Identity and dynamics of mammary stem cells during branching morphogenesis

TY - JOUR

T1 - Identity and dynamics of mammary stem cells during branching morphogenesis

AU - Scheele, Colinda L G J

AU - Hannezo, Edouard

AU - Muraro, Mauro J

AU - Zomer, Anoek

AU - Langedijk, Nathalia S M

AU - van Oudenaarden, Alexander

AU - Simons, Benjamin D

AU - van Rheenen, Jacco

PY - 2017/2/16

Y1 - 2017/2/16

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Lineage

KW - Cell Proliferation

KW - Female

KW - Gene Expression Profiling

KW - Mammary Glands, Animal

KW - Mice

KW - Models, Molecular

KW - Morphogenesis

KW - Sexual Maturation

KW - Single-Cell Analysis

KW - Stem Cells

KW - Stochastic Processes

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nature21046

DO - 10.1038/nature21046

M3 - Article

C2 - 28135720

SN - 0028-0836

VL - 542

SP - 313

EP - 317

JO - Nature

JF - Nature

IS - 7641

ER -