Cell versus Chemokine Therapy in a Nonhuman Primate Model of Chronic Intrinsic Urinary Sphincter Deficiency J. Koudy Williams,* Ashley Dean, Sherif Badra, Shannon Lankford, Kimberly Poppante, Gopal Badlani and Karl-Erik Andersson From the Wake Forest Institute for Regenerative Medicine (JKW, AD, SL, KP, KEA) and Department of Urology (GB), Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, Urology Department, Ain-Shams University Hospitals (SB), Cairo, Egypt, and Institute for Clinical Sciences, Department of Obstetrics and Gynecology, Aarhus University (KEA), Aarhus Denmark Purpose: Mixed efficacy results of autologous skeletal muscle precursor cell therapy in women with chronic intrinsic urinary sphincter deficiency have increased interest in the therapeutic value of alternative regenerative medicine approaches. The goal of this study was to compare the effects of the cell homing chemokine CXCL12 (C-X-C motif chemokine 12) and skeletal muscle precursor cells on chronic urinary sphincter regeneration in chronic intrinsic urinary sphincter deficiency. Materials and Methods: Five million autologous skeletal muscle precursor cells or 100 ng CXCL12 were injected in the urinary sphincter complex of adult female cynomolgus monkeys with chronic (6-month history) intrinsic urinary sphincter deficiency. These treatment groups of 3 monkeys per group were compared to a group of 3 with no intrinsic urinary sphincter deficiency and no injection, and a group of 3 with intrinsic urinary sphincter deficiency plus vehicle injection. Maximal urethral pressure was measured at rest, during stimulation of the urinary sphincter pudendal nerves at baseline and again 6 months after treatment. The monkeys were then necropsied. The urinary sphincters were collected for tissue analysis of muscle and collagen content, vascularization and motor endplates. Results: CXCL12 but not skeletal muscle precursor cells increased resting maximal urethral pressure in nonhuman primates with chronic intrinsic urinary sphincter deficiency compared to that in monkeys with intrinsic urinary sphincter plus vehicle injection (p >0.05). Skeletal muscle precursor cells and CXCL12 only partially restored pudendal nerve stimulated increases in maximal urethral pressure (p >0.05), sphincter vascularization and motor endplate expression in monkeys with chronic intrinsic urinary sphincter deficiency. Additionally, CXCL12 but not skeletal muscle precursor cell injections decreased collagen and increased the muscle content of urinary sphincter complex in monkeys with chronic intrinsic urinary sphincter deficiency compared to those with intrinsic urinary sphincter plus vehicle injection and no intrinsic urinary sphincter plus no injection (p <0.05 and >0.05, respectively). Conclusions: These results raise questions about cell therapy for chronic intrinsic urinary sphincter deficiency and identify a chemokine treatment (CXCL12) as a potential alternative treatment of chronic intrinsic urinary sphincter deficiency. Key Words: urinary bladder; urinary incontinence, stress; myoblasts; chemokine CXCL12; cell- and tissue-based therapy Abbreviations and Acronyms CXCR4 ¼ chemokine receptor type 4 DMEM ¼ Dulbecco’s modified Eagle’s medium ISD ¼ intrinsic urinary sphincter deficiency MSC ¼ mesenchymal stem cell MUP ¼ maximal urethral pressure NHP ¼ nonhuman primate skMPC ¼ skeletal muscle precursor cell SUI ¼ stress urinary incontinence Accepted for publication May 25, 2016. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by R01 DK 083688 (Regeneration of the Lower Urinary Tract in Nonhuman Primates). * Correspondence: Wake Forest Institute for Regenerative Medicine, Wake Forest University. 391 Technology Way, Winston-Salem, North Car- olina 27101 (telephone: 336-713-1323; FAX: 336- 713-7290; e-mail: kwilliam@wakehealth.edu ). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 Dochead: Investigative Urology FLA 5.4.0 DTD  JURO13777_proof  29 August 2016  6:10 pm  EO: JU-16-730 0022-5347/16/1966-0001/0 THE JOURNAL OF UROLOGY ® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. http://dx.doi.org/10.1016/j.juro.2016.05.106 Vol. 196, 1-7, December 2016 Printed in U.S.A. www.jurology.com j 1