Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy

Abstract Induced pluripotent stem cells (iPSCs) are promising candidate cells for cardiomyogenesis in the failing heart. However, teratoma/tumour formation originating from undifferentiated iPSCs contaminating the graft is a critical concern for clinical application. Here, we hypothesized that brent...

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Autores principales:	Nagako Sougawa, Shigeru Miyagawa, Satsuki Fukushima, Ai Kawamura, Junya Yokoyama, Emiko Ito, Akima Harada, Kaori Okimoto, Noriko Mochizuki-Oda, Atsuhiro Saito, Yoshiki Sawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cfdeec773a2748ad83c8286f15cb0fb6
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spelling	oai:doaj.org-article:cfdeec773a2748ad83c8286f15cb0fb62021-12-02T15:09:08ZImmunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy10.1038/s41598-018-21923-82045-2322https://doaj.org/article/cfdeec773a2748ad83c8286f15cb0fb62018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21923-8https://doaj.org/toc/2045-2322Abstract Induced pluripotent stem cells (iPSCs) are promising candidate cells for cardiomyogenesis in the failing heart. However, teratoma/tumour formation originating from undifferentiated iPSCs contaminating the graft is a critical concern for clinical application. Here, we hypothesized that brentuximab vedotin, which targets CD30, induces apoptosis in tumourigenic cells, thus increasing the safety of iPSC therapy for heart failure. Flow cytometry analysis identified consistent expression of CD30 in undifferentiated human iPSCs. Addition of brentuximab vedotin in vitro for 72 h efficiently induced cell death in human iPSCs, associated with a significant increase in G2/M phase cells. Brentuximab vedotin significantly reduced Lin28 expression in cardiomyogenically differentiated human iPSCs. Transplantation of human iPSC-derived cardiomyocytes (CMs) without treatment into NOG mice consistently induced teratoma/tumour formation, with a substantial number of Ki-67–positive cells in the graft at 4 months post-transplant, whereas iPSC-derived CMs treated with brentuximab vedotin prior to the transplantation did not show teratoma/tumour formation, which was associated with absence of Ki-67–positive cells in the graft over the same period. These findings suggest that in vitro treatment with brentuximab vedotin, targeting the CD30-positive iPSC fraction, reduced tumourigenicity in human iPSC-derived CMs, potentially providing enhanced safety for iPSC-based cardiomyogenesis therapy in clinical scenarios.Nagako SougawaShigeru MiyagawaSatsuki FukushimaAi KawamuraJunya YokoyamaEmiko ItoAkima HaradaKaori OkimotoNoriko Mochizuki-OdaAtsuhiro SaitoYoshiki SawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nagako Sougawa Shigeru Miyagawa Satsuki Fukushima Ai Kawamura Junya Yokoyama Emiko Ito Akima Harada Kaori Okimoto Noriko Mochizuki-Oda Atsuhiro Saito Yoshiki Sawa Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
description	Abstract Induced pluripotent stem cells (iPSCs) are promising candidate cells for cardiomyogenesis in the failing heart. However, teratoma/tumour formation originating from undifferentiated iPSCs contaminating the graft is a critical concern for clinical application. Here, we hypothesized that brentuximab vedotin, which targets CD30, induces apoptosis in tumourigenic cells, thus increasing the safety of iPSC therapy for heart failure. Flow cytometry analysis identified consistent expression of CD30 in undifferentiated human iPSCs. Addition of brentuximab vedotin in vitro for 72 h efficiently induced cell death in human iPSCs, associated with a significant increase in G2/M phase cells. Brentuximab vedotin significantly reduced Lin28 expression in cardiomyogenically differentiated human iPSCs. Transplantation of human iPSC-derived cardiomyocytes (CMs) without treatment into NOG mice consistently induced teratoma/tumour formation, with a substantial number of Ki-67–positive cells in the graft at 4 months post-transplant, whereas iPSC-derived CMs treated with brentuximab vedotin prior to the transplantation did not show teratoma/tumour formation, which was associated with absence of Ki-67–positive cells in the graft over the same period. These findings suggest that in vitro treatment with brentuximab vedotin, targeting the CD30-positive iPSC fraction, reduced tumourigenicity in human iPSC-derived CMs, potentially providing enhanced safety for iPSC-based cardiomyogenesis therapy in clinical scenarios.
format	article
author	Nagako Sougawa Shigeru Miyagawa Satsuki Fukushima Ai Kawamura Junya Yokoyama Emiko Ito Akima Harada Kaori Okimoto Noriko Mochizuki-Oda Atsuhiro Saito Yoshiki Sawa
author_facet	Nagako Sougawa Shigeru Miyagawa Satsuki Fukushima Ai Kawamura Junya Yokoyama Emiko Ito Akima Harada Kaori Okimoto Noriko Mochizuki-Oda Atsuhiro Saito Yoshiki Sawa
author_sort	Nagako Sougawa
title	Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
title_short	Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
title_full	Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
title_fullStr	Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
title_full_unstemmed	Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy
title_sort	immunologic targeting of cd30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hipsc-based cell therapy
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/cfdeec773a2748ad83c8286f15cb0fb6
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Immunologic targeting of CD30 eliminates tumourigenic human pluripotent stem cells, allowing safer clinical application of hiPSC-based cell therapy

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