In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy

Guiting Lin; Amanda B Reed-Maldonado; Bohan Wang; Yung-Chin Lee; Jun Zhou; Zhihua Lu; Guifang Wang; Lia Banie; Tom F Lue

doi:10.1016/j.jsxm.2017.02.004

In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy

J Sex Med. 2017 Apr;14(4):493-501. doi: 10.1016/j.jsxm.2017.02.004. Epub 2017 Mar 1.

Authors

Guiting Lin¹, Amanda B Reed-Maldonado¹, Bohan Wang², Yung-Chin Lee³, Jun Zhou⁴, Zhihua Lu⁵, Guifang Wang¹, Lia Banie¹, Tom F Lue⁶

Affiliations

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.

PMID: 28258952
DOI: 10.1016/j.jsxm.2017.02.004

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.

Keywords: Endogenous Stem Cells; Erectile Dysfunction; Low-Intensity Extracorporeal Shockwave Therapy; Penile Progenitor Cells; Stem Cells.

MeSH terms

Animals
Deoxyuridine / analogs & derivatives*
Deoxyuridine / therapeutic use
Disease Models, Animal
Endothelial Cells / metabolism
Erectile Dysfunction / metabolism
Erectile Dysfunction / therapy*
High-Energy Shock Waves / therapeutic use*
Humans
Male
Rats
Rats, Sprague-Dawley
Schwann Cells / metabolism
Stem Cells

Substances

5-ethynyl-2'-deoxyuridine
Deoxyuridine