Overall, each year approximately 2 million people with hypoxic-ischemic brain injury die or develop long-term disabling consequences, including motor and cognitive deficits; this condition seriously affects the lives of these patients and their families and has a major socioeconomic impact. Although hypoxia-ischemia is common, the frequency and severity of its consequences have not decreased over the years. Moreover, this condition is usually asymptomatic; by the time diagnosis is made, it is often too late to act. Finally, currently available treatments not only have limited effectiveness and a narrow therapeutic window, but can also cause serious side effects that can worsen the patient’s condition.
Hypoxic-ischemic brain damage is a process caused by a decrease in cerebral blood flow, which leads to insufficient supply of oxygen and glucose to the brain. This causes primary energy deficiency and increased anaerobic metabolism, leading to increased lactate levels (increased lactic acidosis) and decreased ATP concentrations. Blood flow, pH, and metabolite and ATP levels subsequently return to baseline levels. However, after some time, a second energy breakdown occurs due to mitochondrial dysfunction and increased oxidative stress, inflammation and excitotoxicity; these pathophysiological phenomena can last several hours and even days. Astrocytes and microglia cause brain damage.These cells release cytotoxic mediators that alter the integrity and survival of the oligodendrocytes that form myelin; Myelin damage is a pathological hallmark of hypoxia-ischemia and is responsible, at least in part, for the effects of CP. Therefore, it is important to develop treatments that can reduce cytotoxic damage and promote oligodendrocyte survival, with the ultimate goal of preserving white matter integrity.
Apart from therapeutic hypothermia, no other treatment is currently able to reduce the effects of hypoxia-ischemia. Even therapeutic hypothermia has numerous disadvantages, given that it only has a beneficial effect when administered within 6 hours of the event and only in mild cases; therefore, its therapeutic potential is limited. Other treatments that have been demonstrated to be effective in preclinical studies, such as erythropoietin and melatonin, have not proven effective in clinical practice.
Stem cell therapy
In this context, stem cell therapy has been proposed as a potential option to prevent the effects of hypoxia-ischemia, as it can be used to modulate underlying pathophysiological events and/or promote cell survival.
Cord blood cells
For many years, solid umbilical cord tissue was treated as medical waste. However, umbilical cord blood has recently been identified as a valuable source of stem cells and hematopoietic progenitor cells. Hematopoietic stem cells, characterized by the presence of the CD34 marker, are heterogeneous cells of different lines and at different stages of maturation, with a high ability for self-renewal. In addition, these cells, unlike other types of stem cells, are easy to obtain through non-invasive means, easy to store, their donation poses no risk to the donor, and are unlikely to transmit clinically significant infections to the recipient. Additionally, compared to peripheral blood In adults, cord blood has been shown to reduce the immune response to alloantigens and rarely cause graft-versus-host disease.
Most preclinical studies of hypoxic-ischemic brain injury using umbilical cord blood stem cells intravenously. Within 24 hours of hypoxic-ischemic injury, it has been shown to have neuroprotective effects as it reduces levels of inflammation and oxidative stress. showed fibroblast proliferation, neuronal maturation, synaptic strengthening, increased angiogenesis, and restoration of blood flow and blood-brain barrier permeability. Stem cells are presented as having a neuroprotective effect, reducing the levels of pro-inflammatory cytokines, and a neurorestorative effect, promoting the maturation of neurons and neuronal synapses. This led to a reduction in mortality and lesion volume, while motor and cognitive functions were restored.
Clinical trials conducted to date have shown that autologous cord blood stem cell infusion is safe due to the absence of adverse reactions. This treatment has also been found to be safe when combined with hypothermia;
In conclusion, clinical and preclinical studies have shown the efficacy and safety of stem cell therapy, which represents a promising prevention strategy as it reduces pathophysiological processes and promotes neuronal maturation.
Mesenchymal stem cells
As with hematopoietic stem cells, mesenchymal stem cells (MSCs) are undifferentiated multipotent cells that can subsequently differentiate into various lineages, including osteogenic, adipogenic, chondrogenic, and hematopoietic cells. However, in the context of hypoxic-ischemic brain injury, this cell type also differentiates into neurons. Placenta, umbilical cord tissue or blood, adipose tissue and amniotic fluid have been identified as rich sources of MSCs. Additionally, the risk of blood clots or graft-versus-host disease is low given that the cells originate from neonatal tissue.
Treatment with these cells has been found to restore motor function in diseases with similar pathophysiological mechanisms.
Mesenchymal stem cells from umbilical cord tissue
Umbilical cord (umbilical cord lining, perivascular area, Wharton’s jelly, etc.)d.) is one of the main sources of MSCs. These cells have a high proliferation rate, express chemokines and angiogenic growth factors, secrete trophic factors and have pronounced immunomodulatory activity.
This treatment has been found to restore motor and cognitive function, reduce brain damage, and reduce levels of apoptotic markers by reducing microgliosis and astrogliosis and therefore inflammation. Better results were also observed with earlier initiation of treatment, as this increased the release of trophic and angiogenic factors.
To date, umbilical cord tissue stem cells are the only MSCs that have been used in clinical trials. A phase 1 study conducted at Duke University (NCT03635450) showed that intravenous administration of these cells is safe in patients with hypoxic ischemic brain injury. injuries when administered in 1 or 2 doses and after 48 hours or 2 months.
Mesenchymal stem cells from umbilical cord blood
Umbilical cord blood is another source of MSCs. These multipotent cells differentiate into cells of mesodermal, endodermal, or ectodermal origin; the latter type is relevant for hypoxia-ischemia. In all studies, this treatment led to the restoration of motor and cognitive functions by reducing the lesion volume and maintaining neuronal survival, reducing the level of markers of microgliosis and astrogliosis. Moreover, unlike MSCs from umbilical cord tissue, these studies show that more MSCs differentiate into astrocytes and microglia, which may also contribute to the neuroprotective effect of this treatment. It has also been reported that stem cell therapy in combination with hypothermia achieves better results than either treatment alone, regardless of the time of treatment initiation. These results indicate that hypothermia may enhance the neuroprotective effect of stem cell therapy and prolong the window period.
Bone marrow mesenchymal stem cells
Bone marrow-derived MSC therapy has been one of the most commonly used approaches. However, it is no longer used due to the complexity and low yield of these cells. In any case, studies with bone marrow-derived MSCs have provided reliable evidence for the neuroprotective capacity of these cells and their effect on hypoxic-ischemic injury.
Endothelial progenitor cells
Another approach to cell therapy uses endothelial progenitor cells from peripheral blood or bone marrow.Among many other properties, endothelial progenitor cells express CD34, CD133, and vascular endothelial growth factor receptor. These markers may play a fundamental role because they differentially express microRNAs that are involved in preventing apoptosis, cytoskeletal remodeling, differentiation into multiple cell lineages, and promoting neovascularization ; this is important for the treatment of hypoxic-ischemic brain injury.
A single injection of cells resulted in motor recovery, in part due to the release of vasculogenic factors such as fibropellin precursor-2, vascular endothelial growth factor and insulin-like growth factor that promote cell maturation and proliferation and regulate cerebral blood flow.
Neural stem cells
Following an ischemic event, the brain promotes the release of neuronal and glial progenitors to compensate for the loss and dysfunction of neurons and axons. This function is performed by neural stem cells; these self-renewing multipotent cells are capable of differentiating into multiple cell lineages, including neurons, astrocytes, and oligodendrocytes.
Administration of neural stem cells reduced neuroinflammation and promoted myelination and maturation of oligodendroglial progenitor cells. This in turn promoted synaptic plasticity and axonal growth, stabilized blood-brain barrier permeability, and ultimately reduced apoptosis and acute and subacute phase lesion volume and brain tissue loss. in the chronic phase and motor dysfunction.By administering exogenous neural stem cells intrathecally, the technique represents a potential treatment option for preventing hypoxic-ischemic brain injury.
Conclusion
Hypoxic-ischemic brain injury is one of the main causes of ischemic and diffuse changes in the brain – the most common and severe motor disorder. characterized by increased excitotoxicity, oxidative stress and inflammation, which ultimately cause damage to the cerebral cortex and white matter. Stem cell therapy may open up new possibilities for treating a wide range of diseases. This treatment reduces inflammation and oxidative stress and promotes cell survival, maturation and differentiation, ultimately leading to restoration of motor function. Although most clinical trials have used umbilical cord blood stem cells, some trials have also been conducted with MSCs and neural stem cells, demonstrating their safety in humans. In addition, stem cell therapy has been found to enhance the therapeutic effect of concurrent treatments. . These results suggest that stem cell therapy may represent an effective strategy to reduce the severity and incidence of hypoxic-ischemic brain injury.