Induction of Macrophage-Like Immunosuppressive Cells from Mouse ES Cells That Contribute to Prolong Allogeneic Graft Survival

Abstract

Recent progress in regenerative medicine has enabled the utilization of pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) as a donor resource for transplantation. However, immune suppression is still needed when the donor-recipient combination is allogeneic. Protection of ESCs-derived grafts from host immune response might be achieved thought the utilization of immunosuppressive cells generated from ESCs. In the present study, we show that a certain fraction of immunosuppressive cells can be generated from ESCs and help to suppress immune response against allogeneic grafts. ESCs-derived suppressor cells (ES-SCs) resembled macrophages in terms of cell surface molecule and gene expressions. Furthermore, gene expression analysis including microarray showed that ES-SCs have M1/M2 hybrid phenotype with high expression of genes correlated to immunosuppression of T cell response. Indeed, ES-SCs were effective to block allogeneic T cell proliferation in a nitric oxide-dependent manner, and prolonged the survival of ESCs-derived embryoid bodies or cardiomyocytes grafts transplanted into mouse kidney capsule. Thus, we consider the potential use of these ESCs-derived macrophage-like immunosuppressive cells as cellular therapies to promote long-term graft survival in future therapies.

Interleukin-34, a comprehensive review

“…In this regard, PSCs have obtained a great interest in cell‐based regenerative therapies due to their capacity to differentiate into various cells that help to replenish cells lost in various conditions. To avoid immune rejection of PSCs‐derived grafts, PSCs‐derived immunoregulatory cells can importantly help to prolong survival of allografts derived from the same donor of PSCs . IL‐34 has the potential to drive PSCs differentiation into specific cell types such as microglial cells and can provide a critical activation signal of CSF‐1R for the generation of immunosuppressive M2‐polarized M ϕ s .…”

Healing the Broken Heart; The Immunomodulatory Effects of Stem Cell Therapy

“…Whether ESCs can directly regulate humoral immunity within the infarcted heart by deriving specific B lymphocyte lineages or indirectly via ESC derived hematopoietic stem cells/macrophages is poorly understood and warrants further investigation (220,221). The regulatory effect of ESC derived hematopoietic stem cells on lymphocyte populations, specifically on t-lymphocyte populations, has previously been outlined in the "Stem Cells and T Cells" section of the present manuscript (194).…”

“…Recent studies surrounding ESCs identify that these populations are not considered to be immune privileged as the adoptive transfer of primitive ESC populations elicits a massive inflammatory response and can consequently result in the rejection of the administered cell therapy (133,(194)(195)(196)(197)(198)(199)(200)(201). ESCs have been shown to increase MHCI and MHCII expression within the heart, whether these cells were recruited to the heart or underwent de novo generation from ESCs has not been clearly defined (194). Given the primitive nature of ESCs and their superior differential abilities, most of the immunomodulatory work using ESCs is via the manipulation of central tolerance by ESC-derived hemopoietic stem cell establishment (202-205).…”

“…Initial studies suggested ESCs can differentiate into either M1 or M2 M populations and subsequently alter the inflammatory response (206). In a study by Kudo et al an ESC derived suppressor cell line that contains an M1/M2 M phenotype hybrid was generated and demonstrated the ability to mediate T cell response and permit cardiomyocyte engraftment in a nitric oxide (NO) dependent manner (194). Immune suppression is essential for ESC engraftment, however the heterogeneity that can occur from ESC derived immune cell populations could prove problematic and needs to be better optimized.…”

Teratoma: from spontaneous tumors to the pluripotency/malignancy assay

“…Macrophage‐like immunosuppressive cells were produced from mESCs that were injected under the kidney capsule of a mouse 14 days before the transplantation of allogeneic EBs. They contributed to the prolonged survival of teratomas for 14 days …”