Pelvic Organ Prolapse (POP) is a debilitating pelvic floor disorder affecting 25% of all women (1). Reconstructive native tissue surgery is offered based on the severity of POP. Due to the high failure rate, non-degradable polypropylene (PP) vaginal meshes are commonly used to mitigate native tissue repair failures (2).  However, in approximately 10% of women, vaginal meshes led to serious adverse events associated with serious foreign body reactions (FBR) including mesh exposure and erosion. Following several FDA warnings and market withdrawal of most products, there is no effective treatment for POP. Current research is now focused on improving biocompatibility and interactive tissue properties of the mesh using adult stem cells from several sources. We recently reported the design of gelatin blended degradable poly L-lactic acid-co-poly ε-caprolactone nanofibrous mesh (P+G nanomesh) bioengineered with endometrial mesenchymal stem/stromal cells (eMSC) for POP repair. We showed that such bioengineered meshes had high tissue integration, as well as immunomodulatory effects in vivo (3).
This study aimed to quantify the molecules that mediate the Foreign Body Response (FBR) to gelatin blended nanofibrous degradable poly (L-lactic-acid)-co-poly(e-caprolactone) seeded with endometrial mesenchymal stem cells (eMSC) implanted in a mouse model of wound repair and tissue regeneration.

eMSC were isolated from endometrial biopsy by SUSD2 magnetic bead sorting. Electrospun PLACL/G nano-meshes with and without eMSC were implanted in an NSG mouse skin wound repair model for 1 and 6 weeks (n=7 mice/group). The expression of extracellular matrix (ECM), cell adhesion, angiogenesis and immune response genes were quantified using Fluidigm Biomark qPCR.

Our results show significant changes in ECM, angiogenesis and immune response genes in the presence of eMSC. We found a significantly reduced expression of the inflammatory gene Il-6 in the eMSC seeded PLACL/G group compared to PLACL/G alone after one week (P< 0.05). The expression of ECM associated genes including Col-III, Cd44 and Cdh2 increased from one to 6 weeks in the PLACL/eMSC group. Constructs including eMSC showed an increased expression of angiogenesis associated genes including Pdgfa at 6 weeks (P<0.05).

The main finding of this study is the improved biocompatibility of eMSC incorporated P+G nanomesh. Indeed, our finding showed that eMSC, most likely through their paracrine effects, induce the upregulation of ECM and angiogenesis genes during the healing phase of FBR. eMSC have also influenced the expression of MMP and TIMPS. MMP and TIMPS are both involved in tissue remodelling and our results indicate the effect of eMSC on the balance between MMP and TIMPs expression which is essential to prevent fibrosis. eMSC reduced the inflammatory response to implanted nanomesh by downregulating the gene expression of several cytokine/chemokine and co-receptors which leads to reduced leukocytes recruitment and inflammation.

Given that the current failed vaginal meshes are associated with inadequate tissue integration, the use of eMSC to promote anti-inflammatory response, mesh integration and improve tissue repair is an important advance in improving outcomes for POP treatment.

Naygaard I et al. Prevalence of symptomatic pelvic floor disorders in US women. Jama  2008; 300;  1311–1316.
Mukherjee S et al. Mesenchymal stem cell-based bioengineered constructs: foreign body response, cross-talk with macrophages and impact of biomaterial design strategies for pelvic floor disorders. Interface Focus 2019; 9; 25-30.
Mukherjee S et al. Blended Nanostructured Degradable Mesh with Endometrial Mesenchymal Stem Cells Promotes Tissue Integration and Anti-Inflammatory Response in Vivo for Pelvic Floor Application. Biomacromolecules 2019; 14; 454-468.