Rat Mesenchymal Stem Cell Secretome Promotes Elastogenesis and Facilitates Recovery from Simulated Childbirth Injury

Abstract

Vaginal delivery is a risk factor for stress urinary incontinence (SUI). Mesenchymal stem cells (MSCs) home to injured organs and can facilitate repair. The goal of this study was to determine if MSCs home to pelvic organs after simulated childbirth injury and facilitate recovery from SUI via paracrine factors. Three experiments were performed. Eighteen female rats received vaginal distension (VD) or sham VD and labeled intravenous (IV) MSCs to investigate if MSCs home to the pelvic organs. Whole-organ imaging and immunofluorescence were performed 1 week later. Thirty-four female rats received VD and IV MSCs, VD and IV saline, or sham VD and IV saline to investigate if MSCs accelerate recovery of continence. Twenty-nine female rats received VD and periurethral concentrated conditioned media (CCM), VD and periurethral control media, or sham VD and periurethral control media to investigate if factors secreted by MSCs accelerate recovery from VD. Urethral histology and function were assessed 1 week later. Significantly more MSCs were observed in the urethra, vagina, and spleen after VD compared to sham VD. Continence as measured by leak point pressure (LPP) was significantly reduced after VD in rats treated with saline or control media compared to sham VD but not in those given MSCs or CCM. External urethral sphincter (EUS) function as measured by electromyography (EMG) was not improved with MSCs or CCM. Rats treated with MSCs or CCM demonstrated an increase in elastin fibers near the EUS and urethral smooth muscle more similar to that of sham-injured animals than rats treated with saline or control media. MSCs homed to the urethra and vagina and facilitated recovery of continence most likely via secretion of paracrine factors. Both MSCs and CCM have promise as novel noninvasive therapies for SUI.

The potential role of stem cells in the treatment of urinary incontinence

“…MSCs have also been induced to differentiate into a smooth muscle phenotype when exposed to conditioned media from smooth muscle cell cultures or when induced with specific myogenic growth factors for application to bladder reconstruction . More recent work, however, suggests a more complex role of stem cells in functional recovery, with some studies demonstrating that paracrine secretions of MSCs play an important role in the regeneration process [Carvalho et al 2011;Ranganath et al 2012;Dissaranan et al 2013].…”

“…In addition, recent work investigating MSCs for SUI has shown that chemokine ligand 7 (CCL7), a homing factor for MSCs, is upregulated in both the urethra and vagina after vaginal distension (VD), suggesting that intravenously administered MSCs could have the potential to home to sites of injury in SUI [Woo et al 2007;Wood et al 2008;Lenis et al 2012]. Subsequent literature examining intravenous injection of MSCs in a VD rat model of simulated childbirth injury showed that MSCs home to the urethra and vagina and facilitate recovery of continence as measured by leak point pressure (LPP) [Cruz et al 2011;Dissaranan et al 2013]. Recent work by Lenis and colleagues used a rat model of childbirth injury with both virgin rats that had undergone VD and postpartum rats to further investigate the expression of chemokines and receptors involved in stem cell homing and tissue repair [Lenis et al 2013].…”

“…Recent research has demonstrated that, in addition to differentiating into target tissue types, stem cells likely exert a therapeutic effect via the secretion of bioactive factors since few MSCs engraft and remain long term in target tissues, in contrast to their large therapeutic effect [Carvalho et al 2011;Ranganath et al 2012;Dissaranan et al 2013]. MSCs also activate and direct endogenous stem and progenitor cells to areas of injury via the secretion of cytokines and chemokines [Caplan and Dennis, 2006].…”

“…A recent study by Dissaranan and colleagues demonstrates that the secretome of MSCs can facilitate recovery of continence as measured by LPP following VD in a rat model; moreover, rats treated locally with MSC secretome, as contained in conditioned media, exhibited an increase in elastin fibers and urethral smooth muscle, which may have contributed to the restoration of continence [Dissaranan et al 2013]. A study of hamsters with heart failure suggests that MSCs act systemically as well as locally [Shabbir et al 2009].…”

“…Stem cells may also exert a therapeutic effect via the secretion of bioactive factors that have antiapoptotic, antiscarring, neovascularization, and immunomodulatory effects on innate tissues and can direct innate stem and progenitor cells to the area of injury [Gnecchi et al 2008]. Multiple treatment avenues using stem cells for voiding dysfunction, especially SUI, have been evaluated with preclinical animal models and clinical trials demonstrating their potential to restore function via direct effects on the underlying mechanisms that lead to incontinence or voiding dysfunction [Chermansky et al 2004a;Carr et al 2008;Fu et al 2010;Huang et al 2010;Kim et al 2010;Lim et al 2010;Lin et al 2010;Cruz et al 2011;Woo et al 2011;Lee et al 2012;Carr et al 2013;Dissaranan et al 2013;Gotoh et al 2013;Rovner, 2013]. Nonetheless, many challenges remain to translate these promising results to clinical practice.…”