Cell versus Chemokine Therapy in a Nonhuman Primate Model of Chronic Intrinsic Urinary Sphincter Deficiency.
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.



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.



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).



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.
Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina. Electronic address: kwilliam@wakehealth.edu.
J Koudy
JK
Williams
Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
Ashley
A
Dean
Urology Department, Ain-Shams University Hospitals, Cairo, Egypt.
Sherif
S
Badra
Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
Shannon
S
Lankford
Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
Kimberly
K
Poppante
Department of Urology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
Gopal
G
Badlani
Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina; Institute for Clinical Sciences, Department of Obstetrics and Gynecology, Aarhus University, Aarhus, Denmark.
Karl-Erik
KE
Andersson
D000818:Animals; D054377:Chemokine CXCL12 / Q000627:therapeutic use*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D008252:Macaca fascicularis; D032446:Myoblasts / Q000637:transplantation*; D014522:Urethral Diseases / Q000188:drug therapy* / Q000601:surgery*
D054377:Chemokine CXCL12
cell- and tissue-based therapy; chemokine CXCL12; myoblasts; stress; urinary bladder; urinary incontinence