Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Comparison of global gene expression profiles of microdissected human foetal Leydig cells with their normal and hyperplastic adult equivalents

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Education, education, education-now more than ever?

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Inhibin-B secretion and FSH isoform distribution may play an integral part of follicular selection in the natural menstrual cycle

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Reply: Methodological considerations in measuring different AMH splice forms using ELISA: validity of proAMH ELISA

    Research output: Contribution to journalComment/debateResearchpeer-review

  4. Proteolytic processing of anti-Müllerian hormone differs between human fetal testes and adult ovaries

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Allelic imbalance modulates surface expression of the tolerance-inducing HLA-G molecule on primary trophoblast cells

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Measurement of peripheral arterial tonometry in patients with diabetic foot ulcers during courses of hyperbaric oxygen treatment

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Sex-specific estrogen levels and reference intervals from infancy to late adulthood determined by LC-MS/MS

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. The External Genitalia Score (EGS): A European multicenter validation study

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

STUDY QUESTION: Do human adult Leydig cells (ALCs) within hyperplastic micronodules display characteristics of foetal LCs (FLCs)?

SUMMARY ANSWER: The gene expression profiles of FLCs and all ALC subgroups were clearly different, but there were no significant differences in expressed genes between the normally clustered and hyperplastic ALCs.

WHAT IS KNOWN ALREADY: LCs are the primary androgen producing cells in males throughout development and appear in chronologically distinct populations; FLCs, neonatal LCs and ALCs. ALCs are responsible for progression through puberty and for maintenance of reproductive functions in adulthood. In patients with reproductive problems, such as infertility or testicular cancer, and especially in men with high gonadotrophin levels, LC function is often impaired, and LCs may cluster abnormally into hyperplastic micronodules (defined as clusters of >15 LCs in a cross-section).

STUDY DESIGN, SIZE, DURATION: A genome-wide microarray study of LCs microdissected from human foetal and adult tissue samples (n = 12). Additional tissue specimens (n = 15) were used for validation of the mRNA expression data at the protein level.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Frozen human tissue samples were used for the microarray study, including morphologically normal foetal (gestational week 10-11) testis samples, and adult testis specimens with normal LC distribution, LC micronodules or LC micronodules adjacent to hCG-producing testicular germ cell tumours. Transcriptome profiling was performed on Agilent whole human genome microarray 4 × 44 K chips. Microarray data pre-processing and statistical analysis were performed using the limma R/Bioconductor package in the R software, and differentially expressed genes were further analysed for gene set enrichment using the DAVID Bioinformatics software. Selected genes were studied at the protein level by immunohistochemistry.

MAIN RESULTS AND THE ROLE OF CHANCE: The transcriptomes of FLCs and ALCs differed significantly from each other, whereas the profiles of the normally clustered and hyperplastic ALCs were similar despite morphological heterogeneity. The study revealed several genes not known previously to be expressed in LCs during early development, including sulfotransferase family 2A member 1 (SULT2A1), WNT1-inducible signalling pathway protein 2 (WISP2), hydroxyprostaglandin dehydrogenase (HPGD) and insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), whose expression changes were validated at the protein level.

LARGE SCALE DATA: The transcriptomic data are deposited in ArrayExpress (accession code E-MTAB-5453).

LIMITATIONS, REASONS FOR CAUTION: The small number of biological replicates and the necessity of RNA amplification due to the scarcity of human tissues, especially foetal specimens, are the main limitations of the study. Heterogeneous subpopulations of LCs within micronodules were not discriminated during microdissection and might have affected the expression profiling. The study was constrained by the lack of availability of truly normal controls. Testis samples used as 'controls' displayed complete spermatogenesis and were from patients with germ cell neoplasia but with undetectable hCG and normal hormone levels.

WIDER IMPLICATIONS OF THE FINDINGS: The changes in LC morphology and function observed in patients with reproductive disorders possibly reflect subtle changes in the expression of many genes rather than regulatory changes of single genes or pathways. The study provides new insights into the development and maturation of human LCs by the identification of a number of potential functional markers for FLC and ALC.

STUDY FUNDING AND COMPETING INTEREST(S): The study was supported by research grants from the Danish Cancer Society, the Capital Region's Research Fund for Health Research, Rigshospitalet's research funds, the Villum Kann Rasmussen Foundation, the Danish Innovation Fund, ReproUnion, Kirsten and Freddy Johansen's foundation and the Novo Nordisk Foundation. None of the funding agencies had any influence on the study. The authors declare no conflicts of interest.

Original languageEnglish
JournalMolecular Human Reproduction
Volume23
Issue number5
Pages (from-to)339-354
Number of pages16
ISSN1360-9947
DOIs
Publication statusPublished - 1 May 2017

    Research areas

  • Journal Article

ID: 50677146