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Induction of macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic graft survival.

Kudo H, Wada H, Sasaki H, Tsuji H, Otsuka R, Baghdadi M, Kojo S, Chikaraishi T, Seino K - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Urology St. Marianna University School of Medicine, Miyamae-ku, Kawasaki City, Kanagawa, Japan.

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.

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ES-SCs prolonged the survival of allogeneic graft.Host 129X1 or C3H mice were intraperitoneally injected with phosphate buffered saline (PBS, Figure 3A, B, D, E, G and H) or 35 Gy-irradiated ES-SCs (Figure 3C, F and I) 14 days before transplantation. (A–C) Hematoxylin and eosin staining of E14 EB grafts transplanted into renal subcapsule at day 14 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 1.0 mm. (D–F) Immunohistological staining for CD3 antigen (indicating T cell infiltration) of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. (G–I) Hematoxylin and eosin staining of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 100 µm.
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pone-0111826-g003: ES-SCs prolonged the survival of allogeneic graft.Host 129X1 or C3H mice were intraperitoneally injected with phosphate buffered saline (PBS, Figure 3A, B, D, E, G and H) or 35 Gy-irradiated ES-SCs (Figure 3C, F and I) 14 days before transplantation. (A–C) Hematoxylin and eosin staining of E14 EB grafts transplanted into renal subcapsule at day 14 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 1.0 mm. (D–F) Immunohistological staining for CD3 antigen (indicating T cell infiltration) of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. (G–I) Hematoxylin and eosin staining of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 100 µm.

Mentions: Next, we evaluated the effects of ES-SCs on the suppression of allogeneic T cell response in in vivo allogeneic transplantation model. 129 or C3H mice were injected with phosphate buffered saline (PBS) or 35 Gy-irradiated ES-SCs or ES-DCs (1×106 cells). 14 days later, embryoid bodies (EB) derived from E14 ESCs were transplanted into renal subcapsular region of the mice. Graft survival was determined by direct macroscopic inspection of teratoma formation at day 14 and 28 after the transplantation (Fig. S3 in File S1). As indicated in Table 1, syngeneic grafts grew normally at day 28, whereas no allogeneic untreated grafts were detectable even at day 14. On the other hand, allogeneic grafts in recipients that were pretreated with ES-SCs, remarkably survived at least until day 14, but were not detectable at day 28. Pretreatment with ES-DCs did not prolong the graft survival. Microscopic analysis at day 14 confirmed the graft acceptance in syngeneic, allogeneic and ES-SCs-pretreated recipients (Figs. 3A–C). These results suggested that the treatment with ES-SCs has a potential to improve the outcomes of allogeneic transplantation.


Induction of macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic graft survival.

Kudo H, Wada H, Sasaki H, Tsuji H, Otsuka R, Baghdadi M, Kojo S, Chikaraishi T, Seino K - PLoS ONE (2014)

ES-SCs prolonged the survival of allogeneic graft.Host 129X1 or C3H mice were intraperitoneally injected with phosphate buffered saline (PBS, Figure 3A, B, D, E, G and H) or 35 Gy-irradiated ES-SCs (Figure 3C, F and I) 14 days before transplantation. (A–C) Hematoxylin and eosin staining of E14 EB grafts transplanted into renal subcapsule at day 14 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 1.0 mm. (D–F) Immunohistological staining for CD3 antigen (indicating T cell infiltration) of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. (G–I) Hematoxylin and eosin staining of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4214817&req=5

pone-0111826-g003: ES-SCs prolonged the survival of allogeneic graft.Host 129X1 or C3H mice were intraperitoneally injected with phosphate buffered saline (PBS, Figure 3A, B, D, E, G and H) or 35 Gy-irradiated ES-SCs (Figure 3C, F and I) 14 days before transplantation. (A–C) Hematoxylin and eosin staining of E14 EB grafts transplanted into renal subcapsule at day 14 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 1.0 mm. (D–F) Immunohistological staining for CD3 antigen (indicating T cell infiltration) of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. (G–I) Hematoxylin and eosin staining of ESCs-derived cardiomyocytes transplanted into renal subcapsule at day 7 after graft transplantation. Data are shown as representative of two grafts. Scale bars, 100 µm.
Mentions: Next, we evaluated the effects of ES-SCs on the suppression of allogeneic T cell response in in vivo allogeneic transplantation model. 129 or C3H mice were injected with phosphate buffered saline (PBS) or 35 Gy-irradiated ES-SCs or ES-DCs (1×106 cells). 14 days later, embryoid bodies (EB) derived from E14 ESCs were transplanted into renal subcapsular region of the mice. Graft survival was determined by direct macroscopic inspection of teratoma formation at day 14 and 28 after the transplantation (Fig. S3 in File S1). As indicated in Table 1, syngeneic grafts grew normally at day 28, whereas no allogeneic untreated grafts were detectable even at day 14. On the other hand, allogeneic grafts in recipients that were pretreated with ES-SCs, remarkably survived at least until day 14, but were not detectable at day 28. Pretreatment with ES-DCs did not prolong the graft survival. Microscopic analysis at day 14 confirmed the graft acceptance in syngeneic, allogeneic and ES-SCs-pretreated recipients (Figs. 3A–C). These results suggested that the treatment with ES-SCs has a potential to improve the outcomes of allogeneic transplantation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Urology St. Marianna University School of Medicine, Miyamae-ku, Kawasaki City, Kanagawa, Japan.

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.

Show MeSH
Related in: MedlinePlus