Karl-Erik Andersson et al., 2024: Cellular regenerative therapy in stress urinary incontinence: new frontiers?-a narrative review

Tuesday, 19 November 2024

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Karl-Erik Andersson 1 2, Koudy Williams 1
1Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
2Institute for Laboratory Medicine, Lund University, Lund, Sweden.

Abstract

Background and objective: Even if treatment with stem cells has been shown to be safe and effective in many patients with stress urinary incontinence (SUI), there is still room for improvement using other regenerative medicine alternatives. Since the beneficial effects of stem cells are probably mediated by secretion of factors rather than by the cells themselves there is a good rationale for further exploring the therapeutic effects of the secretome and/or its components. However, homing factors such as stromal derived growth factor 1 (SDF-1; CXCL12), stimulation of stem cell growth and stem cell mobilization in vivo using low intensity shock wave therapy (Li-ESWT) or regenerative electrical stimulation (RES), are also promising approaches.

Methods: A literature search was performed based on PubMed, Scopus and Google Scholar. The search criteria included original basic science articles, systematic reviews and randomized control trials. All studies were published between 2000 and 2023. Selected, peer-reviewed studies were further analyzed to identify those of relevance. Keywords searched included: "female stress incontinence", "homing factors", "CXCL12", "secretome", "low intensity shockwave therapy" and "regenerative electrical stimulation". The peer-reviewed publications on the key word subjects that contained a novel addition to the existing body of literature were included.

Key content and findings: There is evidence from studies on non-human primates (NHPs) with experimental urinary sphincter injury that CXCL12 can restore sphincter structure and function. Studies with homing factors in human patients with SUI are still to be performed. A large number of clinical studies on the use of secretome or secretome products from mesenchymal stem cells (MSCs) on indications other than human SUI are already available. However, controlled clinical trials on patients with SUI, have to the best of our knowledge, not yet been performed. Also, RES has not been studied in patients with SUI. In contrast, there is clinical evidence that Li-ESWT may improve female SUI.

Conclusions: Treatment with homing factors, MSC secretome/secretome components, Li-ESWT and RES are promising frontiers in the treatment of human SUI caused by sphincter damage.

Transl Androl Urol. 2024 Aug 31;13(8):1709-1716. doi: 10.21037/tau-22-682. Epub 2023 Jul 24.
PMID: 39280677 PMCID: PMC11399031

Comments 1

Jens Rassweiler on Tuesday, 19 November 2024 10:00

This review article explores emerging therapies for treating female stress urinary incontinence (SUI), focusing on cellular regenerative approaches, particularly mesenchymal stem cells (MSCs) and the factors they secrete. SUI often results from a combination of weakened pelvic support and impaired urethral sphincter function, but traditional treatments like drug therapy and surgical options have limitations, including adverse effects and the risk of recurrence. Consequently, researchers are investigating non-surgical alternatives, such as stem cell therapy (SCT) and regenerative electrical and shockwave therapies, which show potential for tissue repair and function restoration in SUI patients.
Key Points and Emerging Therapies:
1. Stem Cell Therapy (SCT): Studies have shown SCT’s efficacy in SUI treatment, notably with MSCs derived from muscle or adipose tissue, which exhibit promising regenerative properties. MSCs are known to promote tissue repair through their "secretome"—bioactive molecules that possess anti-inflammatory, anti-fibrotic, and angiogenic effects, aiding in tissue healing without requiring direct integration with host tissues.
2. Homing Factors and Cytokines: MSCs are guided by chemotactic factors like CXCL12, which draws them to injury sites. Some studies suggest that even in the absence of actual stem cells, secreted cytokines (e.g., CXCL12 and CCL7) can foster tissue repair by attracting endogenous repair cells. Research has demonstrated this concept in animal models, where CXCL12 and related factors supported sphincter structure and function recovery in SUI.
3. Secretomes: The MSC secretome, composed of proteins, exosomes, and microvesicles, may present an alternative to stem cell transplantation. These secreted elements can promote tissue repair independently, which could simplify treatment by eliminating the need for live cell manipulation and immune considerations. In animal models, secretome treatments have improved SUI-related outcomes, suggesting their potential as a standalone therapy.
4. Low-Intensity Shock Wave Therapy (Li-ESWT): Li-ESWT has shown promising results in clinical trials for SUI, improving urinary leakage and quality of life by stimulating cellular repair processes. This therapy may enhance the body’s regenerative response by recruiting and activating progenitor cells, promoting angiogenesis, and mitigating fibrosis. Recent studies indicate, that Li-ESWT may also stimulate stem cells (Lin & Lue 2024).
5. Regenerative Electrical Stimulation (RES): Although not yet tested clinically for SUI, RES could encourage nerve regeneration and potentially restore continence after childbirth-induced injury by promoting neurotrophic factor release. Preclinical studies in animal models indicate that targeted electrical stimulation of nerves might improve urethral function following injury.
Conclusions: While stem cell-based therapies remain promising for SUI, secretome-based approaches, Li-ESWT, and RES offer non-invasive alternatives that bypass the complexities of cell-based treatments. This may become a very important arm of regenerative therapy.
Further clinical trials are necessary to validate these innovative therapies' safety and effectiveness in human SUI patients. This research direction offers a promising future for non-surgical SUI management, aiming for improved patient outcomes with reduced side effects and greater treatment accessibility.

Jens Rassweiler

This review article explores emerging therapies for treating female stress urinary incontinence (SUI), focusing on cellular regenerative approaches, particularly mesenchymal stem cells (MSCs) and the factors they secrete. SUI often results from a combination of weakened pelvic support and impaired urethral sphincter function, but traditional treatments like drug therapy and surgical options have limitations, including adverse effects and the risk of recurrence. Consequently, researchers are investigating non-surgical alternatives, such as stem cell therapy (SCT) and regenerative electrical and shockwave therapies, which show potential for tissue repair and function restoration in SUI patients.
Key Points and Emerging Therapies:
1.	Stem Cell Therapy (SCT): Studies have shown SCT’s efficacy in SUI treatment, notably with MSCs derived from muscle or adipose tissue, which exhibit promising regenerative properties. MSCs are known to promote tissue repair through their "secretome"—bioactive molecules that possess anti-inflammatory, anti-fibrotic, and angiogenic effects, aiding in tissue healing without requiring direct integration with host tissues.
2.	Homing Factors and Cytokines: MSCs are guided by chemotactic factors like CXCL12, which draws them to injury sites. Some studies suggest that even in the absence of actual stem cells, secreted cytokines (e.g., CXCL12 and CCL7) can foster tissue repair by attracting endogenous repair cells. Research has demonstrated this concept in animal models, where CXCL12 and related factors supported sphincter structure and function recovery in SUI.
3.	Secretomes: The MSC secretome, composed of proteins, exosomes, and microvesicles, may present an alternative to stem cell transplantation. These secreted elements can promote tissue repair independently, which could simplify treatment by eliminating the need for live cell manipulation and immune considerations. In animal models, secretome treatments have improved SUI-related outcomes, suggesting their potential as a standalone therapy.
4.	Low-Intensity Shock Wave Therapy (Li-ESWT): Li-ESWT has shown promising results in clinical trials for SUI, improving urinary leakage and quality of life by stimulating cellular repair processes. This therapy may enhance the body’s regenerative response by recruiting and activating progenitor cells, promoting angiogenesis, and mitigating fibrosis. Recent studies indicate, that Li-ESWT may also stimulate stem cells (Lin & Lue 2024).
5.	Regenerative Electrical Stimulation (RES): Although not yet tested clinically for SUI, RES could encourage nerve regeneration and potentially restore continence after childbirth-induced injury by promoting neurotrophic factor release. Preclinical studies in animal models indicate that targeted electrical stimulation of nerves might improve urethral function following injury.
Conclusions: While stem cell-based therapies remain promising for SUI, secretome-based approaches, Li-ESWT, and RES offer non-invasive alternatives that bypass the complexities of cell-based treatments. This may become a very important arm of regenerative therapy.
Further clinical trials are necessary to validate these innovative therapies' safety and effectiveness in human SUI patients. This research direction offers a promising future for non-surgical SUI management, aiming for improved patient outcomes with reduced side effects and greater treatment accessibility.

Jens Rassweiler

This review article explores emerging therapies for treating female stress urinary incontinence (SUI), focusing on cellular regenerative approaches, particularly mesenchymal stem cells (MSCs) and the factors they secrete. SUI often results from a combination of weakened pelvic support and impaired urethral sphincter function, but traditional treatments like drug therapy and surgical options have limitations, including adverse effects and the risk of recurrence. Consequently, researchers are investigating non-surgical alternatives, such as stem cell therapy (SCT) and regenerative electrical and shockwave therapies, which show potential for tissue repair and function restoration in SUI patients. Key Points and Emerging Therapies: 1. Stem Cell Therapy (SCT): Studies have shown SCT’s efficacy in SUI treatment, notably with MSCs derived from muscle or adipose tissue, which exhibit promising regenerative properties. MSCs are known to promote tissue repair through their "secretome"—bioactive molecules that possess anti-inflammatory, anti-fibrotic, and angiogenic effects, aiding in tissue healing without requiring direct integration with host tissues. 2. Homing Factors and Cytokines: MSCs are guided by chemotactic factors like CXCL12, which draws them to injury sites. Some studies suggest that even in the absence of actual stem cells, secreted cytokines (e.g., CXCL12 and CCL7) can foster tissue repair by attracting endogenous repair cells. Research has demonstrated this concept in animal models, where CXCL12 and related factors supported sphincter structure and function recovery in SUI. 3. Secretomes: The MSC secretome, composed of proteins, exosomes, and microvesicles, may present an alternative to stem cell transplantation. These secreted elements can promote tissue repair independently, which could simplify treatment by eliminating the need for live cell manipulation and immune considerations. In animal models, secretome treatments have improved SUI-related outcomes, suggesting their potential as a standalone therapy. 4. Low-Intensity Shock Wave Therapy (Li-ESWT): Li-ESWT has shown promising results in clinical trials for SUI, improving urinary leakage and quality of life by stimulating cellular repair processes. This therapy may enhance the body’s regenerative response by recruiting and activating progenitor cells, promoting angiogenesis, and mitigating fibrosis. Recent studies indicate, that Li-ESWT may also stimulate stem cells (Lin & Lue 2024). 5. Regenerative Electrical Stimulation (RES): Although not yet tested clinically for SUI, RES could encourage nerve regeneration and potentially restore continence after childbirth-induced injury by promoting neurotrophic factor release. Preclinical studies in animal models indicate that targeted electrical stimulation of nerves might improve urethral function following injury. Conclusions: While stem cell-based therapies remain promising for SUI, secretome-based approaches, Li-ESWT, and RES offer non-invasive alternatives that bypass the complexities of cell-based treatments. This may become a very important arm of regenerative therapy. Further clinical trials are necessary to validate these innovative therapies' safety and effectiveness in human SUI patients. This research direction offers a promising future for non-surgical SUI management, aiming for improved patient outcomes with reduced side effects and greater treatment accessibility. Jens Rassweiler

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