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Single-cell roadmap of human gonadal development.

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This study maps human gonad development using advanced single-cell and spatial transcriptomics. It reveals key regulatory programs for both male and female gonadogenesis, aiding future infertility research and in vitro models.

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Area of Science:

  • Developmental Biology
  • Genetics
  • Reproductive Medicine

Background:

  • Human gonad development (gonadogenesis) is crucial for reproductive health but poorly understood due to limited tissue access and model system limitations.
  • Previous research faced challenges from species-specific differences between humans and mice, hindering the study of human gonadogenesis.
  • Understanding gonadogenesis is vital for addressing gonadal conditions and infertility.

Purpose of the Study:

  • To create a comprehensive spatiotemporal map of human gonad development during the first and second trimesters.
  • To identify human-specific regulatory programs controlling germline and somatic cell lineage development.
  • To compare human gonadogenesis with mouse models to extract conserved and species-specific mechanisms.

Main Methods:

  • Single-cell and spatial transcriptomics were employed to profile human gonads.
  • Chromatin accessibility assays and fluorescent microscopy were utilized for detailed cellular analysis.
  • Comparative analysis with mouse models at equivalent developmental stages was performed.

Main Results:

  • Defined somatic cell states at sex specification, including the bipotent early supporting population.
  • Identified upregulation of the testis-determining factor SRY and sPAX8s in males.
  • Resolved cellular events in females, detailing granulosa cell waves and their role in germ cell differentiation.
  • Characterized human fetal testicular macrophages (SIGLEC15+, TREM2+) and their signaling roles in male gonad development.

Conclusions:

  • Generated a comprehensive spatiotemporal map of human and mouse gonadal differentiation.
  • Uncovered human-specific regulatory programs essential for gonadogenesis.
  • The findings provide a foundation for guiding in vitro gonadogenesis and understanding reproductive disorders.