Erectile dysfunction (ED) is a common health problem in the U.S. Approximately 20 million men in the United States suffer from ED with tens of thousands of new cases diagnosed every year, in addition to being a serious quality of life issue ED is also a sentinel event for potentially lethal conditions such as coronary artery disease. Penile erection is a complex process involving psychological, hormonal, neural, and vascular input. Any disease or condition that affects the relevant systems can cause ED. The most common risk factors for ED in the United States include diabetes, hypertension, hyperiipidemia, cardiac disease, tobacco use, pelvic surgery, and renal failure. In the current funding period we studied growth factor regulation of erectile nerve injury and recovery. We demonstrated that brain derived neurotrophic factor (BDNF) is upregulated in the penis after cavernous nerve injury and can be transported by retrograde axonal transport to the major pelvic ganglion (MPG). We demonstrated that BDNF and VEGF enhance neurite growth in vitro and that the combination of these agents is very effective at enhancing neurite growth from MPGs derived from rats. In in vivo studies, we demonstrated that intracavernous injection of BDNF and vascular endothelial growth factor (VEGF) minimized ED after cavernous nerve injury in rat models. We further demonstrated that BDNF activates the JAK/STAT pathway in the MPG and penis of these animals with two distinct periods of increased activation. Immunohistochemistry and molecular biology studies indicated increased preservation and regeneration of nNOS containing nerve fibers in the penis of these rats. This neuroprotective effect likely plays a key role in restoring erectile function in these animals. Similar protective effects on erectile function and nNOS nerves were noted with intracavernous injection of insulin-like growth factor-1 (IGF-1), neurturin, FK1706, and Growth and Differentiation Factor 5 (GDF-5) at the time of cavernous nerve injury. Unfortunately, obtaining human grade growth factors for a human study ofthese compounds was prohibitively difficult. We have subsequently focused the efforts of our lab on stem cell therapy for ED. We demonstrated that intracavernous injection of embryonic stem cells preserves erectile function after cavernous nerve injury in rats. Due to concerns about embryonic stem cell use, we subsequently elected to focus on autologous somatic stem cells. We have made several important discoveries on the biology of stem cells derived from adipose tissue. Based on immunohistochemical studies for known stem cell markers, these adipose derived stem cells (ADSC) have been demonstrated to have a wide range of differentiation capacity. We have demonstrated that ADSC have the capacity to differentiate into neuron-like cells, endothelial cells, muscle cells, albumin-producing hepatocytes and insulin-producing beta cells when properly induced. We have also discovered that fibroblast growth factor 2 (FGF2) is expressed in ADSC but expression of the protein goes down after cellular differentiation, leading us to conclude that FGF2 plays an important role in regulating ADSC differentiation. Several specific microRNAs are upregulated in ADSC after differentiation, suggesting that microRNA may be very important in fine tuning the differentiation response. Intracavernous injection of autologous ADSC at the .time of cavernous nerve crush injury in rats has been shown to enhance erectile response post-injury;enhanced nNOS nerve fiber staining was detected in the penile tissues of these treated animals. ADSC were also effective in reversing ED and decreasing cellular markers for apoptosis in diabetic animals who received this treatment by intracavernous injection. In the next funding period, we propose to study regulation of ADSC differentiation by FGF2 and micro RNAs. We will also further study the efficacy and long-term safety of these cells as a treatment for ED. Our ultimate goal is to use ADSC to treat not only various types of ED but also other degenerative diseases such as diabetes, urinary incontinence, and cardiovascular disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-UROL (01))
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Rankin, Tracy L
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University of California San Francisco
Schools of Medicine
San Francisco
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Lu, Zhihua; Lin, Guiting; Reed-Maldonado, Amanda et al. (2017) Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A Systematic Review and Meta-analysis. Eur Urol 71:223-233
Lin, Guiting; Reed-Maldonado, Amanda B; Wang, Bohan et al. (2017) In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy. J Sex Med 14:493-501
Lin, Guiting; Zhang, Haiyang; Sun, Fionna et al. (2016) Brain-derived neurotrophic factor promotes nerve regeneration by activating the JAK/STAT pathway in Schwann cells. Transl Androl Urol 5:167-75
Lin, Guiting; Alwaal, Amjad; Zhang, Xiaoyu et al. (2015) Presence of stem/progenitor cells in the rat penis. Stem Cells Dev 24:264-70
Alwaal, Amjad; Hussein, Ahmed Aly; Zaid, Uwais B et al. (2015) Management of Peyronie's disease after collagenase (Xiaflex:®). Curr Drug Targets 16:484-94
Ning, Hongxiu; Lei, Hong-En; Xu, Yong-De et al. (2014) Conversion of adipose-derived stem cells into natural killer-like cells with anti-tumor activities in nude mice. PLoS One 9:e106246
Lin, Ching-Shwun; Xin, Zhongcheng; Dai, Jican et al. (2013) Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther 13:1585-97
Lin, Ching-Shwun; Lue, Tom F (2013) Defining vascular stem cells. Stem Cells Dev 22:1018-26
Lin, Ching-Shwun; Albersen, Maarten; Xin, Zhongcheng et al. (2013) Phosphodiesterase-5 expression and function in the lower urinary tract: a critical review. Urology 81:480-7
Lin, Ching-Shwun; Xin, Zhong-Cheng; Dai, Jican et al. (2013) Commonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges. Histol Histopathol 28:1109-16

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