title: Lysophosphatidic acid enhances survival of human CD34(+) cells in ischemic conditions.
abstract: Several clinical trials are exploring therapeutic effect of human CD34(+) cells in ischemic diseases, including myocardial infarction. Unfortunately, most of the cells die few days after delivery. Herein we show that lysophosphatidic acid (LPA)-treated human umbilical cord blood-derived CD34(+) cells cultured under hypoxic and serum-deprived conditions present 2.2-fold and 1.3-fold higher survival relatively to non-treated cells and prostaglandin E2-treated cells, respectively. The pro-survival effect of LPA is concentration- and time-dependent and it is mediated by the activation of peroxisome proliferator-activator receptor γ (PPARγ) and downstream, by the activation of pro-survival ERK and Akt signaling pathways and the inhibition of mitochondrial apoptotic pathway. In hypoxia and serum-deprived culture conditions, LPA induces CD34(+) cell proliferation without maintaining the their undifferentiating state, and enhances IL-8, IL-6 and G-CSF secretion during the first 12 h compared to non-treated cells. LPA-treated CD34(+) cells delivered in fibrin gels have enhanced survival and improved cardiac fractional shortening at 2 weeks on rat infarcted hearts as compared to hearts treated with placebo. We have developed a new platform to enhance the survival of CD34(+) cells using a natural and cost-effective ligand and demonstrated its utility in the preservation of the functionality of the heart after infarction.
authors.affiliation: Biocant, Cantanhede, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kostic
authors.affiliation: Biocant, Cantanhede, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fidalgo-Carvalho
authors.affiliation: Biocant, Cantanhede, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Sezin
authors.initials: S
authors.lastname: Aday
authors.affiliation: Biocant, Cantanhede, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Vazão
authors.affiliation: Portuguese Institute for Blood and Transplantation, IP, Coimbra, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Carvalheiro
authors.affiliation: Biocant, Cantanhede, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Grãos
authors.affiliation: Department of Cardiology, Coimbra University Hospital Center &Faculty of Medicine University of Coimbra, Coimbra, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Duarte
authors.affiliation: Crioestaminal, Cantanhede, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Cardoso
authors.affiliation: Department of Cardiology, Coimbra University Hospital Center &Faculty of Medicine University of Coimbra, Coimbra, Portugal.
authors.forename: Lino
authors.initials: L
authors.lastname: Gonçalves
authors.affiliation: Department of Anatomical Pathology, University Hospital of Coimbra, Coimbra, Portugal.
authors.forename: Lina
authors.initials: L
authors.lastname: Carvalho
authors.affiliation: Portuguese Institute for Blood and Transplantation, IP, Coimbra, Portugal.
authors.forename: Artur
authors.initials: A
authors.lastname: Paiva
authors.affiliation: Biocant, Cantanhede, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Lino
authors.initials: L
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053453:Caspase 9 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D036101:Cord Blood Stem Cell Transplantation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D016207:Cytokines; D008246:Lysophospholipids; D047495:PPAR gamma; D051028:bcl-2-Associated X Protein; D053453:Caspase 9; C032881:lysophosphatidic acid