Preventing Brain Damage from Hypoxic-Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) causes permanent motor deficit "cerebral palsy (CP)," and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.The brain damage process "HIE cascade" was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE. KEY POINTS: · This study includes new insights about cell therapy for neonatal HIE and CP in schema.. · This study shows precise mechanism of neonatal HIE cascade.. · The mechanism of cell therapy by comparing umbilical cord blood stem cell with MSC is shown.. · The review of recent clinical trials of UC-MSC is shown..

Fig. 1

Mechanism of hypoxic–ischemic encephalopathy (HIE) cascade and cell therapy for HIE cascade. First, HIE induces energy depletion (O2-, Glucose-) in a capillary and glucose reduction in endothelial cell (EC) and in astrocyte. Glucose reduction in astrocyte leads to reduction of pyruvate and lactate that is converted from pyruvate by lactate dehydrogenase 5 (LDH5). And it leads to reduction of lactate and reduction of pyruvate that is converted from lactate-by-lactate dehydrogenase 1(LDH1) in presynaptic site. Then, pyruvate reduction with O2 reduction leads to adenosine triphosphate (ATP) reduction in mitochondria. Glutamate (Glu) is converted to glutamine (Gly) by the action of glutamine synthetase (GS) in astrocyte, and shuttled from astrocyte to neurons, then converted to Glu by glutaminases (GLS). Energy depletion in presynaptic site of neurons activates release of Glu into synapse. A large proportion of the Glu released at the synapse is taken up by astrocytes via excitatory amino acid transporter (EAAT) together with three Na ⁺ ions. This Na ⁺ is extruded by the action of the Na ⁺ /K+ ATPase. Glu uptake cannot work enough in the condition of ATP reduction. Glu at synapse activate N-methyl-D-aspartate glutamate glutamatergic receptor (NMDA GluR), AMPA/Kainate glutamatergic receptor (A/K GluR), and metabolic glutamatergic receptor (mGluR). On the other hand, A/K receptors do not directly allow entry of sufficient calcium to increase intracellular Ca ²⁺ concentration. However, A/K receptors flux large amounts of sodium, depolarizing cell membrane and blocking Ca ²⁺ efflux from neurons by cation/ Ca ²⁺ antiporter (CaCA). Depolarization of cell membrane activates voltage-sensitive Ca channels (VSCC) and facilitate NMDA GluR activation. Signaling of mGluR by Glu, activating phospholipase C (PLC), facilitate inositol 1,4,5-triphosphate (IP3) and activate IP3 induces calcium release (IICR) from endoplasmic reticulum (ER). Furthermore, elevation of intracellular Ca ²⁺ concentration activates calcium-induced calcium release (CICR) from ER. Ca ²⁺ efflux from neurons by Ca ²⁺ -ATPase cannot work enough to prevent elevation of intracellular Ca ²⁺ concentration in the condition of ATP deduction. These multiple mechanisms of HIE induce steep elevation of intracellular Ca ²⁺ concentration from 10 ⁻⁷ M and reach plateau level in several minutes as we show in our article. After plateau level of intracellular Ca ²⁺ concentration, neuronal damage becomes irreversible. Microglia also play an important role of neuronal cell damage in case of HIE. Energy depletion in a capillary induces impairment of microglia and it facilitates cytokines, Glu, reactive oxygen species (ROS), and reactive nitrogen species (RNS). Red circles show protective effects of mesenchymal stem cell (MSC) and umbilical cord blood stem cells (UCBCs) on impairment of microglia, inflammation, oxidative stress (free radicals and ROS/RNS) and apoptosis. Red square shows a protective effect of MSC on excitotoxicity. Red triangle shows a protective effect of bone marrow mononuclear cells (BM-MNCs) on energy reduction in EC via gap junction.

Fig. 2

Timing of promising cell therapies with standard therapies for hypoxic–ischemic encephalopathy cascade. Inflammation, oxidative stress, apoptosis, and necrosis occur through downstream energy depletion, excitotoxicity, and/or impairment of microglia. Cell damage begins immediately after hypoxic–ischemic insult and repair process begin after that. Impairment of microglia, oxidative stress, and apoptosis continues during a period of days to weeks beyond the phase of “secondary energy failure.” Cell therapy could also work for days to weeks after neonatal cardiopulmonary resuscitation (CPR), respiratory circulation support therapy, and therapeutic hypothermia (TH) are over.