Guiting Lin1, Amanda B Reed-Maldonado1, Bohan Wang2, Yung-Chin Lee3, Jun Zhou4, Zhihua Lu5, Guifang Wang1, Lia Banie1, Tom F Lue6. 1. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA. 2. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, The Second Hospital, Zhejiang University, Zhejiang, China. 3. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, Kaohsiung Medical University Hospital, and Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, The Third XiangYa Hospital, Central South University, Changsha, China. 5. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA; Department of Urology, The First Hospital of Jilin University, Changchun, China. 6. Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California-San Francisco, San Francisco, CA, USA. Electronic address: Tom.Lue@ucsf.edu.
Abstract
BACKGROUND: We previously reported that progenitor cells, or stem cells, exist within penile tissue. We hypothesized that acoustic wave stimulation by low-intensity extracorporeal shockwave therapy (Li-ESWT) would activate local stem or progenitor cells within the penis, producing regenerative effects. AIMS: To study the feasibility of in situ penile progenitor cell activation by Li-ESWT. METHODS: We performed a cohort analysis of young and middle-age male Sprague-Dawley rats treated with 5-ethynyl-2'-deoxyuridine (EdU) pulse followed by Li-ESWT. In addition, Li-ESWT was applied to cultured Schwann cells and endothelial cells to study the molecular mechanism involved in cell proliferation. Thirty minutes before Li-ESWT, each rat received an intraperitoneal injection of EdU. Li-ESWT was applied to the penis at very low (0.02 mJ/mm2 at 3 Hz for 300 pulses) or low (0.057 mJ/mm2 at 3 Hz for 500 pulses) energy levels. The endothelial and Schwann cells were treated with very low energy (0.02 mJ/mm2 at 3 Hz for 300 pulses) in vitro. OUTCOMES: At 48 hours or 1 week after Li-ESWT, penile tissues were harvested for histologic study to assess EdU+ and Ki-67+ cells, and cell proliferation, Ki-67 expression, Erk1/2 phosphorylation, translocation, and angiogenesis were examined in cultured Schwann and endothelial cells after Li-ESWT. RESULTS: Li-ESWT significantly increased EdU+ cells within penile erectile tissues (P < .01) at 48 hours and 1 week. There were more cells activated in young animals than in middle-age animals, and the effect depended on dosage. Most activated cells were localized within subtunical spaces. In vitro studies indicated that Li-ESWT stimulated cell proliferation through increased phosphorylation of Erk1/2. CLINICAL TRANSLATION: The present results provide a possible explanation for the clinical benefits seen with Li-ESWT. STRENGTHS AND LIMITATIONS: The main limitation of the present project was the short period of study and the animal model used. Li-ESWT could be less effective in improving erectile function in old animals because of the decreased number and quality of penile stem or progenitor cells associated with aging. CONCLUSION: Li-ESWT activation of local penile progenitor cells might be one of the mechanisms that contribute to the beneficial effects of shockwave treatment for erectile dysfunction, which represents a non-invasive alternative to exogenous stem cell therapy. Lin G, Reed-Maldonado AB, Wang B, et al. In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy. J Sex Med 2017;14:493-501.
BACKGROUND: We previously reported that progenitor cells, or stem cells, exist within penile tissue. We hypothesized that acoustic wave stimulation by low-intensity extracorporeal shockwave therapy (Li-ESWT) would activate local stem or progenitor cells within the penis, producing regenerative effects. AIMS: To study the feasibility of in situ penile progenitor cell activation by Li-ESWT. METHODS: We performed a cohort analysis of young and middle-age male Sprague-Dawley rats treated with 5-ethynyl-2'-deoxyuridine (EdU) pulse followed by Li-ESWT. In addition, Li-ESWT was applied to cultured Schwann cells and endothelial cells to study the molecular mechanism involved in cell proliferation. Thirty minutes before Li-ESWT, each rat received an intraperitoneal injection of EdU. Li-ESWT was applied to the penis at very low (0.02 mJ/mm2 at 3 Hz for 300 pulses) or low (0.057 mJ/mm2 at 3 Hz for 500 pulses) energy levels. The endothelial and Schwann cells were treated with very low energy (0.02 mJ/mm2 at 3 Hz for 300 pulses) in vitro. OUTCOMES: At 48 hours or 1 week after Li-ESWT, penile tissues were harvested for histologic study to assess EdU+ and Ki-67+ cells, and cell proliferation, Ki-67 expression, Erk1/2 phosphorylation, translocation, and angiogenesis were examined in cultured Schwann and endothelial cells after Li-ESWT. RESULTS: Li-ESWT significantly increased EdU+ cells within penile erectile tissues (P < .01) at 48 hours and 1 week. There were more cells activated in young animals than in middle-age animals, and the effect depended on dosage. Most activated cells were localized within subtunical spaces. In vitro studies indicated that Li-ESWT stimulated cell proliferation through increased phosphorylation of Erk1/2. CLINICAL TRANSLATION: The present results provide a possible explanation for the clinical benefits seen with Li-ESWT. STRENGTHS AND LIMITATIONS: The main limitation of the present project was the short period of study and the animal model used. Li-ESWT could be less effective in improving erectile function in old animals because of the decreased number and quality of penile stem or progenitor cells associated with aging. CONCLUSION: Li-ESWT activation of local penile progenitor cells might be one of the mechanisms that contribute to the beneficial effects of shockwave treatment for erectile dysfunction, which represents a non-invasive alternative to exogenous stem cell therapy. Lin G, Reed-Maldonado AB, Wang B, et al. In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy. J Sex Med 2017;14:493-501.
Authors: Hsun Shuan Wang; Yajun Ruan; Lia Banie; Kai Cui; Ning Kang; Dongyi Peng; Tianshu Liu; Tianyu Wang; Bohan Wang; Guifang Wang; Alan W Shindel; Guiting Lin; Tom F Lue Journal: J Sex Med Date: 2018-12-01 Impact factor: 3.802
Authors: Dongyi Peng; Amanda B Reed-Maldonado; Feng Zhou; Yan Tan; Huixing Yuan; Lia Banie; Guifang Wang; Yuxin Tang; Leye He; Guiting Lin; Tom F Lue Journal: J Sex Med Date: 2020-07-12 Impact factor: 3.802
Authors: Xiaoyu Zhang; Yajun Ruan; Alex K Wu; Uwais Zaid; Jaqueline D Villalta; Guifang Wang; Lia Banie; Amanda B Reed-Maldonado; Guiting Lin; Tom F Lue Journal: Urology Date: 2020-04-10 Impact factor: 2.649