Non-Stem Cell-Based  Urethral Regenerative Therapy: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Ying Wang.

Urethral stricture is a common urological disease that seriously affects quality of life. Urethroplasty with grafts is the primary treatment, but the autografts used in clinical practice have unavoidable disadvantages, which have contributed to the development of urethral tissue engineering. Using various types of seed cells in combination with biomaterials to construct a tissue-engineered urethra provides a new treatment method to repair long-segment urethral strictures. Various cell types have been explored and applied in the field of urethral regeneration.

  • stem cell
  • urethral regeneration
  • tissue engineering
  • epithelial cells
  • smooth muscle cells
  • endothelial cells

1. Introduction

Urethral stricture is a pathological narrowing of the urethral lumen associated with excessive fibrosis of the epithelium and surrounding tissues [1]. As a common urological disease, urethral stricture can be caused by various factors such as trauma, inflammation, congenital malformation, and medically induced injury [2]. Urethral stricture can lead to urinary retention, bladder stones, fistula formation, urinary tract infection, hydronephrosis, and, in severe cases, renal failure, thus affecting quality of life, while treatment of urethral stricture also puts considerable pressure on the healthcare system [3,4][3][4]. Treatment of urethral strictures usually employs different repair strategies depending on the length, location, and cause of the injury [5]. Currently, urethroplasty is usually performed clinically using a graft in patients with long-segment urethral strictures/defects, recurrent strictures, or penile urethral strictures [6]. Grafts are usually autologous tissues, such as buccal mucosa, penile flap, and bladder mucosa, but they are limited in number and difficult to obtain. This treatment mode of sacrificing healthy tissues to repair lesions is also controversial because of the numerous complications associated with the donor site [7]. Therefore, reconstructive repair of the injured urethra remains challenging for urologists.
Tissue engineering is a derivative of regenerative medicine, which aims to create organs using cells, biomaterials, and engineering techniques [8]. Tissue-engineered grafts avoid the complications of autologous tissue collection and reduce patient pain. Over the past 30 years, using tissue engineering techniques to construct a tissue-engineered urethra has made great strides and is gradually being incorporated into urological practice. Single biomaterial scaffolds were first applied to urethral reconstruction, which provide good mechanical support and spatial structure for the migration of host cells and facilitate remodeling of the urethral tissue structure, achieving a certain degree of success in urethral repair. Some classical tissue engineering materials, such as small intestinal submucosa (SIS), bladder acellular matrix (BAM), and acellular dermal matrix, have been evaluated in several clinical trials. However, successful repair with a single scaffold is very dependent on a healthy urethral bed at the injury, adequate vascular distribution, and the absence of spongy fibrosis, which otherwise predisposes to chronic immune reactions, fibrosis formation and calcification, and graft shrinkage or restriction, for which a single scaffold is often inadequate to treat long defects [9]. A research shows that the maximum distance to repair the urethra using tubular acellular matrix grafts appears to be only 0.5 cm [10].
The natural healing process of the urethra involves interactions between multiple factors, such as intercellular contacts, secretions from resident and migrating cells, growth factors, cytokines, and various signaling pathways [11]. Therefore, many investigators have begun to explore cell-based regeneration strategies for long-segment urethral repair. A systematic evaluation showed that the long-term success rate of cell–scaffold material complex grafts inoculated with cells was 5.67 times higher than that of the scaffold material alone [12]. Transplanted cells promote rapid vascularization and re-epithelialization of the scaffold material at the graft repair site, reducing local inflammation and scar formation for better repair results [13,14,15][13][14][15]. Therefore, the involvement of cells is indispensable for urethral regeneration, particularly the repair of long-segment urethral defects.
In most cases, the use of differentiated cells in urethral regeneration has been well established and includes mainly epithelial cells, smooth muscle cells, and endothelial cells.

2. Epithelial Cells

Epithelial cells are the key cells in urethra regeneration. A continuous layer of epithelial cells provides a barrier against corrosion effects and urinary fistula, thereby reducing inflammation and fibrous tissue deposition during the healing process [16]. Transitional epithelial cells of the bladder mucosa, mainly obtained by bladder biopsy, are considered the best candidates to reconstruct the epithelial cell layer of the urethra. Although structurally different from the compound columnar epithelium in the urethra, both the transitional epithelium in the bladder and the urethral epithelium are formed by p63+ cells from the urogenital sinus of the fetus [17], and both function as a barrier to urine in the urinary tract. In one study, the bladder mucosa was isolated and digested, and the obtained epithelial cells were cultured in supplemented CnT-07 for proliferation or CnT-02 with 1.07 mM/L CaCl2 for stratification [16]. The expanded autologous bladder epithelial cells were subsequently seeded on a type I collagen-based cell carrier, cultured in layers for 8 days, and labeled with PKH26. The collagen-based cell carrier grafts were then used to repair urethral strictures in minipigs. Immunofluorescence analysis confirmed the epithelial cell phenotype, junction formation, and differentiation at 2 weeks, and that the grafted cells were present at the repair site 6 months after surgery. No recurrence of the stricture was observed in the experimental animals at the final 6-month transplantation [16]. Another study using a rabbit model showed that scaffolds implanted with bladder epithelial cells supported epithelial integrity, stratification, and continuity with the normal urothelium [18]. Wang et al. [19] implanted bladder epithelial cells into human amniotic scaffolds to reduce rejection and improve the biocompatibility of the graft material. The results showed milder inflammatory cell infiltration, i.e., less accumulation of CD4 and CD8 cells, neutrophils, and other types of immune cells, in cell-seeded human amniotic scaffold grafts compared with the epithelial cell-free group. The number of cells obtained by biopsy is limited, and the procedure requires general anesthesia and is invasive. Bladder washing is a feasible alternative to harvesting viable autologous bladder epithelial cells in a non-invasive manner [20]. Amesty et al. [21] obtained autologous epithelial cells by bladder washing and seeded the submucosal matrix of acellular porcine small intestines to construct a tissue-engineered urethra. They found that the epithelial cell seeding group formed multilayered urothelial cells and successfully repaired urethral defects in rabbits. Epithelial cells collected by the bladder washing procedure have the same effect as biopsy acquisition, and it avoids donor site damage caused by biopsy, providing the possibility of obtaining cells several times for repeat procedures if needed [20]. Autologous urethral epithelial cells cannot, however, be obtained from patients with chronic inflammation of the urinary tract [22]. Oral mucosal cells exist in a humid physiological environment similar to the urinary tract and are resistant to a wet environment and infection because of the expression of beta-defensins and interleukin-8 in their membranes [23]. The differences between oral and urethral mucosae are minimal [24], and the collection of oral mucosal epithelial cells can be performed under local anesthesia in a simple and well-tolerated procedure. Therefore, autologous oral-derived epithelial cells are also an effective cell source for urethral regeneration. Huang et al. [25] used lingual keratinocytes seeded in a bacterial cellulose (BC) scaffold to treat rabbit urethral injuries. The cell–scaffold material composite group exhibited faster and more complete epithelial regeneration compared with the BC alone group. Lv et al. [26] cultured autologous lingual keratinocytes and seeded them on a novel three-dimensional (3D) scaffold composed of a combination of silk fibroin (SF) and BC and observed good regeneration of the urothelial cells in a dog urethral repair model. Oral mucosal epithelial cells have been developed to construct a tissue-engineered buccal mucosa for urethral repair and reconstruction, with encouraging results [2,27][2][27]. However, a potential limitation of oral mucosal epithelial cells is their low proliferative capacity and clonogenicity, hindering their large-scale expansion in vitro, which is required for clinical use. Epidermal cells can also be isolated and expanded by minimally invasive methods from hairless skin, such as foreskin, and cultured to form a thick barrier that isolates urine. A study has demonstrated successful repair of rabbit urethral defects using a tubular acellular collagen matrix seeded with foreskin epithelial cells [28]. However, because of complications and malformations at the harvest site associated with a foreskin biopsy, recent studies have begun to explore the use of epidermal cells from other sites for urethral repair procedures. Rogovaya et al. [29] collected rabbit ear epithelial cells and cultured them to prepare cell sheets for rabbit urethral repair. The rabbits regained voluntary urinary function at 4–7 days postoperatively with no scarring or abnormal fistula formation in the urethra. Complete recovery of rabbit urothelial cells was observed at 45 days postoperatively in the grafted area, and the presence of a multilayered migrating epithelium was observed. In another study, Zhang et al. [30] obtained skin epidermal cells (SEC) from rabbit abdominal skin and constructed cryopreserved SEC-AM (amniotic membrane) urethral scaffolds for rabbit urethra repair, which also achieved good results.

3. Mesothelial Cells

Epithelial cells have a low proliferative capacity and often require long culture cycles. Additionally, epithelial cells are unavailable under malignant conditions, a history of lichen sclerosis, or oral disease. Mesothelial cells have a higher proliferative capacity and plasticity than urothelial cells [31]. Studies have reported the successful use of mesothelial cell-lined grafts as urethral grafts, including peritoneal [32] and vaginal endografts [33]. Thus, mesothelial cells may be a suitable alternative to epithelial cells. Jiang et al. [34] seeded mesothelial cells onto autogenous granulation tissue to construct a mesothelium-lined compound graft for tubularized urethroplasty in male rabbits. Histologically, urothelial layers surrounded by increasingly organized smooth muscles were observed in seeded grafts. Conversely, myofibroblast accumulation and extensive scarring occurred in unseeded grafts. Although mesothelial cells of large omentum origin may have some advantages, long-term culture of mesothelial cells appears to be difficult because of early senescence. Thus, further studies on mesothelial cells are needed.

4. Smooth Muscle Cells

The well-developed smooth muscle layer enhances the mechanical properties of the urethra and maintains structural stability during stretching and urination, to some extent avoiding the occurrence of urethral strictures. Therefore, seeding smooth muscle cells (SMCs) for remuscularization of a tissue-engineered urethra is an effective method to possibly repair urethral injury while avoiding strictures. A bladder biopsy is the most common source of SMCs in urethral repair and reconstruction. In one study, bladder muscle tissue was clipped and digested, and a composite SMC scaffold was used to repair urethral defects in rabbits [35]. After 3 months, immunohistochemical examination showed a higher and well-arranged smooth muscle content in the SMC group compared with that in the control group, which resulted in a significantly lower rate of tubular obstruction and complications, including stone formation, urinary fistula, and urethral stricture incidence, in the SMC group. In a report by Lv et al. [36], earlier muscle regeneration was observed in the SMC-seeded scaffold group compared with the unseeded cell group. In another preclinical study, Niu et al. [37] seeded SMCs into a synthetic scaffold for rabbit urethral repair reconstruction and found that it promoted the regeneration of multilayered smooth muscle tissue, obtaining grafting results similar to those of autologous tissue. Similar success was subsequently achieved by their group in a dog model [38]. Ultimately, SMC composite scaffolds result in earlier, more mature muscle regeneration, thereby facilitating the avoidance of urethral strictures. SMCs may also help support epithelial–mesenchymal interactions required for normal maturation of the urothelium [22,39][22][39]. In a preclinical study [14], autologous epithelial and smooth muscle cells were seeded in a tubular collagen scaffold and used for urethroplasty in 15 dogs. After up to 12 months of follow-up, computed tomography urethrograms showed a wide urethral caliber in animals treated with seeded cell grafts. Conversely, six control animals treated with unseeded scaffolds had blocked urethras. The seeded group showed superior epithelial tissue and muscle fiber formation, whereas the unseeded group showed fibrosis and few muscle fibers. In another study, autologous bladder epithelial and smooth muscle cells from nine male rabbits were expanded and seeded onto preconfigured tubular matrices constructed from acellular bladder matrices obtained from the lamina propria. Urethroplasties were performed with tubularized matrices seeded with cells in nine animals and matrices without cells in six animals. The urethrograms showed that animals implanted with cell-seeded matrices maintained a wide urethral caliber without strictures. Conversely, urethras with unseeded scaffolds collapsed and developed strictures [40]. Similarly, Lv et al. [26] successfully repaired urethral defects in dogs using a composite bilayer scaffold of lingual keratinocytes and lingual muscle cells. However, the low proliferative potential of smooth muscle cells and the relatively high trauma during primary cell collection make it difficult to obtain sufficient seeded smooth muscle cells.

5. Endothelial Cells

Blood vessels provide oxygen and nutrients to tissues and are necessary for tissue regeneration; therefore, vascularization of urethral grafts is an important step in the reconstruction of the urethra. Vascular endothelial cells have become a cell type of great interest. In one study, Heller and colleagues isolated human dermal microvascular endothelial cells from the foreskin to develop a pre-vascularized buccal mucosal substitute to repair urethral defects [41]. Their results showed successful pre-vascularization and the formation of dense capillary-like structures in the substitutes, which became functional vessels by anastomosis with host vessels after implantation into nude mice. Although endothelial cells have been shown to play a crucial role in promoting angiogenesis, harvesting primary endothelial cells remains challenging. Table 1 summarized the functions performed by differentiated cells in urethral regeneration.
Table 1.
Summary of the functions performed by differentiated cells in urethral regeneration.
Cell Type Source Function in Urethral Regeneration References
Mucosal epithelial cells Bladder mucosa Support epithelial integrity, stratification, and continuity with normal urothelium; reduce potential rejection reactions; and improve the biocompatibility of the graft material. [16,18,19,21][16][18][19][21]
Oral mucosa Promotion of urethral epithelial regeneration; participation in the construction of tissue-engineered buccal mucosa (TEBM). [2,25,26,27][2][25][26][27]
Skin/foreskin Form a thick barrier to isolate urine. [19,30][19][30]
Mesothelial cells Peritoneal/vaginal endothelial Act as a substitute for epithelial cells. [34]
Smooth muscle cells Bladder Promote earlier, more mature regeneration of urethral smooth muscle; enhance the mechanical properties of grafts; and support the epithelial–mesenchymal interactions required for normal maturation of the urothelium. [14,22,26,[38]40][14][22][2635,]36,37,[38,39,35][36][37][39][40]
Endothelial cells Foreskin Promote tissue angiogenesis and graft vascularization. [41]

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