Pedro M. Pimentel-Coelho

Human cord blood transplantation in a neonatal rat model of hypoxic–ischemic brain damage: functional outcome related to neuroprotection in the striatum

Human umbilical cord blood mononuclear cells (HUCB) have been shown to have a therapeutic role in different models of central nervous system (CNS) damage, including stroke. We evaluated the possible therapeutic potential of HUCB in P7 rats submitted to the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain damage. Our results demonstrated that intraperitoneal transplantation of HUCB, 3 h after the HI insult, resulted in better performance in two developmental sensorimotor reflexes, in the first week after the injury. We also showed a neuroprotective effect in the striatum, and a decrease in the number of activated microglial cells in the cerebral cortex of treated animals. We suggest that HUCB transplantation might rescue striatal neurons from cell death after a neonatal HI injury resulting in better functional recovery.

Cell Therapy for Neonatal Hypoxic–Ischemic Encephalopathy

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of long-term neurological disability in children. Despite advances in supportive care, no treatments for HIE are available at present. The potential use of stem/progenitor cell therapies for neuroprotection or regeneration of the damaged adult brain has been evaluated in several preclinical studies, and the most promising results are now being tested in clinical trials. In recent years, the use of stem/progenitor cell transplantation in animal models of HIE has also been evaluated in several laboratories. It was shown that human umbilical cord blood mononuclear cells and mesenchymal stem/progenitor cells may have a therapeutic potential through multiple mechanisms acting locally in the central nervous system and possibly in peripheral organs of hypoxic-ischemic animals. Neural stem/progenitor cells (NSCs) have also been transplanted in animal models of HIE, migrating long distances to ischemic brain areas and differentiating into neurons. The results of these studies have raised important questions that must be addressed before these findings can be translated to the bedside. In this review, we give a critical overview of the different studies published up to now, and we discuss the endogenous regenerative potential of NSCs of the newborn brain when challenged by an HIE insult. We also discuss the use of cell therapies for the encephalopathy of prematurity.

Trophic activity derived from bone marrow mononuclear cells increases peripheral nerve regeneration by acting on both neuronal and glial cell populations.

A rat model of complete sciatic nerve transection was used to evaluate the effect of bone marrow mononuclear cells (BMMC) transplanted to the injury site immediately after lesion. Rats treated with BMMC had both sensory and motor axons reaching the distal stump earlier compared to untreated animals. In addition, BMMC transplantation reduced cell death in dorsal root ganglia (DRG) compared to control animals. Transplanted BMMC remained in the lesion site for several days but there is no evidence of BMMC differentiation into Schwann cells. However, an increase in the number of Schwann cells, satellite cells and astrocytes was observed in the treated group. Moreover, neutralizing antibodies for nerve growth factor (NGF) (but not for brain-derived neurotrophic factor and ciliary-derived neurotrophic factor) added to the BMMC-conditioned medium reduced neurite growth of sensory and sympathetic neurons in vitro, suggesting that BMMC release NGF, improve regeneration of the sciatic nerve in the adult rat and stimulate Schwann and satellite cell proliferation or a combination of both.

Radial glia-like cells persist in the adult rat brain.

During development, radial glia cells contribute to neuronal migration and neurogenesis, and differentiate into astrocytes by the end of the developmental period. Recently, it was demonstrated that during development, radial glia cells, in addition to their role in migration, also give rise to neuroblasts. Furthermore, radial glial cells remain in the adult brain as adult neural stem cells (NSC) in the subventricular zone (SVZ) around the lateral ventricles (LVs), and generate new neurons continuously throughout adulthood. In this study, we used immunohistochemical and morphological methods to investigate the presence of radial glia-like cells around the LVs during the postnatal development period until adulthood in rats. In all ages of rats studied, we identified cells with morphological and immunocytochemical features that are similar to the radial glia cells found in the embryonic brain. Similarly to the radial glia, these cells express nestin and vimentin, and have a radial morphology, extending perpendicularly as processes from the ventricle wall. These cells also express GFAP, GLAST, and Pax6, and proliferate. In the brains of adult rats, we identified cells with relatively long processes (up to 600 mum) in close apposition with migrating neuroblasts. Our results showed that the radial glia-like cells present in the adult rat brain share several morphological and functional characteristics with the embryonic radial glia. We suggest that the embryonic radial glia cells located around the LV walls do not complete their transformation into astrocytes, but rather persist in adulthood.

The Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

Stroke is the second leading cause of death and the third leading cause of disability worldwide. Approximately 16 million first-ever strokes occur each year, leading to nearly 6 million deaths. Nevertheless, currently, very few therapeutic options are available. Cell therapies have been applied successfully in different hematological diseases, and are currently being investigated for treating ischemic heart disease, with promising results. Recent preclinical studies have indicated that cell therapies may provide structural and functional benefits after stroke. However, the effects of these treatments are not yet fully understood and are the subject of continuing investigation. Meanwhile, different clinical trials for stroke, the majority of them small, nonrandomized, and uncontrolled, have been reported, and their results indicate that cell therapy seems safe and feasible in these conditions. In the last 2 years, the number of published and registered trials has dramatically increased. Here, we review the main findings available in the field, with emphasis on the clinical results. Moreover, we address some of the questions that have been raised to date, to improve future studies.

Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic-ischemic encephalopathy

Despite recent advances in the treatment of neonatal hypoxic–ischemic encephalopathy (HIE) using therapeutic hypothermia, at least 30% of the cooled infants will die or have moderate/severe neurological disability. Umbilical cord blood cells (UCBCs), which are readily available at birth, have been shown to reduce sensorimotor and/or cognitive impairments in several models of brain damage, representing a promising option for the treatment of neurological diseases. In this review, we discuss recent preclinical studies that assessed the effects of UCBC transplantation in the Rice–Vannucci animal model of HIE. We also review the possible cell types and mechanisms involved in the therapeutic effect of UCBC transplantation, including neuroprotection, immunomodulation, and stimulation of neural plasticity and regeneration. In addition, we discuss how neuroimaging methods, such as bioluminescence imaging, nuclear-medicine imaging, or magnetic resonance imaging, could be used to evaluate the biodistribution of UCBCs in both preclinical and clinical studies.

Terapia celular no acidente vascular cerebral

Stroke is the leading cause of death and incapacity in Brazil. Over the last few years, numerous preclinical and clinical studies have been carried out, however to date, none of the drugs tested in these studies were effective in patients. The emerging field of stem cell research has raised hope of therapy to ameliorate the functional loss after strokes. In this review we will discuss the results of several preclinical studies and clinical trials using different types of stem cells in the treatment of strokes.

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito-borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease.

Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

Radiopharmaceutical stem cell tracking for neurological diseases.

Although neurological ailments continue to be some of the main causes of disease burden in the world, current therapies such as pharmacological agents have limited potential in the restoration of neural functions. Cell therapies, firstly applied to treat different hematological diseases, are now being investigated in preclinical and clinical studies for neurological illnesses. However, the potential applications and mechanisms for such treatments are still poorly comprehended and are the focus of permanent research. In this setting, noninvasive in vivo imaging allows better understanding of several aspects of stem cell therapies. Amongst the various methods available, radioisotope cell labeling has become one of the most promising since it permits tracking of cells after injection by different routes to investigate their biodistribution. A significant increase in the number of studies utilizing this method has occurred in the last years. Here, we review the different radiopharmaceuticals, imaging techniques, and findings of the preclinical and clinical reports published up to now. Moreover, we discuss the limitations and future applications of radioisotope cell labeling in the field of cell transplantation for neurological diseases.