Power of pee: Urine-derived stem cells in urological disorders

Abstract

Given that urine-derived stem cells (USCs) originate from the urinary tract system, they hold great potential for treating urological disorders. USCs have several advantages over other types of stem cells, such as easy and noninvasive collection, and abundant supply. USCs can differentiate into different types of cells. This makes them a potential source of cells for tissue engineering and regenerative medicine in the field of urology. In animal models, USCs or USC-derived exosomes regenerate damaged tissues in the treatment of various urological disorders such as urinary incontinence, bladder dysfunction, interstitial cystitis, urethra injury erectile dysfunction, and kidney injury via multiple differentiation potential, angiogenesis, anti-inflammatory, paracrine effects, and immune modulation capability. Overall, the use of USCs in urological disorders is a rapidly developing field, and ongoing research is needed to fully understand their potential applications. However, the early results are promising and suggest that USCs could become a valuable cell source for the treatment of various urological disorders in the future.

Keywords

cell therapy / stem cells / tissue regeneration / urine / urological diseases

1 INTRODUCTION

Urine therapy as an ancient practice has been used to treat various disorders in various cultures for thousands of years. In several traditional medical systems, urine was considered a valuable resource for its purported healing properties and was used to treat different ailments. This ancient practice of urine therapy is controversial and seems lack support by modern medicine. However, stem cells found in urine (i.e., urine-derived stem cells, USCs)[1–3] suggest that it holds potential for personal medicine, proving that urine is not just water material.

Adult stem cells do not only exist in most tissues and organs but also in human body fluids[4]. Stem cells can be isolated from various types of amniotic fluid[5], synovial fluid[6,7], breast milk[8], peripheral blood[9], menstrual blood[10,11], and umbilical cord blood[12]. Like other types of body fluid-derived stem cells, we are the first to discover that USCs display stemness properties, multiple differentiation potential and ability of tissue repairing, and holding potential for the development of new therapies for a wide range of medical conditions[1–3,13–24].

USCs have several advantages over other sources of stem cells, such as bone marrow-derived stem cells (BMSCs) and adipose-derived stem cells (ASCs), including: (1) noninvasive collection: urine is easily obtained through a noninvasive and simple collection process, which eliminates the need for invasive procedures such as bone marrow aspiration or tissue biopsies; (2) abundant supply: urine is a readily available and abundant source of stem cells, as it is continuously produced by the body; (3) low risk of contamination from male urine samples: urine is a sterile body fluid, which reduces the risk of contamination during the collection process; (4) multipotent differentiation potential: USCs have the ability to differentiate into a variety of cell types, including bone, cartilage, fat, muscle, and nerve cells, making them ideal for use in tissue engineering and regenerative medicine; (5) immunomodulatory properties: USCs have been shown to have immunomodulatory properties, which makes them useful in the treatment of autoimmune diseases and for suppressing immune rejection after transplantation; and (6) low risk of tumorigenesis: USCs have a low risk of tumorigenesis compared with other stem cell sources, such as embryonic stem cells, which reduces the risk of cancer development in patients. Overall, USCs have several advantages over other sources of stem cells and have the potential to revolutionize the field of regenerative medicine and tissue engineering.

2 STEMNESS PROPERTIES OF USCS

USCs can be isolated from urine using a simple, easily accessible and low-cost procedure. There are several methods that can be used to culture USCs, including adherent culture, suspension culture, and three-dimensional (3D) culture. Adherent culture is the most common method used for USCs, where the cells are grown as a monolayer on a plastic culture dish. Suspension culture involves the cultivation of USCs in a nonadherent culture vessel, while 3D culture involves the cultivation of USCs in a three-dimensional scaffold, which mimics the natural environment of the cells in the body. Urine is a readily available and abundant source of stem cells, as it is continuously produced by the body. These factors make USCs an attractive option for research and clinical applications in regenerative medicine and tissue engineering.

USCs as a subpopulation of cells isolated from urine possess biological characteristics of stem cells, that is, clonogenicity, high expansion capacity[2,19], gene expression profiles of cell surface markers characteristic of stem cells, multipotent differentiation capacity[22–24], particularly renal cell types such as podocytes[25], and urothelial cells[26], smooth muscle cells and endothelial cells with proangiogenic and neurogenic paracrine effects[3,18], immunomodulatory properties[27], and easily induced pluripotent stem cells[28–31]. Multiple other teams around the world have confirmed these results[32–44] and have used USCs for regeneration of bladder[41], urethra[14], kidney[32,38,45], penal tissue[17,21], bone[36,37,44,46], lungs[47], skin[48], nerves[49], and other types of tissue[16,20,44,46,48–54].

These cells display the ability to self-renew, which means that they can divide and produce more stem cells while maintaining their undifferentiated state. Up to 75% of the USCs collected from young- and middle-aged individuals and 57% of USCs from the senior group (≥50 years old) express telomerase activity (TA⁺) and retained long telomere length[55]. After optimizing our methods, 100–140 USC clones/24 h urine collection were consistently obtained from each individual[19]. A recent clinical trial reported that 1 × 10⁸ muscle progenitor cells achieved optimal outcomes in patients with stress urinary incontinence (SUI), with a significant reduction in stress leaks and pad weight at 12-month follow-up[56]. A 24-h urine sample can provide ample cells (> 1 × 10⁸ cells) at p3 within 3 weeks for the purposes of cell implantation, compared to the 8–10 weeks required to obtain sufficient cells for injection from a muscle biopsy[57]. Thus, autologous USCs could act as a rich and promising source of stem cells for the treatment of internal sphincter dysfunction in older women with SUI.

We have presented strong evidence that voided USCs originate from the parietal cells of kidney glomeruli[3]. These cells retain chromosomal stability over cultured passages in vitro and are safe to use in vivo without any risk of oncogenicity[58–68]. Furthermore, these cells can be easily isolated and expanded[2,3,19], which offers clear advantages over stem cells from other sources such as bone marrow or adipose tissue[40,69]. As isolation of USCs does not require tissue dissociation procedures, cell viability is enhanced, since no digestive enzymes are involved[2,19]. Compared with commonly used adult stem cells, that is, BMSC or ASCs, USCs can be obtained noninvasively through a simple urine sample. In addition, while embryonic stem cells have the potential to differentiate into any cell type in the body, the use of embryonic stem cells is controversial due to ethical concerns regarding the destruction of embryos, USCs have no ethical concerns. Induced pluripotent stem cells have the potential to differentiate into any cell type in the body, and the process of reprogramming can be complex and time-consuming. USCs, on the other hand, can be obtained easily and noninvasively. Overall, the choice of stem cell source depends on the specific medical application and the availability of suitable stem cells. USCs have the advantage of being easily accessible and noninvasive but may not be suitable for all applications.

3 MECHANISMS OF ACTION OF USCS IN UROLOGICAL DISORDERS

The mechanisms of action of USCs in urological disorders are still being studied, but several possible mechanisms have been identified: (1) Regenerative properties: USCs have the ability to differentiate into various cell types, including urothelial cells[26], smooth muscle cells, and endothelial cells. In addition, they can give rise to cell lineages of nonurinary tract tissues, such as osteocytes, chondrocytes, adipocytes and skeletal myocytes. When injected into damaged or diseased tissues in the urinary tract, these stem cells can help regenerate and repair the tissue. (2) Anti-inflammatory effects: USCs have been shown to have anti-inflammatory properties. Inflammatory responses can contribute to tissue damage in urological disorders, and by reducing inflammation, USCs may help to limit tissue damage and promote healing. (3) Immune modulation: USCs have the ability to modulate the immune system. In urological disorders, this could be beneficial because the immune system can sometimes attack healthy tissues in the urinary tract, leading to tissue damage and dysfunction. By modulating the immune response, USCs may help to prevent or limit tissue damage. (4) Paracrine effects: USCs also produce and release various growth factors, cytokines, and other signaling molecules that can stimulate tissue repair and regeneration. These molecules can also recruit other cells to the site of injury or disease, further aiding in tissue repair. Thus, the combination of these mechanisms likely contributes to the therapeutic effects of USCs in urological disorders.

4 UROLOGICAL DISORDERS AND USCS

Stem cell therapy is an emerging approach for the treatment of various urological disorders. Here is an overview of the therapy of USCs for the common urological disorders, mainly urinary incontinence, erectile dysfunction (ED), interstitial cystitis, benign prostatic hyperplasia, and kidney diseases (Table 1).

4.1 Urinary incontinence

USCs can differentiate into skeletal muscle cells and smooth muscle cells but never for potentially treating urinary incontinence[21,74,75]. In addition, USC-derived exosomes improve SUI by promoting the repair of pubococcygeus muscle injury in a rat model[76].

4.2 Erectile dysfunction (ED)

USCs have widely been studied for the treatment of various patterns of ED, including ED rat models induced by diabetes, neural injury, cardiovascular disease, and neurovascular injury[17,79,86,87]. In rodent studies, USC exosomes, extracellular vesicles, or lysate have been shown to promote the growth of new blood vessels and nerve cells in the penis, leading to improved erectile function[58,59,79,88].

4.3 Interstitial cystitis[63,64]

USCs have been used to treat interstitial cystitis by reducing inflammation and promoting tissue regeneration in the bladder. In rat studies, USCs have been shown to reduce bladder inflammation and improve bladder function[63,64].

4.4 Kidney disease

USCs have shown promise in the treatment of various kidney diseases, including chronic kidney disease due to diabetics[67,89], ischemia combined with drug toxicity[68], and acute kidney injury. In animal studies, USCs have been shown to differentiate into kidney cells, inhabit inflammatory, fibrosis, apoptosis, and oxidative stress, and promote the repair and regeneration of damaged kidney tissue[68].

4.5 Urethral reconstruction

USCs have been studied for their potential in urethral reconstruction, particularly in cases of urethral stricture. USCs can differentiate into urothelial cells[1,26], endothelial cells[75], and smooth muscle cells[1], which are essential components of the urethral tissue. USCs seeded on biodegradable scaffolds were successfully used to regenerate urethral tissue and improve urethral function in animal model[14]. Rabbit USC-seeded small intestine submucosa (SIS) created a urethral graft that was successfully implanted in a rabbit model[14], leading to improved urethral function.

4.6 Bladder diseases

USC-seeded SIS scaffold enhanced rapid endothelium healing and smooth muscle regeneration in vivo experiment of bladder regeneration model[84]. The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches. In addition, a more recent study demonstrated a protective effect of USCs on bladder function and remodeling in a rodent model of partial bladder outlet obstruction[85]. USCs therapy improved bladder compliance and maximal voiding pressure declined end-filling pressure and voided volume, enhanced detrusor muscle contractility and carbachol sensitivity, and reduced collagen deposition and muscle cell apoptosis in bladder tissue.

Overall, USCs offer a promising treatment option for various urological disorders. While more research is needed to fully understand the potential of these stem cells and optimize their use, early results suggest that they may provide a safe and effective treatment option for patients with urological disorders. Despite being actively studied, clinical application of USCs has not yet been undertaken. Clinical trials will be started in urological disorders after more research on safety and efficacy of USCs are appropriately done.

Current limitations of the USCs application include: (1) Urine samples from women and diabetic patients may have a higher risk of contamination compared to other populations. Female urine samples may contain vaginal bacteria that can contaminate USCs during the collection, isolation, and expansion processes. Similarly, diabetic urine samples may contain high levels of glucose, which can promote bacterial growth and increase the risk of contamination. To minimize the risk of contamination, it is important to use appropriate collection methods, such as sterile collection cups and catheters, and to follow strict isolation and expansion protocols. In addition, it may be necessary to screen urine specimens for potential contaminants and to develop specific protocols for isolating USCs from specimens with high contamination rates. (2) As with any new therapy, safety considerations must be a top priority. While USCs have shown promising results in animal models, there is limited clinical research on the safety and efficacy of USC-based therapies in humans. More research is needed to determine the long-term safety and efficacy of USC-based therapies. (3) Standardization of protocols is needed. To minimize variability in the characteristics and differentiation potential of USCs, it is important to standardize isolation and expansion protocols. Collaboration with experts in related fields such as tissue engineering and regenerative medicine can help maximize the potential of USC-based therapies.

5 CONCLUSION

The key takeaways from this review are that USCs have great potential for the treatment of urological disorders due to their noninvasive collection, low risk of contamination, abundant supply, and ability to differentiate into different cell types. Animal models have shown promising results in regenerating damaged tissues in the treatment of various urological disorders such as urinary incontinence, bladder dysfunction, interstitial cystitis, urethral injury, ED, and kidney injury through multiple differentiation potential, angiogenesis, anti-inflammatory, paracrine effects, and immunomodulatory capacity. However, further research is needed to optimize the potential applications of USCs in urology. Thorough testing and monitoring of USC-based therapies are essential to ensure their safety and efficacy. Future research directions could include investigating the long-term safety and efficacy of USC-based therapies, improving protocols for USCs isolation and expansion, and exploring new avenues for USCs application in the treatment of urological diseases.

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