Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have therapeutic effects in experimental models of lung injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcriptional regulator that influences cellular metabolism, energetics, and survival under hypoxic conditions. The current study investigated the effects of stabilizing HIF-1α on the therapeutic capacity of MSCs in an experimental mouse model of bacterial pneumonia. HIF-1α stabilization was achieved by the small molecule prolyl-hydroxlase inhibitor, AKB-4924 (Aerpio Therapeutics, Inc.), which blocks the pathway for HIF-1α degradation in the proteosome. In vitro, pre-treatment with AKB-4924 increased HIF-1α levels in MSCs, reduced the kinetics of their cell death when exposed to cytotoxic stimuli, and increased their antibacterial capacity. In vivo, AKB-4924 enhanced MSC therapeutic capacity in experimental pneumonia as quantified by a sustainable survival benefit, greater bacterial clearance from the lung, decreased lung injury, and reduced inflammatory indices. These results suggest that HIF-1α stabilization in MSCs, achieved ex vivo, may represent a promising approach to augment the therapeutic benefit of these cells in severe pneumonia complicated by acute lung in...Continue Reading
References
Oct 1, 1994·Experimental Cell Research·V A PolunovskyP B Bitterman
Nov 14, 1997·American Journal of Respiratory and Critical Care Medicine·J D MrozekM C Mammel
Jul 11, 2001·Critical Care Medicine·D C AngusM R Pinsky
Jul 12, 2005·The Journal of Clinical Investigation·Carole PeyssonnauxRandall S Johnson
Apr 10, 2007·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jianguo XuMauricio Rojas
Jul 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Naveen GuptaMichael A Matthay
Sep 2, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jae W LeeMichael A Matthay
Jun 19, 2010·American Journal of Respiratory and Critical Care Medicine·Shirley H J MeiDuncan J Stewart
Oct 15, 2010·Stem Cells·Anna KrasnodembskayaMichael A Matthay
Oct 19, 2010·Blood·Chih-Chien TsaiShih-Chieh Hung
Oct 22, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xin Lu, Yibin Kang
Mar 1, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Cheryl Y M OkumuraVictor Nizet
Aug 10, 2012·Stem Cells and Development·Inmaculada CerradaPilar Sepúlveda
Aug 14, 2013·Journal of Inflammation·Emma LeireAndrew Hollands
Oct 10, 2013·Stem Cells·Kiave-Yune HoWangYinJean-Sébastien Silvestre
Jun 7, 2014·Frontiers in Immunology·Elke EggenhoferMartin J Hoogduijn
Sep 27, 2014·Stem Cell Research & Therapy·Xianbao LiuLing Wei
May 1, 2015·PLoS Pathogens·Ann E LinVictor Nizet
Jul 4, 2015·Cell Stem Cell·Alan Trounson, Courtney McDonald
Oct 2, 2015·Cell Transplantation·Tiziana SquillaroUmberto Galderisi
Dec 19, 2015·Stem Cells International·Liangpeng LiChunyu Zeng
Jan 29, 2016·PloS One·Lauralyn A McIntyreUNKNOWN Canadian Critical Care Translational Biology Group
Feb 24, 2016·JAMA : the Journal of the American Medical Association·Giacomo BellaniUNKNOWN ESICM Trials Group
Mar 31, 2017·Acta Oncologica·Sourabh Soni, Yogendra S Padwad
Jun 13, 2017·Trends in Pharmacological Sciences·Guan-Zhong QiuWei-Lin Jin
Nov 9, 2017·PloS One·Yung-Yang LiuHaibo Zhang
Nov 29, 2017·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Bailong LiYanyong Yang
Feb 6, 2018·Stem Cells·Naveen GuptaJohn H Griffin
Citations
Sep 10, 2020·Clinical Kidney Journal·Lucia Del Vecchio, Francesco Locatelli
Jun 14, 2019·Stem Cells International·C Randall HarrellVladislav Volarevic
Nov 10, 2020·Cell Transplantation·Wang FengyunFang Bin
Dec 8, 2020·Oxidative Medicine and Cellular Longevity·Yang LiuYanfeng Wang
Nov 4, 2020·Cells·Katarzyna ZielniokLeszek Paczek
Aug 8, 2021·International Journal of Molecular Sciences·Katarzyna ZielniokLeszek Paczek