CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

Background: Cardiovascular disease is the leading cause of death in developed and developing countries. The lack of effective regenerative therapies in the treatment of ischemia‐related diseases requires new therapies to improve clinical outcomes. Thus, MSCs have become a focus in stem cell treatment of myocardial injury. At present, most studies use mixed MSCs in vivo and in vitro. A promising therapeutic strategy for myocardial injury should be using the dominant subgroup with essential biological characteristics. The aim of this study was to utilize the dominant CD73 + subgroup of adipose derived mesenchymal stem cells (ADMSCs) for the therapy of myocardial infarction (MI). Methods: Adult mix gender SD rats, with a body weight of 230±18g, were randomly divided into sham operation group (SHAM), MI group (MI), mixed ADMSCs transplantation group (MI+ADMSCs), CD73 + ADMSCs transplantation group (MI+CD73 + ADMSCs) and CD73 - ADMSCs transplantation group (MI+CD73 - ADMSCs). CD73 + ADMSCs were isolated using flow cytometry and then cultured. Overexpression and inhibition of CD73 gene of ADMSCs using lentiviral vectors. Differential genes analysis of CD73 + ADMSCs vs. CD73 - ADMSCs were based on GO analysis. The effect of CD73 on the secretion of cytokines was measured by ELISA. Myocardial infarction model and cell transplantation model were replicated. Detection of cardiac function of rats by color doppler ultrasound after operation. The expression of VEGF and factor VIII and neovascularization were detected by immunohistochemistry and Western Blotting. Results: We demonstrated that, compared to mixed ADMSCs and CD73 - ADMSCs, CD73 + ADMSCs were more effective in the promotion function of cardiac recovery in a rat model of MI. CD73 + subset promoted vascular regeneration in myocardial injured regions. We also showed that expression of CD73 promoted secretion of VEGF, HIF-1α and HGF factors in ADMSCs. CD73 + ADMSCs displayed significantly different transcription profile compared to CD73 - ADMSCs, in particular, concerning VEGF pathways. Conclusions: Overall, CD73 + ADMSCs were the dominant subgroup and the presence of the surface marker CD73 can be used as a MSCs cell quality control for treatment of myocardial injury by angiogenesis.

[1]  Jui-Che Lin,et al.  Studies of proliferation and chondrogenic differentiation of rat adipose stem cells using an anti-oxidative polyurethane scaffold combined with cyclic compression culture. , 2020, Materials science & engineering. C, Materials for biological applications.

[2]  Š. Kubínová,et al.  A Comparative Analysis of Multipotent Mesenchymal Stromal Cells derived from Different Sources, with a Focus on Neuroregenerative Potential , 2020, Scientific Reports.

[3]  N. Asai,et al.  Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction. , 2019, Circulation research.

[4]  L. Kirshenbaum,et al.  Inflammation in myocardial injury- mesenchymal stem cells as potential immunomodulators. , 2019, American journal of physiology. Heart and circulatory physiology.

[5]  Qing Luo,et al.  Mesenchymal Stem Cell Migration and Tissue Repair , 2019, Cells.

[6]  P. Canoll,et al.  CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A2B Adenosine Receptor Signaling , 2019, The Journal of Neuroscience.

[7]  S. Kletukhina,et al.  Angiogenic Activity of Cytochalasin B-Induced Membrane Vesicles of Human Mesenchymal Stem Cells , 2019, bioRxiv.

[8]  N. Rouas-Freiss,et al.  Biological functions of mesenchymal stem cells and clinical implications , 2019, Cellular and Molecular Life Sciences.

[9]  L. Qiu,et al.  CD73 Expression on Mesenchymal Stem Cells Dictates the Reparative Properties via Its Anti-Inflammatory Activity , 2019, Stem cells international.

[10]  S. Duan,et al.  CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling , 2019, Brain : a journal of neurology.

[11]  C. Stamm,et al.  Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases , 2019, Cellular and Molecular Life Sciences.

[12]  M. Munson,et al.  Exposing the Elusive Exocyst Structure. , 2018, Trends in biochemical sciences.

[13]  S. Eichmüller,et al.  Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E , 2018, Front. Immunol..

[14]  R. David,et al.  Recent Progress in Stem Cell Modification for Cardiac Regeneration , 2018, Stem cells international.

[15]  R. David,et al.  Intramyocardial angiogenetic stem cells and epicardial erythropoietin save the acute ischemic heart , 2018, Disease Models & Mechanisms.

[16]  I. Sekiya,et al.  Prospectively isolated mesenchymal stem/stromal cells are enriched in the CD73+ population and exhibit efficacy after transplantation , 2017, Scientific Reports.

[17]  J. Montero,et al.  Hypoxia Inducible Factor‐1α Potentiates Jagged 1‐Mediated Angiogenesis by Mesenchymal Stem Cell‐Derived Exosomes , 2017, Stem cells.

[18]  A. Bayés‐Genís,et al.  Intracoronary Administration of Allogeneic Adipose Tissue–Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction , 2017, Journal of the American Heart Association.

[19]  C. Rose,et al.  CD73‐derived adenosine and tenascin‐C control cytokine production by epicardium‐derived cells formed after myocardial infarction , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  S. Robson,et al.  The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets , 2017, Immunological reviews.

[21]  Phillip C. Yang,et al.  Exosomes Generated From iPSC-Derivatives: New Direction for Stem Cell Therapy in Human Heart Diseases , 2017, Circulation research.

[22]  K. Kang,et al.  Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis , 2016, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  J. Werkmeister,et al.  Identification and Characterization of Human Endometrial Mesenchymal Stem/Stromal Cells and Their Potential for Cellular Therapy , 2016, Stem cells translational medicine.

[24]  Yaojiong Wu,et al.  Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential , 2016, Cellular and Molecular Life Sciences.

[25]  J. K. Leach,et al.  Increased Survival and Function of Mesenchymal Stem Cell Spheroids Entrapped in Instructive Alginate Hydrogels , 2016, Stem cells translational medicine.

[26]  S. Scheding,et al.  Isolation and characterization of primary bone marrow mesenchymal stromal cells , 2016, Annals of the New York Academy of Sciences.

[27]  S. MacNeil,et al.  Human Mesenchymal Stromal Cells from Different Sources Diverge in Their Expression of Cell Surface Proteins and Display Distinct Differentiation Patterns , 2015, Stem cells international.

[28]  S. Gatti,et al.  Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. , 2015, Clinical science.

[29]  U. Decking,et al.  Extracellular Adenosine Formation by Ecto-5’-Nucleotidase (CD73) Is No Essential Trigger for Early Phase Ischemic Preconditioning , 2015, PloS one.

[30]  G. Anderson,et al.  Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release , 2015, Immunity.

[31]  Raymond M. Wang,et al.  Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction. , 2015, Biomaterials.

[32]  L. Casteilla,et al.  Mouse adipose tissue stromal cells give rise to skeletal and cardiomyogenic cell sub-populations , 2014, Front. Cell Dev. Biol..

[33]  G. Semenza,et al.  Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis , 2014, Proceedings of the National Academy of Sciences.

[34]  Kathleen M Spring,et al.  Anti‐CD73 therapy impairs tumor angiogenesis , 2014, International journal of cancer.

[35]  D. Bonatto,et al.  Reviewing and updating the major molecular markers for stem cells. , 2013, Stem cells and development.

[36]  Z. Ou,et al.  Ecto-5′-nucleotidase (CD73) promotes tumor angiogenesis , 2013, Clinical & Experimental Metastasis.

[37]  He Li,et al.  CD73+ adipose-derived mesenchymal stem cells possess higher potential to differentiate into cardiomyocytes in vitro , 2013, Journal of Molecular Histology.

[38]  G. Duda,et al.  CD73/5'-ecto-nucleotidase acts as a regulatory factor in osteo-/chondrogenic differentiation of mechanically stimulated mesenchymal stromal cells. , 2013, European cells & materials.

[39]  M. Smyth,et al.  CD73: a potent suppressor of antitumor immune responses. , 2012, Trends in immunology.

[40]  Lei Zhang,et al.  VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. , 2011, Cardiovascular Research.

[41]  SatoshiOgawa,et al.  Xenografted Human Amniotic Membrane–Derived Mesenchymal Stem Cells Are Immunologically Tolerated and Transdifferentiated Into Cardiomyocytes , 2010 .

[42]  Matthias Schieker,et al.  Morphological and immunocytochemical characteristics indicate the yield of early progenitors and represent a quality control for human mesenchymal stem cell culturing , 2009, Journal of anatomy.

[43]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[44]  Y. Geng,et al.  Combined therapy with atorvastatin and atorvastatin-pretreated mesenchymal stem cells enhances cardiac performance after acute myocardial infarction by activating SDF-1/CXCR4 axis. , 2019, American journal of translational research.

[45]  S. Fisher,et al.  Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. , 2014, The Cochrane database of systematic reviews.