👤 Payam Rezaie

Traumatic injuries to the central nervous system (CNS), including traumatic brain injury (TBI) and spinal cord injury (TSCI), are among the leading causes of disability and mortality worldwide. The valuable effect of extracellular vesicles (EVs) from mesenchymal stem cells (MSCs-EVs) in the treatment of traumatic injuries has been documented. EVs, including exosomes, are heterogeneous cell-derived particles, contributing to cell communication through exchanging biomolecules between cells. MSCs-EVs can regulate physiological processes, including synaptic plasticity, neuronal firing, development and repair of myelin sheath, neuroprotection, advancement of neuroinflammation, and extent and elimination of protein aggregates. However, natural MSCs-EVs have some limitations. Recent advancements have shown that MSCs-EVs can be engineered for effective and targeted therapy in traumatic injuries. Most experiments have focused on miRNA-engineered MSCs-EVs to boost their therapeutic effects. In TBI models, MSCs-EVs have been modified to deliver miR-124, miR-17-92, miR-124-3p, or BDNF, whereas in TSCI models, EVs have been engineered with miR-216a-5p, miR-146a-5p, miR-133b, miR-146, miR-138-5p, miR-29b, miR-181c, lncGm37494, siRNAs, or Shh. Results from in vitro and animal studies show the substantial potential of engineered MSCs-EVs for protection, neuroregeneration, and functional recovery. But challenges remain in translating these outcomes into clinical trials, including standardization, safety, and delivery efficacy. In this review, we summarize recent knowledge on MSCs-EVs, focusing on their mechanisms of action in CNS traumatic injuries, and discuss the latest developments, inherent advantages, and potential hurdles in evolving these groundbreaking therapeutic approaches. Show less

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions. Show less

Mouse models of neuronal ceroid lipofuscinosis (NCL) exhibit many features of the human disorder, with widespread regional atrophy and significant loss of GABAergic interneurons in the hippocampus and neocortex. Reactive gliosis is a characteristic of all forms of NCL, but it is unclear whether glial activation precedes or is triggered by neuronal loss. To explore this issue we undertook detailed morphological characterization of the Cln3 null mutant (Cln3(-/-)) mouse model of juvenile NCL (JNCL) that revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread loss of hippocampal interneurons that was first evident at 14 months of age. Quantitative image analysis demonstrated upregulation of markers of astrocytic and microglial activation in presymptomatic Cln3(-/-) mice at 5 months of age, many months before significant neuronal loss occurs. These data provide evidence for subtle glial responses early in JNCL pathogenesis. Show less