title: Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: improving the safety of iPS cell transplantation to myocardium.
abstract: Induced pluripotent stem cells (iPS) can differentiate into cardiomyocytes (CM) and represent a promising form of cellular therapy for heart regeneration. However, residual undifferentiated iPS derivates (iPSD), which are not fully eliminated by cell differentiation or purification protocols, may form tumors after transplantation, thus compromising therapeutic application. Inhibition of stearoyl-coA desaturase (SCD) has recently been reported to eliminate undifferentiated human embryonic stem cells, which share many features with iPSD. Here, we tested the effects of PluriSin#1, a small-molecule inhibitor of SCD, on iPS-derived CM. We found that plurisin#1 treatment significantly decreased the mRNA and protein level of Nanog, a marker for both cell pluripotency and tumor progression; importantly, we provide evidence that PluriSin#1 treatment at 20 µM for 1 day significantly induces the apoptosis of Nanog-positive iPSD. In addition, PluriSin#1 treatment at 20 µM for 4 days diminished Nanog-positive stem cells in cultured iPSD while not increasing apoptosis of iPS-derived CM. To investigate whether PluriSin#1 treatment prevents tumorigenicity of iPSD after cell transplantation, we intramyocardially injected PluriSin#1- or DMSO-treated iPSD in a mouse model of myocardial infarction (MI). DMSO-treated iPSD readily formed Nanog-expressing tumors 2 weeks after injection, which was prevented by treatment with PluriSin#1. Moreover, treatment with PluriSin#1 did not change the expression of cTnI, α-MHC, or MLC-2v, markers of cardiac differentiation (P>0.05, n = 4). Importantly, pluriSin#1-treated iPS-derived CM exhibited the ability to engraft and survive in the infarcted myocardium. We conclude that inhibition of SCD holds the potential to enhance the safety of therapeutic application of iPS cells for heart regeneration.
authors.affiliation: Department of Vascular Surgery; Renji Hospital; School of Medicine; Shanghai Jiaotong University; Shanghai, China; Vascular Biology Center; Department of Medicine; Medical College of Georgia/Georgia Regents University; Augusta, GA USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery; Renji Hospital; School of Medicine; Shanghai Jiaotong University; Shanghai, China.
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Feinberg Cardiovascular Research Institute; Department of Medicine-Cardiology; Northwestern University Feinberg School of Medicine; Chicago, IL USA.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Cardiology; Zhongda Hospital; Medical School of Southeast University; Nanjing, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Vascular Biology Center; Department of Medicine; Medical College of Georgia/Georgia Regents University; Augusta, GA USA.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Chatterjee
authors.affiliation: Vascular Biology Center; Department of Medicine; Medical College of Georgia/Georgia Regents University; Augusta, GA USA.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Vascular Biology Center; Department of Medicine; Medical College of Georgia/Georgia Regents University; Augusta, GA USA.
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D017690:Cell Transplantation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033581:Stem Cell Transplantation / Q000009:adverse effects
chemical_list: D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: Nanog; PluriSin#1; iPS; myocardial infarction; tumorigenicity