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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 cells were derived from nestin + cells in Nestin-Cre, Rosa26-YFP flox/+ 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 TβRII in nestin + cell lineage ameliorated stromal hyperplasia. Thus, elevated levels of TGF-β-induced mobilization 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. Stem Cells Translational Medicine 2017;6:394-404., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)