title: Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia.
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 cells were derived from nestin+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 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.
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.|Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Tintani
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Changjun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
authors.affiliation: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Xiongbing
authors.initials: X
authors.lastname: Zu
authors.affiliation: Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Orthopedic Surgery and Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D016022:Case-Control Studies; D019070:Cell Lineage; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D010227:Parabiosis; D010641:Phenotype; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000077294:Receptor, Transforming Growth Factor-beta Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; C577485:Nes protein, mouse; D064231:Nestin; D016212:Transforming Growth Factor beta; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625846:Tgfbr2 protein, mouse
keywords: Benign prostatic hyperplasia; Fibrosis; Mesenchymal stem cells; Stroma; Transforming growth factor-β