Abstract
The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response. Here, we perform single-cell RNA-sequencing (scRNA-seq) of 4113 individual cells from human fetal pituitaries. We characterize divergent developmental trajectories with distinct transitional intermediate states in five hormone-producing cell lineages. Corticotropes exhibit an early intermediate state prior to full differentiation. Three cell types of the PIT-1 lineage (somatotropes, lactotropes and thyrotropes) segregate from a common progenitor coexpressing lineage-specific transcription factors of different sublineages. Gonadotropes experience two multistep developmental trajectories. Furthermore, we identify a fetal gonadotrope cell subtype expressing the primate-specific hormone chorionic gonadotropin. We also characterize the cellular heterogeneity of pituitary stem cells and identify a hybrid epithelial/mesenchymal state and an early-to-late state transition. Here, our results provide insights into the transcriptional landscape of human pituitary development, defining distinct cell substates and subtypes and illustrating transcription factor dynamics during cell fate commitment.
Highlights
The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response
Much of the control comes from five cell types of the anterior pituitary gland including corticotropes that secrete adrenocorticotrophic hormone (ACTH), somatotropes that produce growth hormone (GH), lactotropes that release prolactin (PRL), thyrotropes that produce thyroid-stimulating hormone (TSH) and gonadotropes that produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
For the PIT-1 lineage, integrating our scRNA-seq data with previous mouse genetic studies provides insights into how three distinct cell types are specified from a common progenitor cell
Summary
We identified nine clusters of anterior pituitary endocrine cells including the stem cells (Stem), cycling cells (CC), corticotropes, progenitors of the PIT-1 lineage (Pro.PIT1), somatotropes, lactotropes, thyrotropes, precursors of gonadotropes (Pre. Gonado) and gonadotropes, comprising 2,388 cells (Fig. 1b and Supplementary Fig. 1a). The SCENIC analysis identified activation of known TFs including SOX2, TBX19, POU1F1 and NR5A1 (Fig. 1e and Supplementary Fig. 2c)[17]. Taken together, these results indicated that our data provided comprehensive and precise information on human pituitary development. We identified stem cell-specific genes including SOX2, PROP1, LHX3, HES1, ZFP36L1, ANXA1, NFIB, ZNF521 and NR2F2 (Fig. 2a). NOTCH signaling pathway HES1, NOTCH2, NOTCH2, DTX4 HEDGEHOG signaling pathway GLI1, GLI3,GAS1, PRKX
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