Use of stem cells in perinatal asphyxia: from bench to bedside

0021-7557/10/86-06/451 Jornal de Pediatria Review Article Copyright © 2010 by Sociedade Brasileira de Pediatria Use of stem cells in perinatal asphyxia: from bench to bedside Simone de Paula,1 Samuel Greggio,1 Jaderson Costa DaCosta2 Abstract Objectives: To present recent scientific evidence on the effects of stem cell transplantation in animal models of neonatal hypoxic-ischemic brain injury and address the translational relevance of cell therapy for clinical application in this context. Sources: The PubMed and Scopus databases were used to select articles. The selection criterion was the specificity of articles regarding the subject studied, preferably articles published from 2000 onward. We also reviewed classic articles from previous years that were applicable to this review. Summary of the findings: Stem cells from different exogenous sources may exhibit neuroprotective properties in experimental models of neonatal hypoxia-ischemia. In most animal experiments, the morphological and functional benefits observed were independent of neural differentiation, suggesting associated mechanisms of action, such as the release of trophic factors and inflammatory modulation. Conclusions: Based on the experimental studies analyzed, cell therapy may become a promising therapeutic approach in the treatment of children with hypoxic-ischemic encephalopathy. However, further studies are warranted to elucidate potential mechanisms of action of these cells and to define safe and effective clinical strategies. J Pediatr (Rio J). 2010;86(6):451-464: Hypoxic-ischemic encephalopathy, stem cells, asphyxia, cell therapy. Introduction Neonatal hypoxic-ischemic (HI) brain injury is a major exhibit permanent neuropsychological impairments, such cause of neurological morbidity and mortality in infants. as mental retardation, cerebral palsy, epilepsy, and learning Statistical data suggest an incidence of asphyxia of 2-4 disability.2 per 1,000 full-term births. In Brazil, neonatal asphyxia The most frequent cause of HI encephalopathy is is estimated to occur in approximately 2% of live births.1 severe intrauterine asphyxia, and the main pathogenic Furthermore, 20-50% of asphyxiated newborns die within mechanism attributed to its neuropathology is impaired the neonatal period, and up to 25% of survivors may cerebral blood flow.3 Associated neurotoxic events, such as 1. Mestre. Programa de Pós-Graduação em Saúde da Criança, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil. 2. Doutor. Professor titular, Neurologia, Faculdade de Medicina, PUCRS, Porto Alegre, RS, Brazil. Diretor, Instituto do Cérebro do Rio Grande do Sul (InsCer), PUCRS, Porto Alegre, RS, Brazil. No conflicts of interest declared concerning the publication of this article. Suggested citation: de Paula S, Greggio S, DaCosta JC. Use of stem cells in perinatal asphyxia: from bench to bedside. J Pediatr (Rio J). 2010;86(6):451-464. Manuscript submitted Jun 02 2010, accepted for publication Aug 09 2010. doi:10.2223/JPED.2035 451 452 Jornal de Pediatria - Vol. 86, No. 6, 2010 energy failure, membrane depolarization, excitatory amino acid release, accumulation of free radicals, and apoptosis, occur simultaneously and contribute to cellular dysfunction and neuronal death after HI insults.4 Stem cells in perinatal asphyxia – de Paula S et al. Transplantation of fetal neocortical tissue In 1996, Elsayed et al.15 conducted the first study on the use of cellular resources in the treatment of experimental HI brain injury. In that investigation, the authors assessed the Despite the technological and scientific advances in effects of intracerebral transplantation of fetal neocortical perinatal care of at-risk newborns, the clinical management tissue blocks performed 7 days after induction of HI brain of asphyxiated infants has been limited to maintenance of injury in neonatal rats. Although successful transplants were oxygenation, control of blood pressure and homeostasis, observed in 63% of cases, the study failed to demonstrate treatment of seizures, and control of intracranial significant therapeutic effects on brain atrophy. Additionally, hypertension.5 that study did not conduct a functional assessment New neuroprotective strategies have been investigated of transplanted animals. Another research group also in experimental studies and clinical trials due to the performed intracerebral transplantation of fetal neocortical clinical significance and socioeconomic impact generated tissue 3 days after induction of HI brain injury.16 Instead of by neonatal brain damage. Calcium blockers, inhibitors of using tissue blocks, the authors used cell suspensions to excitatory amino acids and free radicals, use of nitric oxide, facilitate the transplantation procedure. The results showed growth factors, neuropeptides and hypothermia are some improvement in motor function and asymmetry in treated of the current therapeutic approaches that aim to interrupt animals. However, although transplants were identifiable the cascade of neurochemical events triggered by hypoxia- in 72% of the animals 10-12 weeks after implantation, ischemia.4 Except for hypothermia, which shows satisfactory the authors observed absence of cortical cytoarchitecture outcomes only in infants with moderate HI injury, these recovery. therapies have limited results.6 In this context, cell therapy has been explored because it is an up-to-date and promising approach for treatment of severe neurological diseases. Stem cells represent a natural unit of embryonic development and tissue repair, characterized as a subset of immature, undifferentiated and unspecialized cells that have the capacity for self-renewal and differentiation into specific cell lineages.7 Such cells have been found in all postnatal organs and tissues, including the central nervous system (CNS), previously known by the lack of progenitor cells and regenerative potential.8 Recent discoveries have revolutionized the field of stem cell biology by demonstrating the clinical potential of these cells in a variety of human diseases. Initially used in the treatment of hematologic malignancies and autoimmune disorders, transplantation of immature and undifferentiated cells is Neural stem cell transplantation Neural stem cells (NSC) have the capacity for self-renewal and limited capability to generate cells of neuronal and glial lineages. Such cells can be isolated from different regions of the embryonic nervous system or harvested from two specific regions of the adult brain: the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus.7,9 Studies have shown that NSC can migrate and survive in injured brain areas and can be induced to differentiate in vivo and in vitro into neurons, oligodendrocytes and astrocytes, indicating a potential alternative to replacement of cell types affected in (...truncated)