RECONSTRUCTIVE UROLOGY

Apoptosis and effects of intracavernous bone marrow cell injection in a rat model of postprostatectomy erectile dysfunction
Fall PA, Izikki M, Tu L, Swieb S, Giuliano F, Bernabe J, Souktani R, Abbou C, Adnot S, Eddahibi S, Yiou R
Urology Department, Henri Mondor Teaching Hospital, Créteil, France; INSERM Unit 841, Teams 8 and 10, plateforme du petit animal, School of Medicine, Henri Mondor Teaching Hospital, Créteil, France
Eur Urol. 2008; 9. [Epub ahead of print]

• Objectives: To investigate the pathophysiology of postprostatectomy erectile dysfunction (pPED) in a rat model of bilateral cavernous nerve ablation (BCNA) and to assess the effects of local bone marrow mononuclear cell (BMMNC) injection on erectile dysfunction (ED) and cavernosal cellular abnormalities caused by BCNA. Design, Setting, and Participants: This was an experimental study in Fisher rats with BCNA.
• Intervention: Intervention included BNCA, electrical stimulation of the pelvic ganglion, and local BMMNC injection.
• Measurements: Erectile responses to electric pelvic ganglion stimulation were studied. Cavernous tissue was examined to determine the cell types undergoing apoptosis and to detect changes in protein and gene expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) using real-time quantitative polymerase chain reaction (RTQ-PCR) and Western blotting. The effects of local BMMNC injection on these parameters were studied.
• Results and Limitations: Diffuse apoptosis was noted in the connective tissue mesenchymal cells and vascular smooth muscle and endothelial cells. Compared with sham-operated controls, nNOS and eNOS levels were decreased after 3 wk and were normal (eNOS) or increased (nNOS) after 5 wk, suggesting spontaneous nerve regeneration. Despite nNOS recovery, erectile responses to electrical stimulation remained impaired after 5 wk, when mesenchymal cell apoptosis was the main persistent biologic abnormality. BMMNC injection decreased apoptotic cell numbers, accelerated the normalisation of nNOS and eNOS, and partially restored erectile responses at week 5.
• Conclusions: Massive cell apoptosis may play a key role in the pathophysiology of pPED. In this animal model, apoptosis persisted despite spontaneous nerve regeneration, suggesting that the course of BCNA-induced cell dysfunction was independent of reinnervation. BMMNC improved erectile function by inhibiting apoptosis and may hold promise for repairing penile cell damage caused by radical prostatectomy (RP).
  
  
• Editorial Comment
  Erectile dysfunction, which is a result of apoptosis caused by bilateral cavernous nerve ablation, is probably a “worst case scenario” after a radical prostatectomy (1). Even though human nerves cover the prostate surface similar to a net, post-operative erectile dysfunction can occur after an intended nerve sparing (2). The function of this net-like distribution was intraoperatively verified by Kaiho et al. (3). Although impotence following radical prostatectomy is multi-factorial, neurogenic factors also seem to play a major role. The most important prognostic factors for sexual potency recovery after radical prostatectomy are the number of spared nerve fibers, age, and sexual activity prior the surgery.
  Fall and colleagues found in their rat model that bilateral cavernous nerve ablation causes apoptosis predominately in the vimentin +/ a-actin cells and is present throughout the cavernosal bodies, similar to the smooth muscle and the endothelial cells of the cavernosal arteries. With the intracavernosal delivery of bone-marrow mononucleated cells, apoptotic cells will be replaced to recover erectile function (1). This treatment strategy may constitute a promising alternative or complement treatments aimed at stimulating nerve regeneration similar to the recently reported testis stem cells that were differentiated into cells of all three germ layers (4).
  The findings to protect corporal function noted by Fall et al. are not only relevant as a possible treatment immediately after radical prostatectomy, but also may be important for the aging but still sexually active patient. The improved knowledge of the nerve concourses will help to protect function [Sievert et al. Urology 2009, accepted for publication; scheduled for publication in March 2009] which might additionally minimize the erectile dysfunction with intracorporal injected bone-marrow mononucleated cells (2).

References
1. Fall PA, Izikki M, Tu L, Swieb S, Giuliano F, Bernabe J, et al.: Apoptosis and Effects of Intracavernous Bone Marrow Cell Injection in a Rat Model of Postprostatectomy Erectile Dysfunction. Eur Urol. 2008; 9. [Epub ahead of print]
2. Sievert KD, Hennenlotter J, Laible I, Amend B, Schilling D, Anastasiadis A, et al.: The periprostatic autonomic nerves-bundle or layer? Eur Urol. 2008; 54: 1109-17.
3. Kaiho Y, Nakagawa H, Saito H, Ito A, Ishidoya S, Saito S, et al.: Nerves at the Ventral Prostatic Capsule Contribute to Erectile Function: Initial Electrophysiological Assessment in Humans. Eur Urol. 2008; 24. [Epub ahead of print]
4. Conrad S, Renninger M, Hennenlotter J, Wiesner T, Just L, Bonin M, et al.: Generation of pluripotent stem cells from adult human testis. Nature. 2008; 456: 344-9.

Dr. Karl-Dietrich Sievert &
Dr. Arnulf Stenzl
Department of Urology
Eberhard-Karls-University Tuebingen
Tuebingen, Germany
E-mail: arnulf.stenzl@med.uni-tuebingen.de