Abstract
Microglia are the immune cells in the central nervous system surveying environment and reacting to various injuries. Activated microglia may cause impaired synaptic plasticity, therefore modulating and restoring them to neutral phenotype is crucial to counteract a pro-inflammatory, neurotoxic state. In this study, we focused on elucidating whether human umbilical cord (UC) -derived mesenchymal stromal cells (MSCs) can exert immunomodulatory effect and change the phenotype of activated microglia. Primary culture of microglia was activated by lipopolysaccharide (LPS) and was co-cultured with three lots of MSCs. We investigated immunomodulation, actin dynamics and phagocytic capacity of activated microglia, and examined change of Rho GTPase in microglia as the mechanism. MSCs suppressed the expression of IL-1β and pNFκB in LPS-activated microglia, and conversely elevated the expression of IL-1β in resting-surveying microglia with lot-to-lot variation. Morphological and phagocytotic analyses revealed that LPS stimulation significantly increased active Rho GTPase, Rac1, and Cdc42 levels in the microglia, and their morphology changed to amoeboid in which F-actin spread with ruffle formation. The F-actin spreading persisted after removal of LPS stimulation and reduced phagocytosis. On the other hand, MSC co-culture induced bimodal increase in active Rac1 and Cdc42 levels in LPS-activated microglia. Moreover, extended ruffles of F-actin shrinked and concentrated to form an actin ring, thereby restoring phagocytosis. We confirmed inhibition of the PI3K/Akt pathway attenuated F-actin dynamics and phagocytosis restored by MSCs. Overall, we demonstrated that MSCs immunomodulated microglia with lot-to-lot variation, and changed the phenotype of LPS-activated microglia restoring actin dynamics and phagocytosis by increase of active Rho GTPase.
Highlights
Microglia, the immune cells of the central nervous system, are the first responders to brain injury, and are critically involved in various injuries and diseases as key mediators[1]
We found that LPS stimulation decreased phagocytosis of bioparticles, and that this reduction was recovered in the LPS + mesenchymal stromal cells (MSCs) group (Fig. 4a, b)
The present study demonstrated that MSCs can suppress inflammation in LPS-activated microglia, and cause inflammation in NM-cultured microglia with lot-to-lot variation
Summary
The immune cells of the central nervous system, are the first responders to brain injury, and are critically involved in various injuries and diseases as key mediators[1]. Microglia are activated in response to brain injury, and are polarized toward inflammatory. Mukai et al Cell Death Discovery (2021)7:46 have been used in several clinical studies for treating brain injuries[4,5]. MSCs have been isolated from several sources, including bone marrow, umbilical cord blood, adipose tissue, placenta, and umbilical cord (UC)[6,7,8,9,10], and have been reported to perform immunoregulatory roles in inflammatory diseases[11]. Kim et al demonstrated that UC blood-derived MSCs mainly block the activation of microglia, which involved STAT1-mediated cytokine release[12]. Whether UC-MSCs can immunomodulate and change the actin dynamics and phagocytic ability of activated microglia is not clear
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