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 journalArticlepeer-review

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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