The Role Of Macrophages In Tumor Development After ESC Transplantation

Background:Stem cell-based regernative medicine therapies have been expected to be one of most promising treatment for various diseases. However, transplantation of embryonic stem cells (ESC) or induced pluripotent stem cells (iPS) results in the formation of tumor.The tumorigenicity of ESCor iPS is a major obstacle for clinical application. Current strategies like in vitro pre-differentiation of ESC are not effective to reduce teratoma formation and only focus on stem cell per se.Objectives:We here investigate if macrophages from microenvironment of stem cells are crucial driving force in development of tumor.Methodsand results:In our present study, we used undifferentiated ESC as a worst-case scenario for the generation of tumor and demonstrate herein that mouse syngeneic ESC transplants recruit bone marrow-derived macrophages (BMDM) in spinal cord, to maintain their survival and differenciation, to induce alternatively activation (M2polarization) of them, and to induce these macrophages towards an "angiogenic switch" which express abundant multiple growth factors and proteinases such as macrophage migration inhibitory factor (MIF),vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9(MMP-9) that support angiogenesis.Conclusion:This is the first study to demonstrate that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment and alternative activation of BMDM, which may contribute to the initiation and progression of tumor.