Journal Article

Identity and dynamics of mammary stem cells during branching morphogenesis

Zomer, Anoek, Langedijk, Nathalia S. M., Muraro, Mauro J., Hannezo, Edouard, van Rheenen, Jacco, van Oudenaarden, Alexander, Scheele, Colinda L. G. J., Simons, Benjamin D.

2017

Overview

During puberty, the mouse mammary gland develops into a highly branched epithelial network. Owing to the absence of exclusive stem cell markers, the location, multiplicity, dynamics and fate of mammary stem cells (MaSCs), which drive branching morphogenesis, are unknown. Here we show that morphogenesis is driven by proliferative terminal end buds that terminate or bifurcate with near equal probability, in a stochastic and time-invariant manner, leading to a heterogeneous epithelial network. We show that the majority of terminal end bud cells function as highly proliferative, lineage-committed MaSCs that are heterogeneous in their expression profile and short-term contribution to ductal extension. Yet, through cell rearrangements during terminal end bud bifurcation, each MaSC is able to contribute actively to long-term growth. Our study shows that the behaviour of MaSCs is not directly linked to a single expression profile. Instead, morphogenesis relies upon lineage-restricted heterogeneous MaSC populations that function as single equipotent pools in the long term. The formation of the branched epithelial network of the mouse mammary gland during puberty is driven by a heterogeneous population of stem cells at the terminal end buds of the epithelium. Dynamics of mammary stem cells Mammary stem cells drive branching morphogenesis in breast tissue, but their location, dynamics and fate remained unknown. Here, a multidisciplinary approach using lineage tracing, single-cell analysis, mathematical modelling and organ reconstruction defines the characteristics of mammary-gland morphogenesis. The results suggest that lineage-restricted heterogeneous stem cells modulate their proliferation behaviour through cell rearrangements every time branching and elongation of the terminal-end bud occurs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136 / 631/136/532/2436 / 631/532/2436 / Animals / Cell growth / Cell Lineage / Cell Proliferation / Female / Gene Expression Profiling / Humanities and Social Sciences / Keratin / Mammary Glands, Animal - cytology / Mice / Models, Molecular / Morphogenesis / multidisciplinary / Observations / Physiological aspects / Puberty / Rodents / Science / Sexual Maturation / Single-Cell Analysis / Stem cells / Stem Cells - cytology / Stem Cells - metabolism / Stochastic Processes