Mesenchymal stem cells ameliorate partial bladder outlet obstruction-induced epithelial-mesenchymal transition type II independent of mast cell recruitment and degranulation

Abstract

Introduction: Partial bladder outlet obstruction (pBOO) results in increased urinary storage pressure and significant morbidity. Increased pressure results in a sequence of programmed events: an initial inflammatory phase, smooth muscle hypertrophy, and fibrosis. Although epithelial-mesenchymal transition (EMT) and mast cell accumulation play intermediary roles in some fibrotic conditions, their role in pBOO has not yet been elucidated. Mesenchymal stem cell (MSC) therapy is emerging as a promising treatment for several conditions. It potently inhibits bladder deterioration after pBOO; however, its mechanism of action is insufficiently understood. Thus, we hypothesize that EMT type II pathway plays a significant role in pBOO, aided by the recruitment and activation of mast cells, and these are potently inhibited by MSCs.
 Methods: PBOO was surgically induced in female Sprague-Dawley rats and simultaneously treated with MSCs. Treatment effect was determined after two or four weeks, and compared to untreated controls. Immunohistochemistry was used to measure markers characteristic of EMT (vimentin, collagenase, and collagen). Whole and degranulated mast cell counts were also performed.
 Results: PBOO resulted in an increased expression of collagenase, vimentin, and collagen. Mast cell recruitment increased proportionately to the length of bladder obstruction. MSC treatment significantly mitigated the EMT type II response, but mast cell recruitment and degranulation were unaffected.
 Conclusions: Our results demonstrate the involvement of EMT type II in the pathophysiology of pBOO and confirm its mitigation with MSC treatment independent of mast cells response. The observations provide insight into the mechanism of action and have therapeutic ramifications.

Mast cell distribution and prevalence in the murine urinary bladder

“…In the urinary bladder, mast cells have been implicated in the pathogenesis of various disorders, such as overactive bladder [ 9 , 10 ], bladder outlet obstruction [ 11 , 12 ], urinary tract infections [ 13 ], bladder carcinoma [ 14 ] and various forms of cystitis [ 15 – 18 ]. Functionally, mast cells are known for their ability to release a wide range of mediators upon activation, which include: histamine, prostaglandin, proteases (tryptase and chymase), cytokines and chemokines such as IL-6, IL-13, chemokine (C-C motif) ligand (CCL)-2, CCL-3, and tumour necrosis factor-α [ 2 , 27 – 29 ].…”

“…In the urinary bladder, mast cells have been implicated in the pathogenesis of various disorders, such as overactive bladder [ 9 , 10 ], bladder outlet obstruction [ 11 , 12 ], urinary tract infections [ 13 ], bladder carcinoma [ 14 ] and various forms of cystitis, namely interstitial cystitis [ 10 , 15 , 16 ], radiation-induced cystitis [ 17 ] and bacterial cystitis [ 18 ]. In such pathologies, abnormalities have been reported in their activation state, prevalence and distribution.…”