MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation

Abstract

The tumorigenicity of embryonic stem cells (ESCs) and induced pluripotent stem (iPS) cells is a major obstacle for clinical translation. Although teratoma formation can be reduced by in vitro pre-differentiation of ESCs, proliferating neural progenitors can generate tumors, especially under the immunosuppressive treatment. In our present study, we used undifferentiated embryonic stem cells as a worst-case model for teratoma formation and study if niche microenvironment of stem cell growth is a crucial driving force in teratoma development. We demonstrate herein that syngeneic ESC transplants recruit bone marrow (BM)-derived macrophages that produce macrophage migration inhibitory factor (MIF), thereby stimulating angiogenesis and teratoma development. Moreover, we show that teratoma angiogenesis relies on preexisting host endothelial cells and does not require BM-derived endothelial progenitors or endothelial cells differentiated from ESCs. Furthermore, ESCs differentiate into pericytes and pericyte coverage is restricted in MIF KO Mice. Genetic deletion of MIF from the host but not from ESCs specifically reduces angiogenesis and teratoma growth. BM cell-derived MIF contributes to teratoma development and blockade of MIF effectively reduces teratoma development after ESC transplantation. This is the first study to demonstrate that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment of BM-derived macrophages. We propose that infiltrating inflammatory macrophages form niche microenvironments that may be a crucial driving force in the initiation and progression of teratomas.

25 Years On: A Retrospective on Migration Inhibitory Factor in Tumor Angiogenesis

“…In this study, syngeneic embryonic stem cells injected into MIF-deficient mice grew tumors that were a fraction of the size of those developing in MIF wild-type mice, a finding that was attributed to profoundly defective teratoma vascularization. Importantly, reconstitution of MIF wild-type bone marrow into MIF-deficient mice restored microvessel density within the teratomas and, accordingly, restored tumor burden (21). Perhaps even more strikingly, MIF-deficient bone marrow reconstitution dramatically reduced tumor burden in adoptively transferred MIF wild-type mice.…”

“…One of the most profound examples of MIF-dependent neovascularization stems from the finding that bone marrowderived macrophages (BMDMs) recruited to the stroma of teratomas express and secrete MIF that, in turn, dictates the vast bulk of microvessel density within tumor lesions (21). In this study, syngeneic embryonic stem cells injected into MIF-deficient mice grew tumors that were a fraction of the size of those developing in MIF wild-type mice, a finding that was attributed to profoundly defective teratoma vascularization.…”

“…Phenotypes associated with bone marrow reconstitution were found not to be due to endothelial cell progenitors that populate bone marrow but rather due to BMDMs. Specifically, mobilized BMDMs that infiltrated developing teratomas were shown to express/ secrete high levels of MIF that, in turn, directly promote pericyte differentiation and endothelial cell proliferation (21).…”

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

“…3,[63][64][65] For bone marrow transplantation, 10-weekold female Mif 2/2 (n=5) and C57Bl/6N (n=10) WT littermates were used as recipients and 10-week-old male Mif 2/2 (n=3) and C57Bl/6N…”

Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization

“…ESCs can recruit macrophage by secreting molecules, such as MCP-1 and Matrix metallopeptidase-9. 108 In addition, ESCs promote macrophage survival and polarize macrophages toward an M2-like phenotype by releasing factors such as IL-34 and activating STAT3 and STAT6 signaling pathways. 109 Transplanted ESCs may form teratomas, which are constituted by cells from endodermal, mesodermal, and ectodermal lineages.…”