Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia

Abstract

Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans. Graphical abstract

Hypothermia Does Not Boost the Neuroprotection Promoted by Umbilical Cord Blood Cells in a Neonatal Hypoxia-Ischemia Rat Model

“…This difference might be related with the presence of several cell types in the umbilical cord blood instead of an enriched population of MSC or the effects of cell manipulations prior to administration. Nonetheless, increasing evidence suggests that HI insults in the developing brain result in a complex temporal and regional pattern of microglia activation that goes beyond the M1/M2 concept [29]. Most of the studies, including ours, evaluate microglial activation after stem cell therapy in HIE in vivo models using a single marker or focusing on limited time points, which is insufficient considering this complex response (reviewed by [29]).…”

“…Nonetheless, increasing evidence suggests that HI insults in the developing brain result in a complex temporal and regional pattern of microglia activation that goes beyond the M1/M2 concept [29]. Most of the studies, including ours, evaluate microglial activation after stem cell therapy in HIE in vivo models using a single marker or focusing on limited time points, which is insufficient considering this complex response (reviewed by [29]). Thus, to unveil how stem cell therapy interferes with these processes, it will be necessary to use several markers of classical and alternative microglia activation at different stages of brain injury, in future studies.…”

Microglia dynamic response and phenotype heterogeneity in neural regeneration following hypoxic-ischemic brain injury

“…Overemphasizing the M1 and M2 categories may oversimplify the complexity of microglial activation and overlook the molecular and functional dynamics involved. Especially in diseases related to hypoxic-ischemic injury, the response of microglia is a dynamic process that is influenced by factors such as the duration and severity of hypoxia ischemia within the CNS ( 43 – 45 ). Understanding the diverse transcriptional landscape and the dynamic changes of microglia subtypes in hypoxic-ischemic injury is crucial for developing effective therapeutic strategies.…”

The RNA m6A modification might participate in microglial activation during hypoxic–ischemic brain damage in neonatal mice

“…Currently, HIBD pathogenesis is considered to involve multiple cell types, including neurons, astrocytes, and microglia, with phenomena such as energy depletion, excitatory amino acid toxicity, calcium overload, mitochondrial damage, and a delayed inflammatory response all implicated [ 3 ]. Microglial activation is greatly involved in HIBD occurrence as well as progression and is defined by the response to environmental stimuli such as HI [ 4 ]. When activated, microglia usually polarize to an M1 or M2 phenotype, which is functionally distinct [ 5 ].…”