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

Williams, J. Koudy; Dean, Ashley; Badra, Sherif; Lankford, Shannon; Poppante, Kimberly; Badlani, Gopal H.; Andersson, Karl‐Erik

doi:10.1016/j.juro.2016.05.106

Cited by 20 publications

(25 citation statements)

References 21 publications

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“…Anesthesia can blunt urinary reflexes, and may have affected the results. However, similar to what we have shown in nonhuman primates [11], the effects of CXCL12 were pronounced and are most likely valid. It is unclear why the dose of skMPCs was not effective on LPPs.…”

Section: Discussionsupporting

confidence: 89%

Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency

Williams

Dean

Lankford

et al. 2017

Stem Cells Translational Medicine

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Disappointing results of skeletal muscle precursor cell (skMPC) therapy for women with intrinsic urinary sphincter deficiency (ISD) associated urinary incontinence has increased interest in alternative sphincter regenerative approaches. This study was to measure the safety and efficacy of the cell homing chemokine CXCL12 versus skMPCs in a rat model of ISD. Thirty‐six adult female Sprague Dawley rats were divided into 6 treatment (Tx) conditions: (a) no ISD/noTx [Control]; (b) ISD/noTx; (c) ISD + skMPCs; (d) ISD + 3.5 mg CXCL12; (e) ISD + 7mg CXCL12; and (f) ISD + 14 mg CXCL12. Tx's were injected directly into the sphincter complex 30 days post ISD and rats euthanized 30 days post Tx. Blood samples for measurements of kidney and liver function, white and red blood cell counts, were taken at baseline and at euthanasia. Leak point pressures (LPP) were measured prior to, and sphincter collagen/muscle content measured after, euthanasia. There were no effects of treatments on white or red/white blood cell counts, kidney/liver function tests or histopathology of the urinary sphincter complex or surrounding tissues. ISD lowered LPP 35% and sphincter muscle content by 17% versus control rats. CXCL12, but not skMPC injections, restored both LPP to control values in a dose‐dependent fashion. Both skMPCs and CXCL12 restored sphincter muscle content to control values. This chemokine approach may represent a novel therapeutic option for ISD and appears, at least short‐term, to produce little clinical or tissue pathology. Stem Cells Translational Medicine 2017;6:1740–1746

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Section: Discussionsupporting

confidence: 89%

Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency

Williams

Dean

Lankford

et al. 2017

Stem Cells Translational Medicine

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“…In females NHP with chronic SUI, periurethral injection of CXCL12 increased the resting maximal urethral pressure, stimulated neoangiogenesis and motor endplate expression. In addition, CXCL12 decreased collagen and increased the muscle content of urinary sphincter complex . In males NHP with post radical prostatectomy SUI, periurethral injection of CXCL12 at 1 month postoperative increased the ALPP and the intracavernosal pressure.…”

Section: Methodsmentioning

confidence: 92%

“…VEGF works synergistically with CXCL‐12 amplifying the neoangiogenesis and promoting muscle cell survival at the injury site. This phenomenon raises interesting possibilities of CXCL12 therapy (alone or in combination with cells and/or growth factors) for cohorts of patients resistant to cell therapy …”

Section: Methodsmentioning

confidence: 99%

“…This phenomenon raises interesting possibilities of CXCL12 therapy (alone or in combination with cells and/or growth factors) for cohorts of patients resistant to cell therapy. 37,38 Two papers published recently by the same group demonstrated clinical and histological evidence of sphincter and nerve regenerations in female and male NHP models of SUI. 37,38 In females NHP with chronic SUI, periurethral injection of CXCL12 increased the resting maximal urethral pressure, stimulated neoangiogenesis and motor endplate expression.…”

Section: Use Of Low Intensity Extracorporeal Shock Waves To Recruitmentioning

confidence: 99%

“…37,38 Two papers published recently by the same group demonstrated clinical and histological evidence of sphincter and nerve regenerations in female and male NHP models of SUI. 37,38 In females NHP with chronic SUI, periurethral injection of CXCL12 increased the resting maximal urethral pressure, stimulated neoangiogenesis and motor endplate expression. In addition, CXCL12 decreased collagen and increased the muscle content of urinary sphincter complex.…”

Section: Use Of Low Intensity Extracorporeal Shock Waves To Recruitmentioning

confidence: 99%

See 2 more Smart Citations

Applicability of regenerative medicine and tissue engineering for the treatment of stress urinary incontinence in female patients

Zambon

Williams

Bennington

et al. 2019

Neurourology and Urodynamics

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Stress urinary incontinence (SUI) is an age health‐related issue that generates interest due to its considerable public health burden and the controversies surrounding treatment. It is highly prevalent affecting 30–40% of all women during their lifetime. Midurethral slings are the standard of gold standard treatment for female patients with SUI. They have excellent short‐term cure rates; however, their efficacy tends to decrease over time and patients often report urinary incontinence recurrence. This paper addresses the applicability of regenerative medicine and tissue engineering for the treatment of SUI in female patients. Cell‐based treatment with periurethral injection of autologous adipose or muscle‐derived stem cells have been used for SUI; however, the cure rates and SUI recurrence at 1 year were 40% and 70%, respectively. Novel minimally invasive approaches, such as low‐intensity extracorporeal shock wave therapies have shown promising results in SUI animal models. In addition, local injection of growth factors, chemokines, and specific antibodies have shown histological evidence of neoangiogenesis, nerve, and sphincter regeneration in rodents and nonhuman primates with SUI. The use of bioactive factors and proteins secreted by cells, which is called secretomes, have been recognized as key regulators of various mechanisms, such as immunomodulation, angiogenesis, inflammation, apoptosis, and tissue repair. Emerging therapies aiming to replace or restore tissues and organ functionality may improve the long‐term efficacy and in the near future may represent the standard of care for the treatment of SUI.

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Nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: Feasibility of minimally invasive therapy

Zambon

Patel

Hemal

et al. 2018

Neurourology and Urodynamics

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

Abstract: 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.

Cited by 20 publications

References 21 publications

Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency

Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency

Applicability of regenerative medicine and tissue engineering for the treatment of stress urinary incontinence in female patients

Nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: Feasibility of minimally invasive therapy

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