title: Maternal diabetes and high glucose in vitro trigger Sca1+cardiac progenitor cell apoptosis through FoxO3a.
abstract: Recent controversies surrounding the authenticity of c-kit+cardiac progenitor cells significantly push back the advance in regenerative therapies for cardiovascular diseases. There is an urgent need for research in characterizing alternative types of cardiac progenitor cells. Towards this goal, in the present study, we determined the effect of maternal diabetes on Sca1+cardiac progenitor cells. Maternal diabetes induced caspase 3-dependent apoptosis in Sca1+cardiac progenitor cells derived from embryonic day 17.5 (E17.5). Similarly, high glucose in vitro but not the glucose osmotic control mannitol triggered Sca1+cardiac progenitor cell apoptosis in a dose- and time-dependent manner. Both maternal diabetes and high glucose in vitro activated the pro-apoptotic transcription factor, Forkhead O 3a (FoxO3a) via dephosphorylation at threonine 32 (Thr-32) residue. foxo3a gene deletion abolished maternal diabetes-induced Sca1+cardiac progenitor cell apoptosis. The dominant negative FoxO3a mutant without the transactivation domain from the C terminus blocked high glucose-induced Sca1+cardiac progenitor cell apoptosis, whereas the constitutively active FoxO3a mutant with the three phosphorylation sites, Thr-32, Ser-253, and Ser-315, being replaced by alanine residues mimicked the pro-apoptotic effect of high glucose. Thus, maternal diabetes and high glucose in vitro may limit the regenerative potential of Sca1+cardiac progenitor cells by inducing apoptosis through FoxO3a activation. These findings will serve as the guide in optimizing the autologous therapy using Sca1+cardiac progenitor cells in cardiac defect babies born exposed to maternal diabetes.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Penghua
authors.initials: P
authors.lastname: Yang
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Yang
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Sunjay
authors.initials: S
authors.lastname: Kaushal
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Daoyin
authors.initials: D
authors.lastname: Dong
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: wshen@fpi.umaryland.edu.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis; D000067696:Ataxin-1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D053148:Caspase 3; D005947:Glucose
keywords: Apoptosis; Diabetic embryopathy; FoxO3a; High glucose; Maternal diabetes; Sca1(+) cardiac progenitor cells