Research: Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids

Nat Med

. 2024 Mar 4.

 doi: 10.1038/s41591-024-02807-z. Online ahead of print.

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

Mattia Francesco Maria Gerli # 1 2Giuseppe Calà # 3 4Max Arran Beesley 4Beatrice Sina 4 5Lucinda Tullie 4 6Kylin Yunyan Sun 3 4Francesco Panariello 7Federica Michielin 4Joseph R Davidson 4 8Francesca Maria Russo 9Brendan C Jones 4Dani Do Hyang Lee 4Savvas Savvidis 10Theodoros Xenakis 4Ian C Simcock 4 11Anna A Straatman-Iwanowska 12Robert A Hirst 12Anna L David 8 9Christopher O’Callaghan 4Alessandro Olivo 10Simon Eaton 4Stavros P Loukogeorgakis 4 13Davide Cacchiarelli 7 14 15Jan Deprest 8 9Vivian S W Li 6Giovanni Giuseppe Giobbe 4Paolo De Coppi 16 17 18 19 20

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Isolation of tissue-specific fetal stem cells and derivation of primary organoids is limited to samples obtained from termination of pregnancies, hampering prenatal investigation of fetal development and congenital diseases. Therefore, new patient-specific in vitro models are needed. To this aim, isolation and expansion of fetal stem cells during pregnancy, without the need for tissue samples or reprogramming, would be advantageous. Amniotic fluid (AF) is a source of cells from multiple developing organs. Using single-cell analysis, we characterized the cellular identities present in human AF. We identified and isolated viable epithelial stem/progenitor cells of fetal gastrointestinal, renal and pulmonary origin. Upon culture, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule and lung identity. AF organoids exhibit transcriptomic, protein expression and functional features of their tissue of origin. With relevance for prenatal disease modeling, we derived lung organoids from AF and tracheal fluid cells of congenital diaphragmatic hernia fetuses, recapitulating some features of the disease. AF organoids are derived in a timeline compatible with prenatal intervention, potentially allowing investigation of therapeutic tools and regenerative medicine strategies personalized to the fetus at clinically relevant developmental stages.

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