazeiro CA

    更新日期:2003-07-22 00:00:00

  • A neurohypophyseal hormone analog with selective oxytocin-like activities and resistance to enzymatic inactivation: an approach to the design of peptide drugs.

    abstract::Stepwise, synthetic alteration of oxytocin, guided by conformational and enzymological considerations, has led to analogs with specifically modified activity profiles and resistance to enzymatic inactivation. General requirements for the design of peptides with therapeutic value are discussed. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.71.5.1901

    authors: Walter R,Yamanaka T,Sakakibara S

    更新日期:1974-05-01 00:00:00

  • Deoxycytidine kinase and deoxyguanosine kinase of Lactobacillus acidophilus R-26 are colinear products of a single gene.

    abstract::Three of the four deoxynucleoside kinases required for growth of Lactobacillus acidophilus R-26 exist as heterodimeric pairs specific for deoxyadenosine (dAK) and deoxycytidine (dCK) or dAK and deoxyguanosine (dGK). However, only two tandem genes, dak/dgk, are found, and are expressed only as dAK/dGK in transformed Es...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.25.14385

    authors: Ma N,Ikeda S,Guo S,Fieno A,Park I,Grimme S,Ikeda T,Ives DH

    更新日期:1996-12-10 00:00:00

  • Atomic force microscopy reveals parallel mechanical unfolding pathways of T4 lysozyme: evidence for a kinetic partitioning mechanism.

    abstract::Kinetic partitioning is predicted to be a general mechanism for proteins to fold into their well defined native three-dimensional structure from unfolded states following multiple folding pathways. However, experimental evidence supporting this mechanism is still limited. By using single-molecule atomic force microsco...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0706775105

    authors: Peng Q,Li H

    更新日期:2008-02-12 00:00:00

  • Hydrogen sulfide mediates the vasoactivity of garlic.

    abstract::The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H(2)S), an endogenous cardioprotective vascular cell signaling molecule. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0705710104

    authors: Benavides GA,Squadrito GL,Mills RW,Patel HD,Isbell TS,Patel RP,Darley-Usmar VM,Doeller JE,Kraus DW

    更新日期:2007-11-13 00:00:00

  • Structural insights into the mechanisms of Mg2+ uptake, transport, and gating by CorA.

    abstract::Despite the importance of Mg(2+) for numerous cellular activities, the mechanisms underlying its import and homeostasis are poorly understood. The CorA family is ubiquitous and is primarily responsible for Mg(2+) transport. However, the key questions-such as, the ion selectivity, the transport pathway, and the gating ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1210076109

    authors: Guskov A,Nordin N,Reynaud A,Engman H,Lundbäck AK,Jong AJ,Cornvik T,Phua T,Eshaghi S

    更新日期:2012-11-06 00:00:00

  • Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome.

    abstract::A major challenge in interpreting genome sequences is understanding how the genome encodes the information that specifies when and where a gene will be expressed. The first step in this process is the identification of regions of the genome that contain regulatory information. In higher eukaryotes, this cis-regulatory...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.231608898

    authors: Berman BP,Nibu Y,Pfeiffer BD,Tomancak P,Celniker SE,Levine M,Rubin GM,Eisen MB

    更新日期:2002-01-22 00:00:00

  • Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse.

    abstract::The mammalian anx7 gene codes for a Ca(2+)-activated GTPase, which supports Ca(2+)/GTP-dependent secretion events and Ca(2+) channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca(2+) signaling in secreting pancreatic beta cells, we knocked out the anx7 gene in the mouse and tested the i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.24.13783

    authors: Srivastava M,Atwater I,Glasman M,Leighton X,Goping G,Caohuy H,Miller G,Pichel J,Westphal H,Mears D,Rojas E,Pollard HB

    更新日期:1999-11-23 00:00:00

  • Structure and function in rhodopsin: asymmetric reconstitution of rhodopsin in liposomes.

    abstract::We report on preparation of rhodopsin proteoliposomes with the cytoplasmic domain of rhodopsin facing the exterior of the proteoliposomes. Rhodopsin purified from rod outer segments of bovine retinae by immunoaffinity chromatography in octyl glucoside was reconstituted into liposomes prepared from soybean phospholipid...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.212518899

    authors: Niu L,Kim JM,Khorana HG

    更新日期:2002-10-15 00:00:00

  • The tail domain of lamin Dm0 binds histones H2A and H2B.

    abstract::In multicellular organisms, the higher order organization of chromatin during interphase and the reassembly of the nuclear envelope during mitosis are thought to involve an interaction between the nuclear lamina and chromatin. The nuclear distribution of lamins and of peripheral chromatin is highly correlated in vivo,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.6.2852

    authors: Goldberg M,Harel A,Brandeis M,Rechsteiner T,Richmond TJ,Weiss AM,Gruenbaum Y

    更新日期:1999-03-16 00:00:00

  • IFNalpha kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model.

    abstract::A major involvement of IFNalpha in the etiopathogenesis of systemic lupus erythematosus has been suggested by clinical observations, including the increase of serum levels of this cytokine in patients with active disease. Supporting this hypothesis, we have shown that expression of IFNalpha from a recombinant adenovir...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0900615106

    authors: Zagury D,Le Buanec H,Mathian A,Larcier P,Burnett R,Amoura Z,Emilie D,Peltre G,Bensussan A,Bizzini B,Gallo RC,Koutouzov S

    更新日期:2009-03-31 00:00:00

  • Demethylation and expression of murine mammary tumor proviruses in mouse thymoma cell lines.

    abstract::Murine mammary tumor virus (MMTV) expression is analyzed in a T-lymphoid cell line (T1M1) sensitive to the killing effect of glucocorticoids and in two of its variants, one resistant (T1M1r) and one supersensitive (T1M1ss) to glucocorticoid-induced lymphocytolysis. In the T1M1 line, MMTV is expressed and induced appro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.1.110

    authors: Mermod JJ,Bourgeois S,Defer N,Crépin M

    更新日期:1983-01-01 00:00:00

  • The nature of the TRAP-Anti-TRAP complex.

    abstract::Tryptophan biosynthesis is subject to exquisite control in species of Bacillus and has become one of the best-studied model systems in gene regulation. The protein TRAP (trp RNA-binding attenuation protein) predominantly forms a ring-shaped 11-mer, which binds cognate RNA in the presence of tryptophan to suppress expr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0801032106

    authors: Watanabe M,Heddle JG,Kikuchi K,Unzai S,Akashi S,Park SY,Tame JR

    更新日期:2009-02-17 00:00:00

  • Protective immunity to Schistosoma haematobium infection is primarily an anti-fecundity response stimulated by the death of adult worms.

    abstract::Protective immunity against human schistosome infection develops slowly, for reasons that are not yet fully understood. For many decades, researchers have attempted to infer properties of the immune response from epidemiological studies, with mathematical models frequently being used to bridge the gap between immunolo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1121051109

    authors: Mitchell KM,Mutapi F,Savill NJ,Woolhouse ME

    更新日期:2012-08-14 00:00:00

  • Unexpected tautomeric equilibria of the carbanion-enamine intermediate in pyruvate oxidase highlight unrecognized chemical versatility of thiamin.

    abstract::Thiamin diphosphate, the vitamin B1 coenzyme, plays critical roles in fundamental metabolic pathways that require acyl carbanion equivalents. Studies on chemical models and enzymes had suggested that these carbanions are resonance-stabilized as enamines. A crystal structure of this intermediate in pyruvate oxidase at ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1201280109

    authors: Meyer D,Neumann P,Koers E,Sjuts H,Lüdtke S,Sheldrick GM,Ficner R,Tittmann K

    更新日期:2012-07-03 00:00:00

  • Reovirus-induced modification of cap-dependent translation in infected L cells.

    abstract::The translational apparatus in cell-free extracts prepared from L cells infected with reovirus undergoes a time-dependent transition from cap dependence to cap independence. Extracts from uninfected L cells translate capped reovirus mRNA at high efficiency and synthesize the expected three size classes of reovirus pol...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.1.152

    authors: Skup D,Millward S

    更新日期:1980-01-01 00:00:00

  • MetJ repressor interactions with DNA probed by in-cell NMR.

    abstract::Atomic level characterization of proteins and other macromolecules in the living cell is challenging. Recent advances in NMR instrumentation and methods, however, have enabled in-cell studies with prospects for multidimensional spectral characterization of individual macromolecular components. We present NMR data on t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0811130106

    authors: Augustus AM,Reardon PN,Spicer LD

    更新日期:2009-03-31 00:00:00

  • Ca2+ bursts occur around a local minimal concentration of attractant and trigger sperm chemotactic response.

    abstract::Ca(2+) is known to have important roles in sperm chemotaxis, although the relationship between intracellular Ca(2+) concentration ([Ca(2+)](i)) and modulation of the swimming and chemotactic behavior of spermatozoa has not been elucidated. Using a high-speed Ca(2+) imaging system, we examined the chemotactic behavior ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0808580105

    authors: Shiba K,Baba SA,Inoue T,Yoshida M

    更新日期:2008-12-09 00:00:00

  • Efficient replacement of plasma membrane outer leaflet phospholipids and sphingolipids in cells with exogenous lipids.

    abstract::Our understanding of membranes and membrane lipid function has lagged far behind that of nucleic acids and proteins, largely because it is difficult to manipulate cellular membrane lipid composition. To help solve this problem, we show that methyl-α-cyclodextrin (MαCD)-catalyzed lipid exchange can be used to maximally...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1610705113

    authors: Li G,Kim J,Huang Z,St Clair JR,Brown DA,London E

    更新日期:2016-12-06 00:00:00

  • The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation.

    abstract::Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decrease...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.25.12086

    authors: Pinsky DJ,Naka Y,Chowdhury NC,Liao H,Oz MC,Michler RE,Kubaszewski E,Malinski T,Stern DM

    更新日期:1994-12-06 00:00:00

  • gamma-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty.

    abstract::To test the hypothesis that the pubertal increase in luteinizing hormone-releasing hormone (LHRH) release is withheld by a dominant inhibitory neuronal system, the role of gamma-aminobutyric acid (GABA), a known inhibitory neurotransmitter, in the control of LHRH release was examined in conscious female monkeys at the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.1.395

    authors: Mitsushima D,Hei DL,Terasawa E

    更新日期:1994-01-04 00:00:00

  • RovA, a global regulator of Yersinia pestis, specifically required for bubonic plague.

    abstract::The pathogenic species of Yersinia contain the transcriptional regulator RovA. In Yersinia pseudotuberculosis and Yersinia enterocolitica, RovA regulates expression of the invasion factor invasin (inv), which mediates translocation across the intestinal epithelium. A Y. enterocolitica rovA mutant has a significant dec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0603456103

    authors: Cathelyn JS,Crosby SD,Lathem WW,Goldman WE,Miller VL

    更新日期:2006-09-05 00:00:00

  • The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

    abstract::The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the re...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1905787116

    authors: McMurran CE,Guzman de la Fuente A,Penalva R,Ben Menachem-Zidon O,Dombrowski Y,Falconer J,Gonzalez GA,Zhao C,Krause FN,Young AMH,Griffin JL,Jones CA,Hollins C,Heimesaat MM,Fitzgerald DC,Franklin RJM

    更新日期:2019-12-10 00:00:00

  • Histone demethylase KDM5B is a key regulator of genome stability.

    abstract::Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1324036111

    authors: Li X,Liu L,Yang S,Song N,Zhou X,Gao J,Yu N,Shan L,Wang Q,Liang J,Xuan C,Wang Y,Shang Y,Shi L

    更新日期:2014-05-13 00:00:00

  • Role of the F-box protein Skp2 in lymphomagenesis.

    abstract::The F-box protein Skp2 (S-phase kinase-associated protein 2) positively regulates the G(1)-S transition by controlling the stability of several G(1) regulators, such as the cell cycle inhibitor p27. We show here that Skp2 expression correlates directly with grade of malignancy and inversely with p27 levels in human ly...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.041475098

    authors: Latres E,Chiarle R,Schulman BA,Pavletich NP,Pellicer A,Inghirami G,Pagano M

    更新日期:2001-02-27 00:00:00

  • Direct measurement of the protein response to an electrostatic perturbation that mimics the catalytic cycle in ketosteroid isomerase.

    abstract::Understanding how electric fields and their fluctuations in the active site of enzymes affect efficient catalysis represents a critical objective of biochemical research. We have directly measured the dynamics of the electric field in the active site of a highly proficient enzyme, Δ(5)-3-ketosteroid isomerase (KSI), i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1113874108

    authors: Jha SK,Ji M,Gaffney KJ,Boxer SG

    更新日期:2011-10-04 00:00:00

  • Glutamic and aminoadipic semialdehydes are the main carbonyl products of metal-catalyzed oxidation of proteins.

    abstract::Metal-catalyzed oxidation results in loss of function and structural alteration of proteins. The oxidative process affects a variety of side amino acid groups, some of which are converted to carbonyl compounds. Spectrophotometric measurement of these moieties, after their reaction with 2,4-dinitrophenylhydrazine, is a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.011526698

    authors: Requena JR,Chao CC,Levine RL,Stadtman ER

    更新日期:2001-01-02 00:00:00

  • Subgenome chromosome walking in wheat: a 450-kb physical contig in Triticum monococcum L. spans the Lr10 resistance locus in hexaploid wheat (Triticum aestivum L.).

    abstract::For many agronomically important plant genes, only their position on a genetic map is known. In the absence of an efficient transposon tagging system, such genes have to be isolated by map-based cloning. In bread wheat Triticum aestivum, the genome is hexaploid, has a size of 1.6 x 10(10) bp, and contains more than 80...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.230361597

    authors: Stein N,Feuillet C,Wicker T,Schlagenhauf E,Keller B

    更新日期:2000-11-21 00:00:00