SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts

Tobias Deuse; Dong Wang; Mandy Stubbendorff; Ryo Itagaki; Antje Grabosch; Laura C. Greaves; Malik Alawi; Anne Grünewald; Xiaomeng Hu; Xiaoqin Hua; Joachim Velden; Hermann Reichenspurner; Robert C. Robbins; Rudolf Jaenisch; Irving L. Weissman; Sonja Schrepfer

doi:10.1016/j.stem.2014.11.003

SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts

Tobias Deuse, Dong Wang, Mandy Stubbendorff, Ryo Itagaki, Antje Grabosch, Laura C. Greaves, Malik Alawi, Anne Grünewald, Xiaomeng Hu, Xiaoqin Hua, Joachim Velden, Hermann Reichenspurner, Robert C. Robbins, Rudolf Jaenisch, Irving L. Weissman, Sonja Schrepfer^*

^*Corresponding author for this work

Clinic of Neurology

56 Citations (Scopus)

Abstract

The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.

Original language	English
Journal	Cell Stem Cell
Volume	16
Issue number	1
Pages (from-to)	33-38
Number of pages	6
ISSN	1934-5909
DOIs	https://doi.org/10.1016/j.stem.2014.11.003
Publication status	Published - 08.01.2015

Funding

We thank Kirsten Fischer Lindahl for her critical comments and editing of the manuscript. We further thank Christiane Pahrmann for performing all cell cultures and for her overall technical assistance and Oktay Kirak and Hidde Ploegh for generating the experimental cells. We extend special thanks to the UKE Imaging Facility (UMIF, Bernd Zobiak) and the UKE Animal Facility. This study was supported by the Else-Kröner-Fresenius-Stiftung (2012_EKES.04; T.D.), a grant from the Fondation Leducq (CDA 2013-2015; S.S.), and the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG: SCHR992/3-1 and SCHR992/4-1; S.S.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

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Deuse, T., Wang, D., Stubbendorff, M., Itagaki, R., Grabosch, A., Greaves, L. C., Alawi, M., Grünewald, A., Hu, X., Hua, X., Velden, J., Reichenspurner, H., Robbins, R. C., Jaenisch, R., Weissman, I. L., & Schrepfer, S. (2015). SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts. Cell Stem Cell, 16(1), 33-38. https://doi.org/10.1016/j.stem.2014.11.003

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title = "SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts",

abstract = "The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.",

author = "Tobias Deuse and Dong Wang and Mandy Stubbendorff and Ryo Itagaki and Antje Grabosch and Greaves, \{Laura C.\} and Malik Alawi and Anne Gr{\"u}newald and Xiaomeng Hu and Xiaoqin Hua and Joachim Velden and Hermann Reichenspurner and Robbins, \{Robert C.\} and Rudolf Jaenisch and Weissman, \{Irving L.\} and Sonja Schrepfer",

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Deuse, T, Wang, D, Stubbendorff, M, Itagaki, R, Grabosch, A, Greaves, LC, Alawi, M, Grünewald, A, Hu, X, Hua, X, Velden, J, Reichenspurner, H, Robbins, RC, Jaenisch, R, Weissman, IL & Schrepfer, S 2015, 'SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts', Cell Stem Cell, vol. 16, no. 1, pp. 33-38. https://doi.org/10.1016/j.stem.2014.11.003

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T1 - SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts

AU - Deuse, Tobias

AU - Wang, Dong

AU - Stubbendorff, Mandy

AU - Itagaki, Ryo

AU - Grabosch, Antje

AU - Greaves, Laura C.

AU - Alawi, Malik

AU - Grünewald, Anne

AU - Hu, Xiaomeng

AU - Hua, Xiaoqin

AU - Velden, Joachim

AU - Reichenspurner, Hermann

AU - Robbins, Robert C.

AU - Jaenisch, Rudolf

AU - Weissman, Irving L.

AU - Schrepfer, Sonja

PY - 2015/1/8

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N2 - The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.

AB - The generation of pluripotent stem cells by somatic cell nuclear transfer (SCNT) has recently been achieved in human cells and sparked new interest in this technology. The authors reporting this methodical breakthrough speculated that SCNT would allow the creation of patient-matched embryonic stem cells, even in patients with hereditary mitochondrial diseases. However, herein we show that mismatched mitochondria in nuclear-transfer-derived embryonic stem cells (NT-ESCs) possess alloantigenicity and are subject to immune rejection. In a murine transplantation setup, we demonstrate that allogeneic mitochondria in NT-ESCs, which are nucleus-identical to the recipient, may trigger an adaptive alloimmune response that impairs the survival of NT-ESC grafts. The immune response is adaptive, directed against mitochondrial content, and amenable for tolerance induction. Mitochondrial alloantigenicity should therefore be considered when developing therapeutic SCNT-based strategies.

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SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts

Abstract

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UN SDGs

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