Regenerative medicine provides a valuable therapeutic framework for remedying remedy difficult-to-treat diseases and impaired tissue. The term “regenerative medicine” was first used by Kaiser in 1992 [1]. Cell-based therapy and tissue engineering are the two most significant components of regenerative medicine, and each of them can be applied independently or in combination to generate synergistic effects [2]. In the history of regenerative medicine in urology, Atala et al. [3,4] showed promising results by implanting a tissue-engineered bladder and urethra using autologous cells and scaffolds in humans for the first time. Since then, extensive research has investigated the possibility of using stem cells for therapeutic purposes in various difficult-to-treat urologic diseases such as incontinence, neurogenic bladder (NB), erectile dysfunction, and interstitial cystitis/bladder pain syndrome [5].

Stem cell therapy has been invaluable in the treatment of numerous serious diseases that cannot be adequately treated with existing therapeutic modalities. Therefore, NB associated with central nervous injury or dysfunction is an optimal candidate for stem cell therapy because it is challenging to promote the recovery of injuries or degenerative changes in the central nervous system [6-8]. Disability induced by spinal cord injury (SCI) is a serious problem that impacts quality of life, and its prevalence is noteworthy, although the exact incidence has not been determined. In aging societies, falls are common among elderly individuals, which has contributed to an increasing incidence of SCI [9,10]. One of the most common problems in SCI patients is NB; however, the current medical and surgical treatment of NB focuses only on modulating the function of the bladder, not on promoting recovery of the SCI [11,12]. In addition, the therapeutic outcome of NB treatment is generally insufficient because the SCI is often permanent. Thus, neuronal regeneration using stem cell therapy may contribute to the restoration of functional impairment after SCI.

At present, the Wnt/β-catenin signaling pathway, the Rho/Rock signaling pathway, the Notch signaling pathway, and the JAK-STAT3 signaling pathway have been considered as possible signaling pathways associated with neural regeneration after stem cell therapy. After SCI activation of the Wnt/β-catenin signaling pathway promotes neural regeneration, while the Rho/Rock signaling pathway, the Notch signaling pathway, and the JAK-STAT3 signaling pathway inhibit neural regeneration. The Wnt/β-catenin signaling pathway contributes to the development of the nervous system and is activated in the early period after SCI and subsequently decreases with time. Wnt expression increases rapidly in the acute phase of SCI. Therefore, increased expression of Wnt plays a role in recruiting endogenous neural stem cells and in restoring damaged neural tissue [13-20]. Thus, up- or down-regulation of these signaling pathways influences the neural differentiation of stem cells.

To improve the role of stem cells in repairing damaged tissue, the microenvironmental balance around stem cells is also important. The extracellular matrix (ECM), cytokines, and tissue-specific cells modulate the microenvironment, and an imbalance of these components inhibits neural regeneration. The ECM is a 3-dimensional network that shapes the central nervous system, and breakdown of the ECM after SCI influences neuronal and nonneuronal cell migration, communication, and survival, which are important for recovery from SCI. Therefore, ensuring an adequate ECM for the damaged spinal cord is a therapeutic approach that aims to provide a proper environment for repair after SCI [21]. Several studies have shown a synergistic effect after combined treatment with biocompatible scaffolds and stem cells [22-24]. Moreover, the paracrine effect of stem cells promotes neural regeneration by regulating neurotrophic factors, cytokines, and chemokines [25].

Multiple preclinical studies have investigated the use of various types of stem cells after SCI, evaluating the roles of mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and neural stem cells in morphological and functional recovery after SCI. Many studies have investigated stem cell therapy with MSC have been performed because MSCs because MSCs have considerable potential for differentiation and anti-inflammatory and immunomodulatory properties [26]. MSCs can be isolated from various tissues, such as the bone marrow, umbilical cord, adipose tissue, and oral mucosa. All types of MSCs have been shown to lead to neural regeneration in a SCI animal model induced by spinal cord transection and contusion. Moreover, therapeutic effects of MSCs have been observed in both the acute and chronic phases after SCI. Regarding the route of administration, direct injection to the injured area and intravenous or intrathecal administration of MSCs have led to improved neural regeneration [27-32]. Bone marrow mesenchymal stem cells (BM-MSC) is low immunogenicity compared with MSCs from other tissue. However, considerable pain that occurs during the process of obtaining BM-MSC from bone marrow is an issue. In contrast, adipose-derived stem cells (ADSCs) have the advantage of being readily obtainable from adipose tissue. Therefore, the patient experiences less pain than when BM-MSCs are used.

Many studies have investigated the use of iPSCs because iPSCs derived from autologous somatic cells have similar characteristics to embryonic stem cells, therevy circumventing ethical issues [33]. Several studies have shown autologous iPSC-derived neural precursor cells exerted effects on neural regeneration through remyelination after SCI [34-36]. However, iPSCs have a higher rate of tumorigenicity due to the epigenetic memory of the original somatic cells and reprogramming. Neural stem cells are obtained from the brain (lateral ventricle, dentate gyrus of the hippocampus) and the central canal of the spinal cord. Neural stem cells can differentiate into neurons, astrocytes, and oligodendrocytes in the nervous system [37]. Previous studies of neural stem cells showed axonal regeneration at the injured area and functional recovery [38].

A considerable number of clinical trials that have evaluated the effects and safety of stem cell therapy in SCI patients on the basis of preclinical research. Therefore, a review of clinical trials registered on ClinicalTrials.gov was performed to evaluate the outcomes of stem cell therapy in SCI patients. In total, 30 clinical trials were identified (complete: n=18 and ongoing: n=12), excluding withdrawn and terminated studies. Six of the 18 completed studies reported the results of the trials (Table 1). The completed clinical trials were phase 1 or 2 studies, and types of stem cells were autologous BM-MSCs, autologous ADSCs, and umbilical cord mesenchymal stem cells (UC-MSCs) [39-43]. There was only one phase 3 clinical trial, which compared a stem cell transplantation group, a rehabilitation group, and a blank control group [43]. The route of administration was injection the injured area, intrathecal injection, and intravenous infusion. Three studies performed stem cell therapy together with other treatments, such as decompression of the spinal lesion; physiotherapy involving mat activities, strengthening exercises, self-range of motion, ambulation training for paraplegic patients, and cardiopulmonary training; and rehabilitation therapy [39,41,43].

The baseline severity of SCI was classified according to the American Spinal Injury Association (ASIA) impairment score. After stem cell treatment, sensory and motor function was evaluated with the ASIA impairment score, the Association Impairment Scale score, and somatosensory evoked potentials. Some studies used computed tomography and magnetic resonance imaging of the spinal cord to assess structural changes after stem cell treatment. The 6 studies that reported results showed improvements in sensory and motor function, regardless of the types of stem cells and administration route. A combination of stem cell therapy with physiotherapy and rehabilitation therapy showed remarkable improvements in motor function compared with the patients treated with physiotherapy and rehabilitation therapy only. In addition, no severe adverse events were observed in any studies, and only mild and transient adverse events such as headache, low-level pain, and nonspecific tingling sensations were reported.

NB is a commonly observed functional impairment after SCI, and several animal studies have evaluated the effects of stem cell therapy on bladder function. Previous studies used various SCI animal models to represent NB in SCI patients, and SCI was induced by contusion, transection, and needle-stick injury of the spinal cord [44-50]. Five different sources were used: BM-MSCs, human UC-MSCs, neuronal stem cells, human MSCs, and oral mucosa stem cells. Most of the studies administered stem cells through direct injection to the injured area between 3 days and 13 weeks after the injury. Bladder function was evaluated by performing a urodynamic study (UDS) after stem cell therapy. Compared with the SCI group without treatment, the stem cell therapy group showed decreased voiding pressure and non-voiding contraction and increased bladder compliance and bladder capacity. In addition to UDS, some previous studies simultaneously evaluated sensory and motor function. Functional changes after stem cell therapy varied from minimal to a significant improvement.

There were 10 clinical trials of stem cell therapy for NB after SCI that included evaluations of bladder function. Among them, 5 studies were completed, and 5 studies were ongoing (Table 2). All of them except 1 study (phase 3) [43] were phase 1 or 2 clinical trials, and they used stem cells such as autologous BM-MSCs, UC-MSCs, Wharton’s jelly MSCs, and human-spinal cord-derived neural stem cells. The administration route in most of these studies was intrathecal injection. In 1 study (NCT01909154; see Table 1), a second injection was performed 3 months after the first injection. Bladder function was evaluated with UDS in the completed clinical trials except for 1 study (NCT02570932). Increased maximum cytometric capacity, improved compliance, and decreased detrusor pressure were noted, with results comparable to those of preclinical studies. However, these improvements of UDS did not reduce urinary incontinence or eliminate the need for clean intermittent catheterization (CIC). Five ongoing clinical trials are planning to evaluate bladder function with UDS, measurements of postvoid residual urine volume, and data obtained via questionnaires.

Increasingly many preclinical and clinical studies have investigated the effects of stem cell therapy on NB related to SCI, and several positive results have been reported in previous clinical trials. However, many questions remain about the effects and safety of stem cell therapy. Most of the previous clinical trials were not randomized trials, did not have a control group, and included a small number of patients. Moreover, the dose, route of administration, and timing were different in each of the studies. Furthermore, no studies demonstrated functional recovery of voiding; as mentioned above, patients still had persistent urinary incontinence and a continuing need for CIC. Furthermore, no study showed improvements in sensory and motor function after stem cell therapy. Therefore, further studies are necessary to demonstrate clear evidence regarding stem cell therapy and the appropriate direction for standardization of therapeutic methods. Moreover, the Tissue Engineering & Regenerative Medicine International Society (TERMIS) suggested 5 significant drivers for the translation of regenerative medicine, including stem cell therapy, to real clinical practice [51]. The major drivers pointed out by TERMIS are: fully validated manufacturing capability for stem cells, reimbursement for NB related to SCI, regulation of the design and development of stem cells that will show consistent effect and safety, collaboration among various researchers and economic actors, and clinical development plans to reduce the risk of failure.

Stem cell therapy is a promising therapeutic option for NB related to SCI, and many preclinical and clinical studies have been conducted to demonstrate the efficacy and safety of stem cell therapy. Several clinical trials have demonstrated improvements in bladder function. However, clear evidence is lacking because most of the extant clinical trials were not high-quality, and therapeutic methods varied among the studies. Therefore, there is a pressing need for further studies to demonstrate evidence of the therapeutic potential of stem cell therapy and to enable the translation of stem cell therapy to real-world practice.