Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations

Abstract Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. H...

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Autores principales:	Karsten Burkert, Hadiseh Taheri, Sarkawt Hamad, Matteo Oliverio, Gabriel Peinkofer, Jan-Wilhelm Kornfeld, Wacharee Harnying, Kurt Pfannkuche, Jürgen Hescheler, Albrecht Berkessel, Tomo Šarić
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c42a4101eb364861aadfd22f6d533faa
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spelling	oai:doaj.org-article:c42a4101eb364861aadfd22f6d533faa2021-12-02T13:57:58ZSalicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations10.1038/s41598-021-81351-z2045-2322https://doaj.org/article/c42a4101eb364861aadfd22f6d533faa2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81351-zhttps://doaj.org/toc/2045-2322Abstract Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. Half maximal inhibitory concentrations (IC50) of small molecules SM2 and SM6 were, respectively, 9- and 18-fold higher for human than murine PSCs, while the IC50 of SM8 was comparable for both PSC groups. Treatment of murine embryoid bodies in suspension differentiation cultures with the most effective small molecule SM6 significantly reduced PSC and non-PSC contamination and enriched CM populations that would otherwise be eliminated in genetic selection approaches. All tested salicylic diamines exerted their toxicity by inhibiting the oxygen consumption rate (OCR) in PSCs. No or only minimal and reversible effects on OCR, sarcomeric integrity, DNA stability, apoptosis rate, ROS levels or beating frequency were observed in PSC-CMs, although effects on human PSC-CMs seemed to be more deleterious at higher SM-concentrations. Teratoma formation from SM6-treated murine PSC-CMs was abolished or delayed compared to untreated cells. We conclude that salicylic diamines represent promising compounds for PSC removal and enrichment of CMs without the need for other selection strategies.Karsten BurkertHadiseh TaheriSarkawt HamadMatteo OliverioGabriel PeinkoferJan-Wilhelm KornfeldWacharee HarnyingKurt PfannkucheJürgen HeschelerAlbrecht BerkesselTomo ŠarićNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karsten Burkert Hadiseh Taheri Sarkawt Hamad Matteo Oliverio Gabriel Peinkofer Jan-Wilhelm Kornfeld Wacharee Harnying Kurt Pfannkuche Jürgen Hescheler Albrecht Berkessel Tomo Šarić Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
description	Abstract Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. Half maximal inhibitory concentrations (IC50) of small molecules SM2 and SM6 were, respectively, 9- and 18-fold higher for human than murine PSCs, while the IC50 of SM8 was comparable for both PSC groups. Treatment of murine embryoid bodies in suspension differentiation cultures with the most effective small molecule SM6 significantly reduced PSC and non-PSC contamination and enriched CM populations that would otherwise be eliminated in genetic selection approaches. All tested salicylic diamines exerted their toxicity by inhibiting the oxygen consumption rate (OCR) in PSCs. No or only minimal and reversible effects on OCR, sarcomeric integrity, DNA stability, apoptosis rate, ROS levels or beating frequency were observed in PSC-CMs, although effects on human PSC-CMs seemed to be more deleterious at higher SM-concentrations. Teratoma formation from SM6-treated murine PSC-CMs was abolished or delayed compared to untreated cells. We conclude that salicylic diamines represent promising compounds for PSC removal and enrichment of CMs without the need for other selection strategies.
format	article
author	Karsten Burkert Hadiseh Taheri Sarkawt Hamad Matteo Oliverio Gabriel Peinkofer Jan-Wilhelm Kornfeld Wacharee Harnying Kurt Pfannkuche Jürgen Hescheler Albrecht Berkessel Tomo Šarić
author_facet	Karsten Burkert Hadiseh Taheri Sarkawt Hamad Matteo Oliverio Gabriel Peinkofer Jan-Wilhelm Kornfeld Wacharee Harnying Kurt Pfannkuche Jürgen Hescheler Albrecht Berkessel Tomo Šarić
author_sort	Karsten Burkert
title	Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
title_short	Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
title_full	Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
title_fullStr	Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
title_full_unstemmed	Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
title_sort	salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c42a4101eb364861aadfd22f6d533faa
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Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations

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