Tatsuya Morishima1,2, Julia Skokowa3, Yun Xu4, Masoud Nasri4, Benjamin Dannenmann4, Perihan Mir4,5, Azadeh Zahabi4, Karl Welte5. 1. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany. tatsuyam@kumamoto-u.ac.jp. 2. present address: International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan. tatsuyam@kumamoto-u.ac.jp. 3. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany. Julia.Skokowa@med.uni-tuebingen.de. 4. Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany. 5. University Children's Hospital Tübingen, Tübingen, Germany.
Abstract
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRT pathway in the regulation of maintenance and differentiation of human-induced pluripotent stem (iPS) cells is not fully elucidated. METHODS: We evaluated the effects of specific inhibitors of NAMPT or SIRT2 on the pluripotency, proliferation, survival, and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells. RESULTS: We demonstrated that NAMPT is indispensable for the maintenance, survival, and hematopoietic differentiation of iPS cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affect hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system. CONCLUSIONS: Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.
BACKGROUND:Nicotinamide phosphoribosyltransferase (NAMPT) regulates cellular functions through the protein deacetylation activity of nicotinamide adenine dinucleotide (NAD+)-dependent sirtuins (SIRTs). SIRTs regulate functions of histones and none-histone proteins. The role of NAMPT/SIRT pathway in the regulation of maintenance and differentiation of human-induced pluripotent stem (iPS) cells is not fully elucidated. METHODS: We evaluated the effects of specific inhibitors of NAMPT or SIRT2 on the pluripotency, proliferation, survival, and hematopoietic differentiation of human iPS cells. We also studied the molecular mechanism downstream of NAMPT/SIRTs in iPS cells. RESULTS: We demonstrated that NAMPT is indispensable for the maintenance, survival, and hematopoietic differentiation of iPS cells. We found that inhibition of NAMPT or SIRT2 in iPS cells induces p53 protein by promoting its lysine acetylation. This leads to activation of the p53 target, p21, with subsequent cell cycle arrest and induction of apoptosis in iPS cells. NAMPT and SIRT2 inhibition also affect hematopoietic differentiation of iPS cells in an embryoid body (EB)-based cell culture system. CONCLUSIONS: Our data demonstrate the essential role of the NAMPT/SIRT2/p53/p21 signaling axis in the maintenance and hematopoietic differentiation of iPS cells.
Authors: Ramon Clèries; Jordi Galvez; Meritxell Espino; Josepa Ribes; Virginia Nunes; Miguel López de Heredia Journal: Comput Biol Med Date: 2012-01-24 Impact factor: 4.589
Authors: Lan Dan; Olga Klimenkova; Maxim Klimiankou; Jan-Henning Klusman; Marry M van den Heuvel-Eibrink; Dirk Reinhardt; Karl Welte; Julia Skokowa Journal: Haematologica Date: 2011-12-29 Impact factor: 9.941
Authors: Xuan Ou; Hee-Don Chae; Rui-Hong Wang; William C Shelley; Scott Cooper; Tammi Taylor; Young-June Kim; Chu-Xia Deng; Mervin C Yoder; Hal E Broxmeyer Journal: Blood Date: 2010-10-21 Impact factor: 22.113
Authors: Yingjia Zhang; Qingyan Au; Menghua Zhang; Jack R Barber; Shi Chung Ng; Bin Zhang Journal: Biochem Biophys Res Commun Date: 2009-06-25 Impact factor: 3.575