SUI is one of the few diseases that have been treated with SCs in clinical trials. However, due to ethical and regulatory concerns some of the published studies have since been retracted. As such, overcoming these concerns is perhaps the most important issue going forward for future SC-for-SUI clinical trials. Another issue for future clinical trials is the choice of SC type. As shown in and discussed under “Clinical Trials,” the great majority of past clinical trials tested the therapeutic efficacy of SkMSCs. But, this particular SC type requires a lengthy isolation/propagation process and therefore is not the optimal SC type for clinical application. In contrast, ADSC is a SC type that can be isolated from and transplanted back to the patient on the same day. Furthermore, devices for automated isolation of ADSCs are commercially available, for example, the Celution System by Cytori, Inc. (San Diego, CA) [51
], the Cell Isolation System by Tissue Genesis, Inc. (Honolulu, HI), and the YC-100 Stem Cell Isolator by Medikan Co. (Pusan, South Korea). Thus, in terms of cost, risk, ethics, expediency, and effectiveness, ADSCs should compete favorably.
Since we have demonstrated that IV injection produced similarly therapeutic effects as intraurethral injection [14
], this route of SC administration should be further explored in future studies due to its ease of application. Indeed, a recent study has found that IV-injected BMSCs homed into injured tissues in a VD-induced SUI rat model [62
], and another recent study demonstrated that IV injection of ADSCs produced no adverse side effects in humans or mice [68
]. Thus, the opportune time appears to have arrived for a clinical trial with IV injection of SCs, particularly ADSCs, for the treatment of SUI.
While SC-for-SUI clinical trials have produced favorable outcomes, there remain many issues that can only be resolved by animal testing. However, SUI animal models that have been utilized in published SC-for-SUI studies lack a critical clinical component, namely, the chronic nature of SUI. Specifically, while most SUI patients incurred parturition-related urethral injuries years or decades ago, SUI animal models usually regain urinary continence within weeks. In addition, in most published studies SCs were transplanted soon after the urethral injury; thus, the intervention is preventive in nature, not truly therapeutical. As such, to be more clinically relevant, future preclinical studies should use a chronic type of SUI animal model and conduct SC transplantation several days or even weeks after the initial insult. In regard to the creation of chronic SUI models, Pauwels et al. [35
] have described a repeated VD method and a surgical urethral transposition method. In addition, we have recently shown that intraperitoneal injection of beta-aminopropionitrile (BAPN) in VD-treated rats exacerbated the urethral dysfunction and tissue damage [69
]. This additional treatment with BAPN thus has the potential to increase the durability of both the VD and nerve injury SUI rat models.
One of the most pressing issues in SC research is the lack of a clear understanding of how SCs exert their therapeutic effects. Although SC therapy was conceived on the premise that SCs could differentiate into various cell types and thereby replenish damaged/dysfunctional cells, in recent years it is becoming increasingly clear that cellular differentiation alone is far from adequate to accomplish such goals. For example, in a recent review article Mazo et al. [70
] estimated that up to 1 trillion SCs are needed for replacing the damaged cardiomyocytes in a cardiac failure patient. Even if we assume 100% cardiomyocyte differentiation, up to 2 billion SCs are still needed for transplantation into an experimental rat host—a figure that is 1,000 times higher than what has been used in most published studies. Thus, the chance of a successful cell differentiation–based therapy—even in the preclinical stage—is remote. On the other hand, the paracrine aspect as a mechanism for SC's therapeutic effects is gaining broader acceptance [71
]. The remaining challenges for future studies are finding what paracrine factors and knowing how they exert therapeutic effects. While a detailed discussion on these issues is beyond the scope of this review, suffice it to say that available evidence points to the following factors: (i) angiogenic growth factors such as VEGF and bFGF play key roles in overall tissue regeneration, (ii) neurotrophins such as NGF appear to promote axonal regeneration, (iii) homing factors such as SDF-1 can mobilize the host's own stem/repair cells to injury sites, and (iv) certain interleukins might modulate inflammatory response [72
In summary, future studies should focus on (i) adhering to regulatory guidelines for clinical trials; (ii) selecting the most clinically applicable SC type; (iii) creating a long-term, clinically relevant SUI animal model; (iv) testing the feasibility of IV SC injection; and (v) improving our understanding of SC's therapeutic mechanisms.