Soluble factors from biofilms of wound pathogens modulate human bone marrow-derived stromal cell differentiation, migration, angiogenesis, and cytokine secretion

Abstract

BackgroundChronic, non-healing wounds are often characterized by the persistence of bacteria within biofilms - aggregations of cells encased within a self-produced polysaccharide matrix. Biofilm bacteria exhibit unique characteristics from planktonic, or culture-grown, bacterial phenotype, including diminished responses to antimicrobial therapy and persistence against host immune responses. Mesenchymal stromal cells (MSCs) are host cells characterized by their multifunctional ability to undergo differentiation into multiple cell types and modulation of host-immune responses by secreting factors that promote wound healing. While these characteristics make MSCs an attractive therapeutic for wounds, these pro-healing activities may be differentially influenced in the context of an infection (i.e., biofilm related infections) within chronic wounds. Herein, we evaluated the effect of soluble factors derived from biofilms of clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa on the viability, differentiation, and paracrine activity of human MSCs to evaluate the influence of biofilms on MSC activity in vitro.ResultsExposure of MSCs to biofilm-conditioned medias of S. aureus and P. aeruginosa resulted in reductions in cell viability, in part due to activation of apoptosis. Similarly, exposure to soluble factors from biofilms was also observed to diminish the migration ability of cells and to hinder multi-lineage differentiation of MSCs. In contrast to these findings, exposure of MSCs to soluble factors from biofilms resulted in significant increases in the release of paracrine factors involved in inflammation and wound healing.ConclusionsCollectively, these findings demonstrate that factors produced by biofilms can negatively impact the intrinsic properties of MSCs, in particular limiting the migratory and differentiation capacity of MSCs. Consequently, these studies suggest use/application of stem-cell therapies in the context of infection may have a limited therapeutic effect.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0412-x) contains supplementary material, which is available to authorized users.

Stem cells and chronic wound healing: state of the art

“…Exposure to biofilm-conditioned media as well as isolated soluble biofilm factors alone are both sufficient to impair MSC migration and differentiation while promoting apoptosis. 53 These findings suggest that chronic wounds provide a suboptimal environment for transplanted stem cells, which may thus impede the utility of stem cell therapy in chronic wounds, at least in those with ongoing bacterial colonization with biofilm forming organisms.…”

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect

“…This corroborates the finding in several in vitro studies that have shown that the presence of infection reduces, but does not completely inhibit, the differentiation of MSCs, likely through the effects of soluble factors secreted by the S. aureus biofilm. 17,18 Main effect analysis for BMP-5 expression indicates that infection is an independent negative factor in the production of BMP-5, suggesting that prophylactic treatment with clindamycin could be beneficial from the perspective of infection treatment and restoration of growth factor expression. In addition, clindamycin treated defects, with or without infection, also retain similar VEGF expression to the material control, further demonstrating that defects treated at the time of initial surgery are able to maintain the ability to generate membranes with appropriate growth factor expression.…”

“…14,15 Staphylococcus aureus is the most common infecting agent in long bone osteomyelitis and is known to have deleterious effects on local cell populations. [16][17][18] In vitro studies have shown the effects of S. aureus on local cells to be far reaching, such as decreasing osteoblast viability and differentiation, inhibiting the multilineage potential of mesenchymal stem cells (MSCs), increasing the production of resorptive factors and increasing the production of proinflammatory cytokines. [17][18][19] These effects are not conducive to the regeneration of bone, and thus, local antibiotic delivery is intended to eradicate bacteria to restore the regenerative capacity of local cell types.…”

“…[16][17][18] In vitro studies have shown the effects of S. aureus on local cells to be far reaching, such as decreasing osteoblast viability and differentiation, inhibiting the multilineage potential of mesenchymal stem cells (MSCs), increasing the production of resorptive factors and increasing the production of proinflammatory cytokines. [17][18][19] These effects are not conducive to the regeneration of bone, and thus, local antibiotic delivery is intended to eradicate bacteria to restore the regenerative capacity of local cell types. A study of the characteristics of an induced membrane generated in the presence of antibioticreleasing solid PMMA has demonstrated that antibiotics may also affect the thickness and vascularization of induced membranes in the absence of infection.…”

Role of Helicobacter pylori on cancer of human adipose-derived mesenchymal stem cells and metastasis of tumor cells—an in vitro study

“…They have been discovered to possess tissue replacement and wound healing properties, mainly due to their differentiation ability to many cell types [1,[14][15][16][17][18]. As recent studies demonstrated, stem cells have migrated towards the microenvironments which are infected by H. pylori [1,6]; the main factors for attracting MSCs are chemotaxi cytokines that are particularly released in the chronic infection specially H. pylori infections [1,19]. Stem cells have more abilities than other cells to temporarily put off and control the cells' normal growth and start extra proliferation for their innate duty in ulcer and wound healing [20,21].…”