Abstract
The purpose of this study was to reduce the amount of stem cells used in treating preclinical interstitial cystitis (IC model) by investigating the synergistic effects of multipotent mesenchymal stem cells (M-MSCs; human embryonic stem cell-derived) and N-acetylcysteine (NAC). Eight-week-old female Sprague-Dawley rats were divided into seven groups, i.e., sham (n = 10), lipopolysaccharide/protamine sulfate (LPS/PS; n = 10), LPS/PS + NAC (n = 10), LPS/PS with 25K MSC (n = 10), LPS/PS with 50K MSC (n = 10) LPS/PS + 25K MSC + NAC (n = 10), and LPS/PS + 50K MSC + NAC (n = 10). To induce the IC rat model, protamine sulfate (10 mg, 45 min) and LPS (750 μg, 30 min) were instilled once a week for five consecutive weeks via a transurethral PE-50 catheter. Phosphate-buffered saline (PBS) was used in the sham group. One week after the final instillation, M-MSCs with two suboptimal dosages (i.e., 2.5 or 5.0 × 104 cells) were directly transplanted into the outer-layer of the bladder. Simultaneously, 200 mg/kg of NAC or PBS was intraperitoneally injected daily for five days. The therapeutic outcome was evaluated one week after M-MSC or PBS injection by awake cystometry and histological analysis. Functionally, LPS/PS insult led to irregular micturition, decreased intercontraction intervals, and decreased micturition volume. Both monotherapy and combination therapy significantly increased contraction intervals, increased urination volume, and reduced the residual volume, thereby improving the urination parameters compared to those of the LPS group. In particular, a combination of NAC dramatically reduced the amount of M-MSCs used for significant restoration in histological damage, including inflammation and apoptosis. Both M-MSCs and NAC-based therapy had a beneficial effect on improving voiding dysfunction, regenerating denudated urothelium, and relieving tissue inflammation in the LPS-induced IC/BPS rat model. The combination of M-MSC and NAC was superior to MSC or NAC monotherapy, with therapeutic efficacy that was comparable to that of previously optimized cell dosage (1000K) without compromised therapeutic efficacy.
Highlights
Stem cell therapy is considered a potential alternative treatment for chronic, degenerative disease which has limited therapeutic options with suboptimal efficacy [1,2,3]
We recently proved the superior therapeutic effects and engraftment as well as long-term survival of human embryonic stem cells (ESCs)-derived multipotent mesenchymal stem cells (MSCs) (M-MSCs) compared to their adult tissue counterpart, having employed several Interstitial cystitis/bladder pain syndrome (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]
We have previously identified several IC/BPS animal models that could summarize the different pathogenesis by intravesical instillation of hydrochloride acid (HCl) for an acute model or instillation of PS and LPS for a chronic model, as well as the short- or long-term intravenous injection of ketamine for ketamine-induced cystitis (KC)
Summary
Stem cell therapy is considered a potential alternative treatment for chronic, degenerative disease which has limited therapeutic options with suboptimal efficacy [1,2,3]. Various treatment options, including behavioral therapy, oral pharmacotherapy, intravesical instillation, and surgical therapy, have been suggested for the treatment of IC/BPS, 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]. To obtain sufficient cell numbers with sustained therapeutic potency, large-scale ex vivo expansion is essential, it critically causes the unwanted loss of core function of stem cells and increases the cost for its production
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