Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11444-11453. doi: 10.1073/pnas.1702372116. Epub 2019 May 17.
As 3D culture has become central to investigation of tissue biology, mammary epithelial organoids have emerged as powerful tools for investigation of epithelial cell polarization and carcinogenesis. However, most current protocols start from single cells suspended in Matrigel, which can also restrict cell differentiation and behavior. Here, we show that the noncancerous mammary cell line HMT-3522 S1, when allowed to spontaneously form cell aggregates ("spheroids") in medium without Matrigel, switches to a collective growth mode that recapitulates many attributes of "usual ductal hyperplasia" (UDH), a common benign mammary lesion. Interestingly, these spheroids undergo a complex maturation process reminiscent of embryonic development: solid-cell cords form their own basement membrane, grow on the surface of initially homogeneous cell aggregates, and form asymmetric lumina lined by two distinct cell types that express basal and luminal cytokeratins. This sequence of events provides a cellular mechanism that explains how the characteristic crescent-shaped, asymmetrical lumina form in UDH. Our results suggest that HMT-3522 S1 spheroids are useful as an in vitro model system to study UDH biology, glandular lumen formation, and stem cell biology of the mammary gland.
随着 3D 培养成为组织生物学研究的核心，乳腺上皮类器官已成为研究上皮细胞极化和癌变的有力工具。然而，目前大多数的方案都是从悬浮在基质胶中的单个细胞开始的，这也会限制细胞的分化和行为。在这里，我们展示了非癌细胞系 HMT-3522 S1，当它被允许在没有基质胶的培养基中自发形成细胞聚集体（“球体”）时，会切换到一种集体生长模式，这种模式再现了“普通导管增生”（UDH）的许多特征，UDH 是一种常见的良性乳腺病变。有趣的是，这些球体经历了一个复杂的成熟过程，让人联想到胚胎发育：实心细胞索形成自己的基底膜，在最初同质的细胞聚集体表面生长，并形成由两种不同细胞类型排列的不对称腔，这些细胞类型表达基底和腔角蛋白。这一系列事件提供了一个细胞机制，解释了 UDH 中新月形、不对称腔的形成方式。我们的结果表明，HMT-3522 S1 球体可用作体外模型系统，用于研究 UDH 生物学、腺腔形成以及乳腺的干细胞生物学。
