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The mechanisms and potential of stem cell therapy for penile fibrosis

Nature Reviews Urology volume 16, pages 79–97 (2019)Cite this article

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Abstract

Fibrosis is often caused by chronic tissue injury leading to a persisting inflammatory response with excessive accumulation of extracellular connective tissue proteins. Peyronie’s disease, urethral stricture and penile (corpora cavernosa) fibrosis are localized fibrotic disorders of the penile connective tissues that can substantially impair a patient’s quality of life. Research over the past few decades has revealed the ability of stem cells to secrete a wide range of paracrine factors, a characteristic that could be exploited therapeutically to prevent and treat several inflammatory and fibrotic diseases. In preclinical studies, mesenchymal stem cells (MSCs) have proven to be the most effective and readily available type of stem cells for therapeutic use. An important advantage of MSCs is their ability to circumvent the immune system and function as immunomodulatory ‘drug stores’ to influence multiple cell types simultaneously. Many studies using stem cells have been applied exclusively to corpora cavernosa fibrosis owing to its well-established disease models. A plethora of preclinical data suggest the benefit of stem cells for use in penile fibrosis. However, their exact mechanism of action and optimal timing and mode of administration must be determined before clinical translation.

Key points

  • Fibrosis is a state of excessive wound-healing leading to the replacement of the local parenchyma with stiff and afunctional extracellular matrix, resulting in loss of organ function in advanced stages.

  • Owing to the complex network of cell types and interactions involved in fibrosis, very few effective medical treatment options are currently available for patients with fibrotic diseases, including penile fibrosis.

  • Stem cells can interrupt several key processes in the fibrotic cascade simultaneously and, therefore, have great potential as novel antifibrotic therapies.

  • Penile fibrosis can occur in the corpora cavernosa, tunica albuginea or urethra.

  • A large number of preclinical studies have investigated the effect of stem cells for the treatment of penile fibrosis, and have reported encouraging results.

  • Certain limitations (such as isolation, timing, administration and dosage) need to be addressed before preclinical findings can be translated into the clinical setting.

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Fig. 1: Overview of the wound-healing process and fibrosis.
Fig. 2: Penile fibrosis.
Fig. 3: Pro-inflammatory and anti-inflammatory MSC phenotypes.
Fig. 4: The origin of myofibroblasts.

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Acknowledgements

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Nature Reviews Urology thanks I. Kovanecz and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium

    Uros Milenkovic, Maarten Albersen & Fabio Castiglione

  2. The Institute of Urology, University College of London Hospital (UCLH), London, UK

    Fabio Castiglione

  3. Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy

    Fabio Castiglione

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Glossary

Tunica albuginea

The connective tissue sheath surrounding the erectile tissue (corpora cavernosa) of the penis.

Corpora cavernosa

Sponge-like regions of the erectile tissue that contain most of the blood during a penile erection. (Singular: corpus cavernosum).

Priapism

A condition whereby the penis remains in an erectile state without any stimulation, or after the stimulation has ended, for more than 4 hours.

Mesenchymal stem cells

(MSCs). Multipotent stromal cells with the ability to differentiate into several cell types within their germ layer (osteoblasts, chondrocytes, myocytes and adipocytes).

Corpus spongiosum

Spongy tissue surrounding the male urethra within the penis.

Totipotent stem cells

These stem cells have the capacity to divide and develop into cells from all three germ cell layers and into extra-embryonic tissues (for example, placenta). The zygote is an example of such a cell.

Pluripotent stem cells

These stem cells have the capacity to divide and develop into cells from all three germ cell layers, but not into extra-embryonic tissues (for example, placenta). Embryonic stem cells are examples of such cells.

Multipotent stem cells

These stem cells have the capacity to divide and develop into cells from a specific tissue or organ. Most adult stem cells are examples of such cells.

Neuropraxia

Temporary loss of motor and/or sensory function in a nerve from the peripheral nervous system as a result of impaired nerve conduction. Neuropraxia usually recovers fully after 6–8 weeks.

Wallerian degeneration

Active nerve degeneration resulting from a nerve being cut or crushed, whereby the axonal tail distal to the damage (furthest from the neuronal body) degenerates.

Space of Smith

A vascular, loose, areolar connective tissue sleeve that separates the corpus cavernosum from the tunica albuginea.

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Milenkovic, U., Albersen, M. & Castiglione, F. The mechanisms and potential of stem cell therapy for penile fibrosis. Nat Rev Urol 16, 79–97 (2019). https://doi.org/10.1038/s41585-018-0109-7

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