Improved efficacy and in vivo cellular properties of human embryonic stem cell derivative in a preclinical model of bladder pain syndrome

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease characterized by severe pelvic pain and urinary frequency. Mesenchymal stem cell (MSC) therapy is a promising approach to treat incurable IC/BPS. Here, we show greater therapeutic efficacy of human embryonic stem cell (hESC)-derived multipotent stem cells (M-MSCs) than adult bone-marrow (BM)-derived counterparts for treating IC/BPS and also monitor long-term safety and in vivo properties of transplanted M-MSCs in living animals. Controlled hESC differentiation and isolation procedures resulted in pure M-MSCs displaying typical MSC behavior. In a hydrochloric-acid instillation-induced IC/BPS animal model, a single local injection of M-MSCs ameliorated bladder symptoms of IC/BPS with superior efficacy compared to BM-derived MSCs in ameliorating bladder voiding function and histological injuries including urothelium denudation, mast-cell infiltration, tissue fibrosis, apoptosis, and visceral hypersensitivity. Little adverse outcomes such as abnormal growth, tumorigenesis, or immune-mediated transplant rejection were observed over 12-months post-injection. Intravital confocal fluorescence imaging tracked the persistence of the transplanted cells over 6-months in living animals. The infused M-MSCs differentiated into multiple cell types and gradually integrated into vascular-like structures. The present study provides the first evidence for improved therapeutic efficacy, long-term safety, and in vivo distribution and cellular properties of hESC derivatives in preclinical models of IC/BPS.

Patterns and predictors of Hunner lesion recurrence in patients with interstitial cystitis

“…In a study of postoperative adjuvant instillation, additional instillation decreased symptom recurrence, but not HLs recurrence . Future studies should, therefore, focus on approaches to the restoration of the damaged bladder using, for example, stem cell injection, which has demonstrated therapeutic efficacy in IC rat models . In these models, stem cell injection was seen to restore urothelial denudation and ameliorate fibrosis and mast cell infiltration.…”

“…20 Future studies should, therefore, focus on approaches to the restoration of the damaged bladder using, for example, stem cell injection, which has demonstrated therapeutic efficacy in IC rat models. 21,22,23 In these models, stem cell injection was seen to restore urothelial denudation and ameliorate fibrosis and mast cell infiltration. The current study is limited by the retrospective, single-center study design, and the small sample size.…”

Synergistic Effects of N-Acetylcysteine and Mesenchymal Stem Cell in a Lipopolysaccharide-Induced Interstitial Cystitis Rat Model

“…Stem cell therapy is considered a potential alternative treatment for chronic, degenerative disease which has limited therapeutic options with suboptimal efficacy [1][2][3]. Interstitial cystitis/bladder pain syndrome (IC/BPS), a symptomatic diagnosis characterized by chronic pelvic pain that lasts for more than six weeks and frequently accompanies lower urinary tract symptoms such as frequency and urgency in the absence of infection and other pathologies, is an ideal candidate for stem cell therapy [4][5][6][7]. Various treatment options, including behavioral therapy, oral pharmacotherapy, intravesical instillation, and surgical therapy, have been suggested for the treatment of IC/BPS, although none of them provide a definite cure for the disease.…”

“…In this regard, a treatment with mesenchymal stem cells (MSCs) is currently considered a new potential direction for treatment of IC/BPS in several preclinical settings [4][5][6][7][8]. The potential effects of MSCs in IC/BPS are related to their ability to produce a subset of biologically active substances with anti-inflammatory, anti-fibrosis, and tissue regenerating properties.…”

“…To overcome these issues, embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) have recently been employed as a promising alternative supply in order to provide sufficient cell numbers with enhanced in vivo survival, engraftment, and functionality for sustained therapeutic potency [11,12]. We recently proved the superior therapeutic effects and engraftment as well as long-term survival of human ESC-derived multipotent MSCs (M-MSCs) compared to their adult tissue counterpart, having employed several IC/BPS animal models that recapitulate the different pathogenesis by intravesical instillation of hydrochloride acid (HCl) or lipopolysaccharide/protamine sulfate (LPS/PS) as well as intravenous injection of ketamine [5][6][7].…”