Understanding the effects of an inflammatory milieu on the development of mesenchymal stem cells: implication for treating inflammatory diseases

Abstract

Abstract Mesenchymal stem cells (MSCs), multipotent cells found in various adult tissues, are an attractive source of cells for cellular therapy and regenerative medicine. Reasons include their ease to expand, plasticity to generate cells of all germ layers, reduced ethical concerns, and ability to be available as ‘off the shelf’ cells for immediate use in transplantation. MSCs can respond differently to varying microenvironments to perform distinct immune functions. The microenvironment can also affect the developmental state of MSCs. Better understanding of how the microenvironment influences MSC multipotency is crucial for effective translational use of these cells in the clinic. This study tested the hypothesis that the changes in an inflammatory microenvironment will influence MSC function. To study these effects, an in vitro model of GvHD was developed by culturing MSCs in a three-dimensional model – rather than in a traditional monolayer – under physiological conditions. The GvHD model was generated based on a modified two-way mixed lymphocyte reaction. The cells were then assessed for phenotype, proliferation, and viability. Following growth in suspension, the MSCs continued to express an MSC phenotype. Proliferation and viability studies suggested that, although the cells were proliferating, they underwent cell death at a quicker rate than their two-dimensional culture counterparts. When cultured in the GvHD model, MSCs exhibited increased viability as compared to culture in the three-dimensional system alone. This in vitro GvHD model will elucidate factors within the inflammatory milieu that alter MSC multipotency. Identifying these factors will allow for more controlled and effective clinical use of MSCs.