title: MIF produced by bone marrow-derived macrophages contributes to teratoma progression after embryonic stem cell transplantation.
abstract: Although stem cell therapy holds promise as a potential treatment in a number of diseases, the tumorigenicity of embryonic stem cells (ESC) and induced pluripotent stem cells remains a major obstacle. In vitro predifferentiation of ESCs can help prevent the risk of teratoma formation, yet proliferating neural progenitors can generate tumors, especially in the presence of immunosuppressive therapy. In this study, we investigated the effects of the microenvironment on stem cell growth and teratoma development using undifferentiated ESCs. Syngeneic ESC transplantation triggered an inflammatory response that involved the recruitment of bone marrow (BM)-derived macrophages. These macrophages differentiated into an M2 or angiogenic phenotype that expressed multiple angiogenic growth factors and proteinases, such as macrophage migration inhibitory factor (MIF), VEGF, and matrix metalloproteinase 9, creating a microenvironment that supported the initiation of teratoma development. Genetic deletion of MIF from the host but not from ESCs specifically reduced angiogenesis and teratoma growth, and MIF inhibition effectively reduced teratoma development after ESC transplantation. Together, our findings show that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment and activation of BM-derived macrophages, which may be a crucial driving force in the initiation and progression of teratomas.
authors.affiliation: W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Jianqing
authors.initials: J
authors.lastname: Fan
authors.forename: Kai
authors.initials: K
authors.lastname: Cao
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Duan
authors.forename: Xijing
authors.initials: X
authors.lastname: Zhang
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Mingmei
authors.initials: M
authors.lastname: Wu
authors.forename: Iman
authors.initials: I
authors.lastname: Tadmori
authors.forename: Tianyi
authors.initials: T
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Dongming
authors.initials: D
authors.lastname: Sun
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
authors.forename: Wise
authors.initials: W
authors.lastname: Young
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D018450:Disease Progression; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation*; D042783:Endothelial Cells / Q000502:physiology; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D008262:Macrophage Activation; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology; D055153:Stem Cell Niche; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D013724:Teratoma / Q000098:blood supply / Q000209:etiology* / Q000473:pathology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse