For many years, umbilical cord solid tissue was treated as medical waste.19,22,23 However, umbilical cord blood has recently been identified as a valuable source of stem cells and haematopoietic precursor cells.19,22,23 Haematopoietic stem cells, characterised by presence of the CD34 marker, are heterogeneous cells from different lineages and at different stages of maturation that present a high capacity for self-renewal.19,22,23 Furthermore, these cells, unlike other types of stem cells, are easily obtained through non-invasive means, are easy to store, and their donation poses no risk to the donor and is highly unlikely to transmit clinically relevant infections to the recipient.19,22,23 Furthermore, compared to adult peripheral blood, umbilical cord blood has been found to decrease the immune response to alloantigens and rarely causes graft-versus-host disease.19,22,23 However, umbilical cord blood collection should be optimised to increase the amount of cells obtained.19,22,23

Most preclinical studies into hypoxic-ischaemic brain injury with umbilical cord blood stem cells have used rats (Table 1).17,24–29 These studies use the Rice-Vannucci model, in which animals undergo unilateral common carotid artery ligation and are subsequently exposed to a hypoxic environment.24,30 In exceptional cases, these studies have also been conducted in sheep and rabbits.17,31,32 Stem cells are generally administered intraperitoneally or intravenously,17,24–28,33 at a dose ranging from 106 to 107 cells, with no significant differences observed between doses.17,24–29,33 When treatment was started within 24 hours of hypoxic-ischaemic injury, it was shown to have a neuroprotective effect as it reduced the levels of inflammation and oxidative stress.17,25,31,32,34 However, when treatment was started beyond 24 hours after injury, animals displayed fibroblast proliferation, neuronal maturation, synaptic enhancement, increased angiogenesis, and restored blood flow and blood–brain barrier permeability.17,24,26–29 Most trials were conducted at 24 hours, when a synergistic effect occurs and stem cells present both a neuroprotective effect, reducing the levels of proinflammatory cytokines, and a neurorestorative effect, promoting the maturation of neurons and neuronal synapses.17,24,26–29 This resulted in a decrease in mortality and lesion volume, with animals recovering motor and cognitive function.17,24–29

The clinical trials conducted to date have shown that infusion of autologous umbilical cord blood stem cells is safe, due to the lack of adverse reactions.23,34 Furthermore, most treatments have been administered in several doses, starting 24 hours after hypoxic-ischaemic injury (Table 2). This treatment has also been found to be safe when combined with hypothermia; however, no in vivo studies have demonstrated whether the efficacy of both treatments improves when they are administered in combination.17–19,23,34

In conclusion, clinical and preclinical trials have shown the efficacy and safety of stem cell therapy, which constitutes a promising strategy for preventing CP, as it reduces the pathophysiological processes and promotes neuronal maturation.

As is the case with haematopoietic stem cells, mesenchymal stem cells (MSC) are undifferentiated multipotent cells that can subsequently differentiate into different lineages, including osteogenic, adipogenic, chondrogenic, and haematopoietic lineage cells.17–19,22,23 However, in the context of hypoxic-ischaemic brain injury, this cell type has also been observed to differentiate into neurons.19 The placenta, umbilical cord tissue or blood, adipose tissue, and amniotic fluid have been identified as rich sources of MSCs.17–19,22,23 Furthermore, the risk of thrombus formation or graft-versus-host disease is low, given that the cells are derived from neonatal tissue.19

Treatment with these cells has been found to recover motor function in diseases with similar pathophysiological mechanisms (Table 1).19 Below, we review the preclinical trials conducted to date on animal models of hypoxic-ischaemic brain injury treated with mesenchymal stem cells of different origin.

Another approach to cell therapy uses endothelial progenitor cells from peripheral blood or bone marrow.62–67 Among many other properties, endothelial progenitor cells express CD34, CD133, and vascular endothelial growth factor receptor.62–67 These markers may play a fundamental role, since they differentially express microRNAs that are involved in the prevention of apoptosis, cytoskeleton remodelling, differentiation into multiple cell lineages, and promoting neovascularisation; this is essential for the treatment of hypoxic-ischaemic brain injury.19,62–67

Rice-Vannucci models have shown that the administration of endothelial progenitor cells 1–2 days after injury improved motor function and decreased lesion volume.19,28,36,68 A single dose of 105 cells administered intraperitoneally achieved motor recovery, in part due to the release of such vasculogenic factors as fibropellin-2 precursor, vascular endothelial growth factor, and insulin-like growth factor 118,19,22 as a result of a phenotypic change to M2 microglia18,19,22,36; this promotes cell maturation and proliferation and regulates cerebral blood flow (Table 1).18,19,22,69,70

After an ischaemic event, the brain promotes the release of neuronal and glial progenitors to compensate for the neuronal and axonal loss and dysfunction.6,18,71 This function is performed by neural stem cells; these self-renewing multipotent cells are able to differentiate into multiple cell lines, including neurons, astrocytes, and oligodendrocytes.18,72,73 Unfortunately, the release of such proapoptotic factors as calpain and caspase 3 renders the release of neuroblasts and glial progenitors ineffective: approximately 90% of neural progenitor cells will die and the remaining 10% will not be functional.18,74–76 New therapies are being developed to boost self-renewal through the administration of exogenous neural stem cells.18

In preclinical trials, the Rice-Vannucci model is once again the most frequently used.18,77–83 In all cases, animals were administered either 105 or 106 cells, mainly via the intracranial route,18,77–82 although the intranasal route has also been used.18,83 Regardless of the time of treatment onset (from 2 hours to 10 days after injury),18,77–83 administration of neural stem cells reduced neuroinflammation18,78,81,83 and promoted myelination and maturation of oligodendroglial progenitor cells.18,77,80,82,83 This, in turn, promoted synaptic plasticity and axonal growth, stabilised blood-brain barrier permeability, and ultimately reduced apoptosis and lesion volume in the acute and subacute phase, loss of brain tissue in the chronic phase, and motor dysfunction.18,77–82 Furthermore, all these benefits were observed independently of the source of the neural stem cells (embryonic tissue, fetal brain tissue, adult subventricular zone tissue, etc).18,77–82 However, the authors recommend starting treatment no sooner than 24 hours after injury, so that cell viability is not compromised by inflammation and excitotoxicity secondary to brain injury (Table 1).18,78,79,83

In addition to its efficacy, clinical trials conducted at Beijing Hospital (China) have demonstrated the safety of this treatment when administered intrathecally over 2 days in combination with hypothermia (NCT02854579). Therefore, administration of exogenous neural stem cells constitutes a potential treatment for preventing hypoxic-ischaemic brain injury (Table 2).