Biology subjects

Simcock, I. C.

Publications and source records attributed to Simcock, I. C..

3 recordsLinked to original sources

bioRxiv2023

Mapping the anatomical and transcriptional landscape of early human fetal ovary development

The complex genetic mechanisms underlying human ovary development can give rise to clinical phenotypes if disrupted, such as Primary Ovarian Insufficiency and Differences of Sex Development. Through a clinically-focused lens, we combine single-nuclei RNA sequencing, bulk RNA sequencing, and micro-focus computed tomography to elucidate the anatomy and transcriptional landscape of the human fetal ovary across key developmental timepoints (Carnegie Stage 22 until 20 weeks post conception). We show the marked growth and distinct morphological changes within the fetal ovary at the critical timepoint of germ cell expansion, and demonstrate that the fetal ovary becomes more transcriptomically distinct from the testis with age. We describe novel ovary developmental pathways, relating to neuroendocrine signalling, energy homeostasis, mitochondrial networks, piRNA processes, and inflammasome regulation. We define transcriptional regulators and candidate genes for meiosis within the developing ovary. Together, this work advances our fundamental understanding of human ovary development and clinical ovarian insufficiency phenotypes.

genomics↗

bioRxiv2023

Single cell-guided prenatal derivation of primary epithelial organoids from the human amniotic and tracheal fluids.

Despite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define individual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem/progenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To confirm this, we derived lung organoids from AF and tracheal fluid (TF) cells of Congenital Diaphragmatic Hernia (CDH) fetuses and found that they show differences to non-CDH controls and can recapitulate some pathological features of the disease. Amniotic Fluid Organoids (AFO) allow investigation of fetal epithelial tissues at clinically relevant developmental stages and may enable the development of therapeutic tools tailored to the fetus, as well as to predicting the effects of such therapies.

cell biology↗

bioRxiv2022

A cell atlas of human adrenal cortex development and disease

The adrenal glands synthesize and release essential steroid hormones such as cortisol and aldosterone, but the mechanisms underlying human adrenal gland development are not fully understood. Here, we combined single-cell and bulk RNA-sequencing, spatial transcriptomics, immunohistochemistry and micro-focus computed tomography to investigate key aspects of adrenal development in the first 20 weeks of gestation. We demonstrate rapid adrenal growth and vascularization, with cell division in the outer definitive zone (DZ). Steroidogenic pathways favor androgen synthesis in the central fetal zone (FZ), but DZ capacity to synthesize cortisol and aldosterone develops with time. Core transcriptional regulators were identified, with a role for HOPX in the DZ. Potential ligand- receptor interactions between mesenchyme and adrenal cortex were seen (e.g., RSPO3/LGR4). Growth-promoting imprinted genes were enriched in the developing cortex (e.g. IGF2, PEG3). These findings reveal new aspects of human adrenal development, and have clinical implications for understanding primary adrenal insufficiency and related postnatal adrenal disorders, such as adrenal tumor development, steroid disorders and neonatal stress.

developmental biology↗