Author(s): Kostic, I ; Fidalgo-Carvalho, I ; Aday, S ; Vazão, H ; Carvalheiro, T ; Grãos, M ; Duarte, A ; Cardoso, C ; Gonçalves, L ; Carvalho, L ; Paiva, A ; Ferreira, L
Date: 2015
Persistent ID: http://hdl.handle.net/10400.4/2082
Origin: Repositório do Centro Hospitalar e Universitário de Coimbra
Subject(s): Antigénio CD34; Sobrevivência Celular; Células-Tronco Hematopoéticas; Isquemia; Lisofosfolipídeos; Enfarte do Miocárdio
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.
