FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation

Background The poor survival rates of transplanted mesenchymal stem cells (MSCs) in harsh microenvironments impair the efficacy of MSCs transplantation in myocardial infarction (MI). Extrinsic apoptosis pathways play an important role in the apoptosis of transplanted MSCs, and Fas apoptosis inhibitory molecule (FAIM) is involved in regulation of the extrinsic apoptosis pathway. Thus, we aimed to explore whether FAIM augmentation protects MSCs against stress-induced apoptosis and thereby improves the therapeutic efficacy of MSCs. Methods We ligated the left anterior descending coronary artery (LAD) in the mouse heart to generate an MI model and then injected FAIM-overexpressing MSCs (MSCsFAIM) into the peri-infarction area in vivo. Moreover, FAIM-overexpressing MSCs were challenged with oxygen, serum, and glucose deprivation (OGD) in vitro, which mimicked the harsh microenvironment that occurs in cardiac infarction. Results FAIM was markedly downregulated under OGD conditions, and FAIM overexpression protected MSCs against OGD-induced apoptosis. MSCsFAIM transplantation improved cell retention, strengthened angiogenesis, and ameliorated heart function. The antiapoptotic effect of FAIM was mediated by cellular-FLICE inhibitory protein (c-FLIP), and FAIM augmentation improved the protein expression of c-FLIP by reducing ubiquitin–proteasome-dependent c-FLIP degradation. Furthermore, FAIM inhibited the activation of JNK, and treatment with the JNK inhibitor SP600125 abrogated the reduction in c-FLIP protein expression caused by FAIM silencing. Conclusions Overall, these results indicated that FAIM curbed the JNK-mediated, ubiquitination–proteasome-dependent degradation of c-FLIP, thereby improving the survival of transplanted MSCs and enhancing their efficacy in MI. This study may provide a novel approach to strengthen the therapeutic effect of MSC-based therapy.

[1]  Rizwan Kalani,et al.  Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association , 2022, Circulation.

[2]  Changyou Gao,et al.  Multifunctional elastomer cardiac patches for preventing left ventricle remodeling after myocardial infarction in vivo. , 2022, Biomaterials.

[3]  N. Ivanisenko,et al.  Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks. , 2021, Trends in cancer.

[4]  Jianyi(Jay) Zhang,et al.  Basic and Translational Research in Cardiac Repair and Regeneration , 2021, Journal of the American College of Cardiology.

[5]  Bentong Yu,et al.  FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma , 2021, Autophagy.

[6]  Bingyun Li,et al.  Injectable and conductive cardiac patches repair infarcted myocardium in rats and minipigs , 2021, Nature Biomedical Engineering.

[7]  V. Thakur,et al.  Recent Advances in Cardiac Tissue Engineering for the Management of Myocardium Infarction , 2021, Cells.

[8]  R. Simó,et al.  Faim knockout leads to gliosis and late‐onset neurodegeneration of photoreceptors in the mouse retina , 2021, Journal of neuroscience research.

[9]  J. Willerson,et al.  Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction , 2021, Science Translational Medicine.

[10]  Jianyi(Jay) Zhang,et al.  Cyclin D2 Overexpression Enhances the Efficacy of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Myocardial Repair in a Swine Model of Myocardial Infarction , 2021, Circulation.

[11]  K. Red-Horse,et al.  miR-106a–363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury , 2021, Basic Research in Cardiology.

[12]  Minjian Kong,et al.  SRT1720 Pretreatment Promotes Mitochondrial Biogenesis of Aged Human Mesenchymal Stem Cells and Improves Their Engraftment in Post-infarct Non-Human Primate Hearts. , 2021, Stem cells and development.

[13]  Da-Zhi Wang,et al.  Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction. , 2020, Circulation.

[14]  J. Zhao,et al.  TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway , 2020, Frontiers in Cell and Developmental Biology.

[15]  Gerard P. Quinn,et al.  The pseudo-caspase FLIP(L) regulates cell fate following p53 activation , 2020, Proceedings of the National Academy of Sciences.

[16]  W. El-Deiry,et al.  Targeting apoptosis in cancer therapy , 2020, Nature Reviews Clinical Oncology.

[17]  H. Kaku,et al.  FAIM Is a Non-redundant Defender of Cellular Viability in the Face of Heat and Oxidative Stress and Interferes With Accumulation of Stress-Induced Protein Aggregates , 2020, Frontiers in Molecular Biosciences.

[18]  E. Garí,et al.  SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L , 2020, Cell Death & Disease.

[19]  K. Lam,et al.  FAIM: An Antagonist of Fas-Killing and Beyond , 2019, Cells.

[20]  Jianyi(Jay) Zhang,et al.  Regenerative Potential of Neonatal Porcine Hearts , 2018, Circulation.

[21]  D. Longley,et al.  FLIP as a therapeutic target in cancer , 2018, The FEBS journal.

[22]  P. Menasché.  Cell therapy trials for heart regeneration — lessons learned and future directions , 2018, Nature Reviews Cardiology.

[23]  Lil Pabon,et al.  Human ESC-Derived Cardiomyocytes Restore Function in Infarcted Hearts of Non-Human Primates , 2018, Nature Biotechnology.

[24]  Jing Zhao,et al.  Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation , 2018, Cell Death & Disease.

[25]  E. Marbán.  A mechanistic roadmap for the clinical application of cardiac cell therapies , 2018, Nature Biomedical Engineering.

[26]  Jing Zhao,et al.  Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates , 2018, Circulation research.

[27]  V. Fast,et al.  Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell–Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine , 2017, Circulation.

[28]  J. Comella,et al.  Identification and characterization of new isoforms of human fas apoptotic inhibitory molecule (FAIM) , 2017, PloS one.

[29]  J. Zhao,et al.  SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction , 2017, Cell Death & Disease.

[30]  K. Schulze-Osthoff,et al.  c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity. , 2017, Cell reports.

[31]  Wei Zhu,et al.  Tissue-Specific Progenitor and Stem Cells Exosomes Derived From Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor , 2016 .

[32]  Liangpeng Li,et al.  How to Improve the Survival of Transplanted Mesenchymal Stem Cell in Ischemic Heart? , 2015, Stem cells international.

[33]  Robert Zweigerdt,et al.  Cardiac differentiation of human pluripotent stem cells in scalable suspension culture , 2015, Nature Protocols.

[34]  Y. Jang,et al.  Modulation of Fas–Fas Ligand Interaction Rehabilitates Hypoxia-Induced Apoptosis of Mesenchymal Stem Cells in Ischemic Myocardium Niche , 2015, Cell transplantation.

[35]  Eva Brauchle,et al.  Generation and Assessment of Functional Biomaterial Scaffolds for Applications in Cardiovascular Tissue Engineering and Regenerative Medicine , 2015, Advanced healthcare materials.

[36]  M. Rosen,et al.  Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. , 2014, Journal of the American College of Cardiology.

[37]  I. Lavrik,et al.  Systems biology of death receptor networks: live and let die , 2014, Cell Death and Disease.

[38]  John C Reed,et al.  Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-dependent Degradation of Anti-apoptotic c-FLIP Protein* , 2013, The Journal of Biological Chemistry.

[39]  A. Safa,et al.  c-FLIP, a master anti-apoptotic regulator. , 2012, Experimental oncology.

[40]  M. Tendera,et al.  Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? , 2012, Leukemia.

[41]  A. Jahanian-Najafabadi,et al.  Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity , 2012, Cell Stress and Chaperones.

[42]  H. Steller,et al.  Programmed Cell Death in Animal Development and Disease , 2011, Cell.

[43]  E. Olson,et al.  Transient Regenerative Potential of the Neonatal Mouse Heart , 2011, Science.

[44]  D. Green,et al.  FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. , 2011, The Biochemical journal.

[45]  K. Lam,et al.  Fas Apoptosis Inhibitory Molecule Regulates T Cell Receptor-mediated Apoptosis of Thymocytes by Modulating Akt Activation and Nur77 Expression* , 2010, The Journal of Biological Chemistry.

[46]  Eduardo Marbán,et al.  Assessment and Optimization of Cell Engraftment After Transplantation Into the Heart , 2010, Circulation research.

[47]  J. Eriksson,et al.  PKC-mediated phosphorylation regulates c-FLIP ubiquitylation and stability , 2009, Cell Death and Differentiation.

[48]  Q. Zeng,et al.  Genetic deletion of faim reveals its role in modulating c-FLIP expression during CD95-mediated apoptosis of lymphocytes and hepatocytes , 2009, Cell Death and Differentiation.

[49]  Byung‐Soo Kim,et al.  Mesenchymal stem cells for treatment of myocardial infarction. , 2008, International journal of stem cells.

[50]  E. Soriano,et al.  The Long Form of Fas Apoptotic Inhibitory Molecule Is Expressed Specifically in Neurons and Protects Them against Death Receptor-Triggered Apoptosis , 2007, The Journal of Neuroscience.

[51]  A. Davies,et al.  The death receptor antagonist FAIM promotes neurite outgrowth by a mechanism that depends on ERK and NF-κB signaling , 2004, The Journal of cell biology.

[52]  Paul D. Kessler,et al.  Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart , 2002, Circulation.

[53]  M. Djerbi,et al.  Characterization of the Human FLICE‐Inhibitory Protein Locus and Comparison of the Anti‐Apoptotic Activity of Four Different FLIP Isoforms , 2001, Scandinavian journal of immunology.

[54]  C. Bode,et al.  The role of apoptosis in myocardial ischemia: a critical appraisal , 2001, Basic Research in Cardiology.

[55]  T. J. Donohoe,et al.  An alternatively spliced long form of Fas apoptosis inhibitory molecule (FAIM) with tissue-specific expression in the brain. , 2001, Molecular immunology.

[56]  G. M. Fischer,et al.  A Novel Gene Coding for a Fas Apoptosis Inhibitory Molecule (FAIM) Isolated from Inducibly Fas-resistant B Lymphocytes , 1999, The Journal of experimental medicine.

[57]  M. Peter,et al.  Cytotoxicity‐dependent APO‐1 (Fas/CD95)‐associated proteins form a death‐inducing signaling complex (DISC) with the receptor. , 1995, The EMBO journal.