ARSENIC TRIOXIDE BLOCKED PROLIFERATION AND CARDIOMYOCYTE DIFFERENTIATION OF HUMAN INDUCED PLURIPOTENT STEM CELLS: IMPLICATION IN CARDIAC DEVELOPMENTAL TOXICITY

Publication date: 2019

DOI: 10.1016/j.toxlet.2019.03.008

Abstract:

Arsenictrioxide(ATO)hasbeenrecommendedasthefirst-lineagentforthetreatmentofacutepromyelocytic leukaemia(APL),duetoitssubstantialanticancereffect.NumerousclinicalreportshaveindicatedthatATOisa developmentaltoxicantwhichcanresultinbirthdefectsofhumanbeings.Butwhetherarsenictrioxidecanlead to human cardiac developmental toxicity remains largely unknown. So the present study aims to explore the influenceandmechanismsofATOonhumancardiacdevelopmentbyusingavitrocardiacdifferentiationmodel ofhumaninducedpluripotentstemcells(hiPSCs).Herewefoundthatclinicallyachievableconcentrations(0.1, 0.5 and 1μM) of ATO resulted in a significant inhibition of proliferation during the whole process of cardiac differentiationofhiPSCs.Meanwhile,TUNELassayrevealedthatATOcouldcausecellapoptosisduringcardiac differentiationinaconcentration-dependentmanner.Consistently,wefoundthatATOreducedtheexpressions ofmesodermmarkersBrachyuryandEOMES,cardiacprogenitorcellmarkersGATA-4,MESP-1andTBX-5,and cardiacspecificmarkerα-actininindifferentiatedhiPSCs.Furthermore,ATOtreatmenthadcausedDNAdamage which was shown in the upregulation of γH2AX, a sensitive marker for DNA double-strand breaks. Taken together, ATO blocked cardiomyocyte differentiation, induced apoptosis and cell growth arrest during cardiac differentiationofhiPSCs,whichmightbeassociatedwithDNAdamage.

Издатель: Elsevier Science Publishing Company, Inc.

Тип: Article