R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal

Genes Dev. 2014 Oct 15;28(20):2205-18. doi: 10.1101/gad.245142.114. Epub 2014 Sep 26.


Signals from the niche play pivotal roles in regulating adult stem cell self-renewal. Previous studies indicated that the steroid hormones can expand mammary stem cells (MaSCs) in vivo. However, the facilitating local niche factors that directly contribute to the MaSC expansion remain unclear. Here we identify R-spondin1 (Rspo1) as a novel hormonal mediator in the mammary gland. Pregnancy and hormonal treatment up-regulate Rspo1 expression. Rspo1 cooperates with another hormonal mediator, Wnt4, to promote MaSC self-renewal through Wnt/β-catenin signaling. Knockdown of Rspo1 and Wnt4 simultaneously abolishes the stem cell reconstitution ability. In culture, hormonal treatment that stimulates the expression of both Rspo1 and Wnt4 can completely substitute for exogenous Wnt proteins, potently expand MaSCs, and maintain their full development potential in transplantation. Our data unveil the intriguing concept that hormones induce a collaborative local niche environment for stem cells.

Keywords: Rspo1; Wnt4; hormone; luminal cell; mammary stem cell; niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Female
  • Gene Knockdown Techniques
  • Mice, Inbred BALB C
  • Signal Transduction
  • Stem Cells / cytology*
  • Thrombospondins / genetics
  • Thrombospondins / metabolism*
  • Up-Regulation
  • Wnt4 Protein / genetics
  • Wnt4 Protein / metabolism


  • RSPO1 protein, mouse
  • Thrombospondins
  • Wnt4 Protein