Microglia modulate proliferation, neurite generation and differentiation of human neural progenitor cells

Abstract

Microglia, the primary immune cells of the brain, significantly influence the fate of neurons after neural damage. Depending on the local environment, they exhibit a wide range of phenotypes, including patrolling (naïve), proinflammatory, and anti-inflammatory characteristics, which greatly affects neurotoxicity. Despite the fact that neural progenitor cells (NPCs) and hippocampal neurons represent cell populations, which play pivotal role in neural regeneration, interaction between microglia and these cell types is poorly studied. In the present work, we investigated how microglial cells affect the proliferation and neurite outgrowth of human stem cell-derived NPCs, and how microglia stimulation with proinflammatory or anti-inflammatory agents modulates this interaction. We found that naïve microglia slightly diminish NPC proliferation and have no effect on neurite outgrowth. In contrast, proinflammatory stimulated microglia promote both proliferation and neurite generation, whereas microglia stimulated with anti-inflammatory cytokines augment neurite outgrowth leaving NPC proliferation unaffected. We also studied how microglia influence neurite development and differentiation of hippocampal dentate gyrus granule cells differentiated from NPCs. We found that proinflammatory stimulated microglia inhibit axonal development but facilitate dendrite generation in these differentiating neurons. Our results elucidate a fine-tuned modulatory effect of microglial cells on cell types crucial for neural regeneration, opening perspectives for novel regenerative therapeutic interventions.

Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocampal Neurogenesis

“…Based on the differentiation protocol described previously [ 36 ] and used several times in our laboratory [ 37 , 41 , 42 , 43 ], we first created neural progenitors from an iPSC line of a healthy donor individual. Among the neural progenitor markers, SRY-box transcription factor 2 (SOX2) and Nestin were used to characterize NPCs.…”

Role of microglia after subarachnoid hemorrhage

“…14,114 As the profiles of microglia increasingly favor the M2 state, they begin performing neuroprotective functions such as inactivating inflammation, promoting remyelination, repairing the BBB, and facilitating neural regeneration and neurite outgrowth. 115 The population expansion of microglia observed in preclinical animal models has parallels in humans. Human studies performed using CSF and peripheral blood samples from patients with SAH identified low numbers of microglia immediately after SAH, which progressively increased during the DCI period.…”

Promoting Alzheimer’s disease research and therapy with stem cell technology

“…In support of this, a study by Popova et al [ 204 ] showed that microglia could induce transcriptional changes in neural stem cells and reduce interferon signaling response genes, while interferon-induced transmembrane protein 3 (IFITM3) was previously shown to upregulate γ-secretase activity to increase Aβ production. By co-culturing activated microglia with NPC, Lilienberg et al [ 67 ] demonstrated that naïve microglia do not affect the proliferation of NPCs and enhanced neurosynaptic growth. Using this co-culture system, the authors also observed that the nitro blebbistatin-triggered synaptic development was enhanced by naïve microglia.…”

“…Using this co-culture system, the authors also observed that the nitro blebbistatin-triggered synaptic development was enhanced by naïve microglia. [ 67 ]. Popova et al [ 204 ] showed that microglia can induce transcriptional changes in neural stem cells and accelerate the emergence of synchronized oscillatory network activity in brain organoids, which has implications for the integration of stem cells into the original neural network following transplantation.…”