Lysophosphatidic acid enhances survival of human CD34(+) cells in ischemic conditions

• Autor(a) principal: Kostic, Ivana
• Data de Publicação: 2015
• Outros Autores: Fidalgo-Carvalho, Isabel, Aday, Sezin, Vazão, Helena, Carvalheiro, Tiago, Grãos, Mário, Duarte, António, Cardoso, Carla, Gonçalves, Lino, Carvalho, Lina, Paiva, Artur, Ferreira, Lino
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/109318; https://doi.org/10.1038/srep16406
• topic: Animals; Antigens, CD34; Apoptosis; Caspase 9; Cell Differentiation; Cell Hypoxia; Cell Proliferation; Cell Survival; Cells, Cultured; Cord Blood Stem Cell Transplantation; Cytokines; Disease Models, Animal; Fetal Blood; Hematopoietic Stem Cells; Humans; Ischemia; Lysophospholipids; Male; Myocardial Infarction; PPAR gamma; Rats; Signal Transduction; Treatment Outcome; bcl-2-Associated X Protein

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.