Aberrant transforming growth factor-β activation recruits Mesenchymal stem cells during prostatic hyperplasia

Long Wang, Liang Xie, Francis Tintani, Hui Xie, Changjun Li, Zhuang Cui, Mei Wan, Xiongbing Zu, Lin Qi, Xu Cao

Research output: Contribution to journalArticle

Abstract

Benign prostatic hyperplasia (BPH) is the overgrowth of prostate tissues with high prevalence in older men. BPH pathogenesis is not completely understood, but it is believed to be a result of de novo overgrowth of prostatic stroma. In this study, we show that aberrant activation of transforming growth factor-β(TGF-β)mobilizes mesenchymal/stromal stem cells (MSCs) in circulating blood, which are recruited for the prostatic stromal hyperplasia. Elevated levels of active TGF-β were observed in both a phenylephrine-induced prostatic hyperplasia mouse model and human BPH tissues. Nestin lineage tracing revealed that 39.6% ± 6.3% of fibroblasts and 73.3% ± 4.2% smooth muscle cellswere derived fromnestin+ cells in Nestin-Cre, Rosa26-YFPflox/+ mice. Nestin+ MSCs were increased in the prostatic hyperplasia mice. Our parabiosis experiment demonstrate that nestin+ MSCs were mobilized and recruited to the prostatic stroma of wild-type mice and gave rise to the fibroblasts. Moreover, injection of a TGF-β neutralizing antibody (1D11) inhibits mobilization of MSCs, their recruitment to the prostatic stroma and hyperplasia. Importantly, knockout of TbRII in nestin+ cell lineage ameliorated stromal hyperplasia. Thus, elevated levels of TGF-β-inducedmobilization and recruitment of MSCs to the reactive stroma resulting in overgrowth of prostate tissues in BPH and, thus, inhibition of TGF-β activity could be a potential therapy for BPH.

Original languageEnglish (US)
Pages (from-to)394-404
Number of pages11
JournalStem Cells Translational Medicine
Volume6
Issue number2
DOIs
StatePublished - Feb 2017

Keywords

  • Benign prostatic hyperplasia
  • Fibrosis
  • Mesenchymal stem cells
  • Stroma
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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