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DTSTAMP:20260424T062916Z
UID:1750073400@ist.ac.at
DTSTART:20250616T133000
DTEND:20250616T143000
DESCRIPTION:Speaker: Verena Schmied\nhosted by Caroline Muller\nAbstract: P
 renatal immune challenges pose significant risks to human embryonic brain 
 and eye development. However\, we still lack knowledge about the safe usag
 e of anti-inflammatory drugs during pregnancy. Human induced pluripotent s
 tem cell (hIPSC)-derived brain organoid models provide a unique opportunit
 y to investigate neuronal development and have started to explore function
 al consequences upon viral infection. However\, brain organoids usually la
 ck microglia\, the brain-resident immune cells which actively participate 
 in neuronal development. At the same time\, microglia are known for their 
 immune-sensing properties and will contribute to viral-mediated effects. I
 n my thesis\, I investigated the multifunctional roles of human microglia 
 during retinal development and explored their potential contributions to t
 he consequences of viral infections.First\, we characterized the innate oc
 currence of IBA1+-microglia-like cells within the retinal organoid differe
 ntiation (Bartalska et al.\, 2022). Therefore\, we differentiate hIPSC usi
 ng an unguided retinal organoid differentiation protocol and observe that 
 innately developing IBA1+-cells enrich in mesenchymal over retinal structu
 res. To enrich for IBA1+-microglia precursors (preMG)\, we guided the diff
 erentiation with a low-dosed BMP4 application. We characterized preMG for 
 their microglia-like identity and validated their functionality. Next\, w
 e assemble preMG into 3D-retinal organoids and observe that microglia-like
  cells (iMG) populate the outer plexiform layer once it forms (Schmied et 
 al.\, 2025). However\, at this developmental stage\, the ganglion cell num
 ber decreases in 3D-retinal organoids. Thus\, we adapted the model into 2D
  which promotes their survival. Integrated iMG engulf ganglion cells and c
 ontrol their cell number. In parallel\, we apply the immunostimulant POLY(
 I:C) to mimic a fetal viral infection. Although POLY(I:C) stimulation affe
 cts iMG phenotype\, it does not influence their interaction with ganglion 
 cells. Furthermore\, iMG presence significantly contributes to the superna
 tant’s inflammatory secretome and increases retinal cell proliferation. 
 Simultaneous exposure to the non-steroidal anti-inflammatory drug (NSAID) 
 ibuprofen dampens POLY(I:C)-mediated consequences of the iMG phenotype and
  ameliorates cell proliferation. Remarkably\, while POLY(I:C) disrupts neu
 ronal calcium dynamics independent of iMG presence\, ibuprofen rescues thi
 s effect only in the presence of iMG. Mechanistically\, ibuprofen blocks t
 he enzymes cyclooxygenase 1 and 2 (COX1/ PTGS1 and COX2/ PTGS2) simultaneo
 usly\, from which iMG predominantly express COX1. Selective inhibition of 
 COX1 does not restore the calcium peak amplitude upon POLY(I:C) stimulatio
 n\, indicating ibuprofen’s effect depends on the presence and interplay 
 of both\, COX1 and COX2. In summary\, our results underscore the importan
 ce of microglia during neurodevelopment\, in the context of prenatal immun
 e challenges and provide insight into the mechanisms by which ibuprofen ex
 erts its protective effects during embryonic development.
LOCATION:Office Bldg West / Ground floor / Heinzel Seminar Room (I21.EG.101
 ) and Zoom\, ISTA
ORGANIZER:
SUMMARY:Verena Schmied: Thesis Defense: HUMAN MICROGLIA IMPACT NEURONAL DEV
 ELOPMENT IN RETINAL ORGANOIDS 
URL:https://talks-calendar.ista.ac.at/events/5864
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