PDF(Pubmed)
Abstract：
Ectodermal appendages, such as the mammary gland (MG), are thought to have evolved from hair-associated apocrine glands to serve the function of milk secretion. Through the directed differentiation of mouse embryonic stem cells (mESCs), here, we report the generation of multilineage ESC-derived mammary organoids (MEMOs). We adapted the skin organoid model, inducing the dermal mesenchyme to transform into mammary-specific mesenchyme via the sequential activation of Bone Morphogenetic Protein 4 (BMP4) and Parathyroid Hormone-related Protein (PTHrP) and inhibition of hedgehog (HH) signaling. Using single-cell RNA sequencing, we identified gene expression profiles that demonstrate the presence of mammary-specific epithelial cells, fibroblasts, and adipocytes. MEMOs undergo ductal morphogenesis in Matrigel and can reconstitute the MG in vivo. Further, we demonstrate that the loss of function in placode regulators LEF1 and TBX3 in mESCs results in impaired skin and MEMO generation. In summary, our MEMO model is a robust tool for studying the development of ectodermal appendages, and it provides a foundation for regenerative medicine and disease modeling.
摘要：
外胚层附属物,如乳腺（MG），被认为是从与头发相关的大汗腺进化而来的，以发挥乳汁分泌的功能。通过小鼠胚胎干细胞（mESCs）的定向分化，在这里，我们报道了多谱系ESC衍生的乳腺类器官（MEMO）的产生。我们调整了皮肤类器官模型，通过依次激活骨形态发生蛋白4（BMP4）和甲状旁腺激素相关蛋白（PTHrP）并抑制刺猬（HH）信号，诱导真皮间质转化为乳腺特异性间质。使用单细胞RNA测序，我们确定了基因表达谱，证明存在乳腺特异性上皮细胞，成纤维细胞,和脂肪细胞。MEMO在Matrigel中经历导管形态发生，并可以在体内重建MG。Further,我们证明mESCs中placode调节剂LEF1和TBX3的功能丧失会导致皮肤和MEMO生成受损。总之,我们的MEMO模型是研究外胚层附属物发育的强大工具，它为再生医学和疾病建模提供了基础。
