J Sex Med. 2012 Jul;9(7):1834-41. doi: 10.1111/j.1743-6109.2012.02753.x. Epub 2012 Apr 30.
Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction.
1Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143-0738, USA.
Radiation therapy (RT) for prostate cancer is frequently associated with posttreatment erectile dysfunction (ED).
To investigate whether injection of adipose-derived stem cells (ADSCs) can ameliorate RT-associated ED.
Thirty male rats were divided into three groups. The control + phosphate-buffered saline (PBS) group received tail-vein injection of PBS. The radiation + PBS group received radiation over the prostate and tail-vein injection of PBS. The radiation + ADSC group received radiation over the prostate and tail-vein injection of ADSCs, which were labeled with 5-ethynyl-2-deoxyuridine (EdU). Seventeen weeks later,erectile function was evaluated by intracavernous pressure (ICP) in response to electrostimulation of cavernous nerves (CNs). Penile tissue and major pelvic ganglia (MPG) were examined by immunofluorescence (IF) and EdU staining.
MAIN OUTCOME MEASURES:
Erectile function was measured by ICP. Protein expression was examined by IF, followed by image analysis and quantification.
Radiation over the prostate caused a significant decrease in erectile function and in the expression of neuronal nitric oxide synthase (nNOS) in penis and MPG. Cavernous smooth muscle (CSM) but not endothelial content was also reduced. Injection of ADSCs significantly restored erectile function, nNOS expression, and CSM content in the irradiated rats. EdU-positive cells were visible in MPG.
Radiation appears to cause ED via CN injury. ADSC injection can restore erectile function via CN regeneration.
Int J Urol. 2014 Dec;21(12):1280-5. doi: 10.1111/iju.12585. Epub 2014 Jul 30.
Mesenchymal stem cell therapy in treatment of erectile dysfunction: autologous or allogeneic cell sources?
1Department of Urology, Marmara University School of Medicine, Istanbul, Turkey.
To compare the efficacy of intracavernosal injection of autologous and allogeneic mesenchymal stem cells as potential treatment of erectile dysfunction in an experimental rat model.
Mesenchymal stem cells were isolated from rat paratesticular fat tissue. Bilateral cavernous nerve injury was carried out followed by immediate intracavernosal injection of either autologous or allogeneic mesenchymal stem cells or mesenchymal stem cell lysates. One month after injection, erectile function was evaluated by means of intracavernosal pressure measurement. All rats were eventually killed, and penile tissues were taken for immunhistochemical and molecular investigation.
A total of 36 Sprague-Dawley rats were used. The mean maximum intracavernosal pressure in the sham-operated, autologous and allogeneic mesenchymal stem cell injection groups were significantly better compared with the vehicle injection group (80.5 [3.56], 71.1 [2.9] and 69.2 [3.2] vs 40.33 [4.4], respectively). Mean maximum intracavernosal pressure to mean arterial pressure ratios in the autologous and allogeneicmesenchymal stem cell and mesenchymal stem cell lysate injection groups were not significantly different.
Intracavernosal injection of both autologous or allogeneic mesenchymal stem cells improve erectile functions in a rat model of cavernous nerve injury. Allogeneic mesenchymal stem cells might provide clinicians with ready to use, standardized and, in certain cases, more effective products. More studies focusing on long-term immunological aspects of allogeneic mesenchymal stem cells are required.
adipose derived; allogeneic; autologous; mesenchymal stem cells; neurogenic erectile dysfunction
J Sex Med. 2010 Jan;7(1 Pt 1):89-98.
Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells.
1Department of Urology, University of California School of Medicine-Knuppe Molecular Urology Laboratory, San Francisco, CA 94143-0738, USA.
Erectile dysfunction (ED) is a major complication of type 2 diabetes, and many diabetic men with ED are refractory to common ED therapies.
To determine whether autologous adipose tissue-derived stem cells (ADSCs) injected into the penis of impotent type 2 diabetic rats improveerectile function.
MAIN OUTCOME MEASURES:
Blood glucose levels, intracavernous pressure (ICP) increase upon cavernous nerve (CN) electrostimulation, and immunohistochemistry.
Twenty-two male Zucker diabetic fatty (ZDF) rats were used. At 22 weeks of age, all the animals underwent unilateral CN electrostimulation and ICP measurement to confirm impotence. Paragonadal adipose tissue was harvested to procure ADSCs. The impotent animals were randomized to ADSC treatment and sham control groups. At 23 weeks of age, the treatment group animals underwent a penile injection of 1 million ADSCs; the control group animals received vehicle only. Erectile function studies were repeated at 26 weeks of age, followed by tissue harvest.
The rats developed diabetes within the first 10 weeks of age. At 22 weeks of age, 20 out of the 22 rats presented with ED. The post-treatment ICP increase during CN stimulation and ICP increase/mean arterial pressure were significantly higher in the treatment group compared with controls. Three weeks after injection into the corpus cavernosum, only a small number of BrdU-labeled ADSCs was detectable within corporaltissue of the treatment group. There was a significant increase in neuronal nitric oxide synthase (nNOS) in the penile dorsal nerve and in the number of endothelial cells in the corpora cavernosa of the rats in the treatment group.
Autologous ADSCs injected into the penis were effective to improve erectile function and to alter the microarchitecture of the corpus cavernosum. Since the number of ADSCs retained in the corpus cavernosum is very small, we postulate that their paracrine function, not trans-differentiation to smooth muscle or endothelial cells, is responsible for the improvement in penile function.
EBioMedicine. 2016 Mar 19. doi: http://dx.doi.org/10.1016/j.ebiom.2016.01.024
Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial
Haahr MK1,5,6, Jensen CH2,5, Toyserkani NM3,5,6, Andersen DC2,5,6, Damkier P2,6, Sorensen JA3,5,6, Lund L1,5,6, Skeikh SP2,4,5.
1Department of Urology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark
2Laboratory of Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
3Department of Plastic Surgery, Odense University Hospital, Odense, Denmark
4Institute of Molecular Medicine, University of Southern Denmark, Winsloewparken 21 3rd, 5000 Odense C, Denmark
5The Danish Centre for Regenerative Medicine (www.danishcrm.com); Odense University Hospital, Denmark
6Clinical Institute, University of Southern Denmark, 5000 Odense C, Denmark
Prostate cancer is the most common cancer in men, and radical prostatectomy (RP) often results in erectile dysfunction (ED) and a substantially reduced quality of life. The efficacy of current interventions, principal treatment with PDE-5 inhibitors, is not satisfactory and this condition presents an unmet medical need. Preclinical studies using adipose-derived stem cells to treat ED have shown promising results. Herein, we report the results of a human phase 1 trial with autologous adipose-derived regenerative cells (ADRCs) freshly isolated after a liposuction.
Seventeen men suffering from post RP ED, with no recovery using conventional therapy, were enrolled in a prospective phase 1 open-label and single-arm study. All subjects had RP performed 5–18 months before enrolment, and were followed for 6 months after intracavernosal transplantation. ADRCs were analyzed for the presence of stem cell surface markers, viability and ability to differentiate. Primary endpoint was the safety and tolerance of the cell therapy while the secondary outcome was improvement of erectile function. Any adverse events were reported and erectile function was assessed by IIEF-5 scores. The study is registered with ClinicalTrials.gov, NCT02240823.
Intracavernous injection of ADRCs was well-tolerated and only minor events related to the liposuction and cell injections were reported at the one-month evaluation, but none at later time points. Overall during the study period, 8 of 17 men recovered their erectile function and were able to accomplish sexual intercourse. Post-hoc stratification according to urinary continence status was performed. Accordingly, for continent men (median IIEFinclusion = 7 (95% CI 5–12), 8 out of 11 men recovered erectile function (IIEF6months = 17 (6–23)), corresponding to a mean difference of 0.57 (0.38–0.85; p = 0.0069), versus inclusion. In contrast, incontinent men did not regain erectile function (median IIEF1/3/6 months = 5 (95% CI 5–6); mean difference 1 (95% CI 0.85–1.18), p > 0.9999).
In this phase I trial a single intracavernosal injection of freshly isolated autologous ADRCs was a safe procedure. A potential efficacy is suggested by a significant improvement in IIEF-5 scores and erectile function. We suggest that ADRCs represent a promising interventional therapy of ED following prostatectomy.
Journal of Translational Medicine. 2013 jun 9. doi: 10.1186/1479-5876-11-139
Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction?
Ichim TE1, Warbington T2, Cristea O3, Chin JL3, Patel AN4.
1Institute for Molecular Medicine, Huntington Beach, CA, USA
2Creative Medical Health Inc, 2007 W Peoria Avenue, Phoenix AZ 85029, USA
3University of Western Ontario, London, Canada
4University of Utah, Salt Lake City, UT, USA
While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.