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A dynamic culture system that models the intricacy of the mammary gland

Nature Reviews Molecular Cell Biology volume 25, page 248 (2024)Cite this article

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Organoid culture technology provides a valuable cell biology model with which to study organ development, homeostatic maintenance and pathological conditions. It holds great potential for advancing drug-target screening and precision therapy in clinical medicine. Nevertheless, the establishment of organoid culture systems that faithfully replicate the intricate morphological and functional properties of tissues and model their in vivo dynamics poses a considerable challenge. This challenge is particularly pronounced in mammary glands, which comprise extensively branched networks of ducts that undergo periodical hormonal regulations (known as the estrus cycle).

To accurately recapitulate the complexity and functionality of the mammary gland in vitro, we followed the principle of embryonic mammary morphogenesis to establish an in vitro mammary structure through four sequential steps: stem-cell sphere formation, polarity establishment, symmetry breaking, and pattern duplication. Spheroids derived from expanded culture of adult mouse mammary stem cells were seeded into an extracellular matrix optimized to enhance the establishment of apicobasal polarity. After that, the exogenous morphogenetic factor FGF2 was introduced to facilitate motility-mediated cellular reorganization to break the symmetry and induce branching. A pseudo-estrus cycle was subsequently introduced with oscillating oestrogen and progesterone to drive periodical mammary differentiation, ductal extension and lateral branching. We further improved the system by incorporating feeder cells that reestablish the stromal microenvironment to foster in vivo-like cellular identity and heterogeneity. Ultimately, we developed a dynamic and controllable mini-gland culture system from genetically modifiable somatic stem cells that supported long-term (4-month) maintenance of mammary gland structures with appropriate cellular heterogeneity, function and stem-cell activity.

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Related article

  • Yuan, L. et al. Reconstruction of dynamic mammary mini gland in vitro for normal physiology and oncogenesis. Nat. Methods 20, 2021–2033 (2023)

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  1. Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, China

    Lei Yuan

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  1. Lei Yuan
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Correspondence to Lei Yuan.

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Yuan, L. A dynamic culture system that models the intricacy of the mammary gland. Nat Rev Mol Cell Biol 25, 248 (2024). https://doi.org/10.1038/s41580-024-00704-4

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  • DOI: https://doi.org/10.1038/s41580-024-00704-4

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