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RECONSTRUCTIVE
UROLOGY
Improved
sphincter contractility after allogenic muscle-derived progenitor cell
injection into the denervated rat urethra
Cannon TW, Lee JY, Somogyi G, Pruchnic R, Smith CP, Huard J, Chancellor
MB
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania, USA
Urology. 2003; 62: 958-63
- Objectives:
To study the physiologic outcome of allogenic transplant of muscle-derived
progenitor cells (MDPCs) in the denervated female rat urethra.
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Methods:
MDPCs were isolated from muscle biopsies of normal 6-week-old Sprague-Dawley
rats and purified using the preplate technique. Sciatic nerve-transected
rats were used as a model of stress urinary incontinence. The experimental
group was divided into three subgroups: control, denervated plus 20
microL saline injection, and denervated plus allogenic MDPCs (1 to 1.5
106 cells) injection. Two weeks after injection, urethral muscle strips
were prepared and underwent electrical field stimulation. The pharmacologic
effects of d-tubocurare, phentolamine, and tetrodotoxin on the urethral
strips were assessed by contractions induced by electrical field stimulation.
The urethral tissues also underwent immunohistochemical staining for
fast myosin heavy chain and CD4-activated lymphocytes.
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Results:
Urethral denervation resulted in a significant decrease of the maximal
fast-twitch muscle contraction amplitude to only 8.77% of the normal
urethra and partial impairment of smooth muscle contractility. Injection
of MDPCs into the denervated sphincter significantly improved the fast-twitch
muscle contraction amplitude to 87.02% of normal animals. Immunohistochemistry
revealed a large amount of new skeletal muscle fiber formation at the
injection site of the urethra with minimal inflammation. CD4 staining
showed minimal lymphocyte infiltration around the MDPC injection sites.
- Conclusions:
Urethral denervation resulted in near-total abolishment of the skeletal
muscle and partial impairment of smooth muscle contractility. Allogenic
MDPCs survived 2 weeks in sciatic nerve-transected urethra with minimal
inflammation. This is the first report of the restoration of deficient
urethral sphincter function through muscle-derived progenitor cell tissue
engineering. MDPC-mediated cellular urethral myoplasty warrants additional
investigation as a new method to treat stress urinary incontinence.
- Editorial
Comment
The idea to enhance urinary sphincter function by injecting in vitro
cultivated cells into a dysfunctional sphincter is fascinating. This
group as well as others has presented experimental work showing the
possible benefit of such a procedure. The authors are the first ones
to provide a peer reviewed paper on the outcome of injecting in vitro
cultivated progenitor muscle cells. This work is remarkable with regards
to two aspects. Apart from an improvement of urethral sphincter function
by muscle-derived progenitor cell injection, it also demonstrates the
effect of urethral denervation. This denervation resulted not only in
a near total loss of function of the skeletal muscle (i.e. rhabdosphincter)
but also in a partial impairment of smooth muscle contractility. This
confirms clinical findings that autonomic nerve preservation may also
have a beneficial effect on urinary continence.
An improvement in sphincter tonus by injecting autologous muscle derived
progenitor cell injection has been demonstrated previously by another
group (Strasser et al., Eur Urol. 2003; 43: A 350). This work was carried
out in pigs, which in many ways have more similarity to the clinical
situation than rats. However, no peer reviewed published manuscript
exists yet.
As it seems we are entering a new period with regards to the treatment
of stress urinary incontinence. Instead of just injecting bulking agents
or passively closing the urethra with a silicone cuff, we may be able
to restore or improve remnant insufficient rhabdosphincter function.
Dr. Arnulf Stenzl
Professor and Chairman of Urology
Eberhard-Karls-University Tuebingen
Tuebingen, Germany
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