Stem cells redirect the neuroinflammatory trajectory of primed microglia in an ovine chorioamnionitis model.

Antenatal infection (e.g. chorioamnionitis), an important risk factor for preterm birth, can induce a fetal systemic inflammatory response (FIRS), initiating neuroinflammation. Microglia, as principal resident immune cells of the brain, are key targets for therapeutic interventions such as Multipotent adult progenitor cells (MAPC). We analyzed the effects of intravenous MAPC therapy on microglia and peripheral immune cells at the blood-brain barrier (BBB) in an ovine chorioamnionitis model. Ovine fetuses were intra-amniotic (i.a.) exposed to lipopolysaccharide (LPS) to induce FIRS, or saline (SAL) at 125 days gestational age (dGA), followed by intravenous MAPC therapy or SAL at 127 dGA. After sacrifice (132 dGA), isolated microglia were analyzed by qRT-PCR and RNA sequencing. Microglial function was assessed through efferocytosis of Jurkat cells. Additionally, immunohistochemistry of immune cells (CD45, IBA-1, MPO) and their ANXA1 co-expression were quantified in brain parenchyma and BBB. Antenatal inflammation resulted in an increased efferocytotic capacity following in vitro LPS re-exposure and gene ontology annotations revealed significant changes in immunomodulatory genes, indicating microglial priming. This was further confirmed through selective upregulation of IL-10 and ANXA1, accompanied by increased COX-2 in MAPC-treated animals following i.a. LPS exposure. This was paralleled by increased numbers of ANXA1+ immune cells at the BBB and brain parenchyma. Microglial RNA transcriptomic analysis underlined the immunomodulatory and postulated neuroprotective effects of MAPC therapy. We conclude that antenatal inflammation primes microglia which can be targeted by MAPC therapy. Early redirection of neuroinflammation may preserve neural integrity and prevent subsequent neurocognitive impairments in later life.