Prenatal administration of multipotent adult progenitor cells modulates the systemic and cerebral immune response in an ovine model of chorioamnionitis

Luise Klein; Daan R M G Ophelders; Daniel van den Hove; Maurits Damoiseaux; Bart P F Rutten; Chris P M Reutelingsperger; Leon J Schurgers; Tim G A M Wolfs

doi:10.1016/j.bbih.2022.100458

Prenatal administration of multipotent adult progenitor cells modulates the systemic and cerebral immune response in an ovine model of chorioamnionitis

Brain Behav Immun Health. 2022 May 2:23:100458. doi: 10.1016/j.bbih.2022.100458. eCollection 2022 Aug.

Authors

Luise Klein^{1

2

3}, Daan R M G Ophelders^{1

2}, Daniel van den Hove^{3

4

5}, Maurits Damoiseaux^{1

2}, Bart P F Rutten^{3

5}, Chris P M Reutelingsperger⁶, Leon J Schurgers⁶, Tim G A M Wolfs^{1

2}

Affiliations

¹ School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands.
² Department of Pediatrics, Maastricht University, Maastricht, the Netherlands.
³ School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands.
⁴ Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
⁵ Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, the Netherlands.
⁶ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.

Abstract

Systemic and cerebral inflammation following antenatal infection (e.g. chorioamnionitis) and dysregulation of the blood brain barrier (BBB) are major risk factors for abnormal neonatal brain development. Administration of multipotent adult progenitor cells (MAPCs) represents an interesting pharmacological strategy as modulator of the peripheral and cerebral immune response and protector of BBB integrity. We studied the immunomodulatory and protective cerebrovascular potential of prenatally administered MAPCs in a preclinical ovine model for antenatal inflammation. Ovine fetuses were intra-amniotically (i.a.) exposed to lipopolysaccharide (LPS) or saline at gestational day 125, followed by the intravenous administration of 1*10⁷ MAPCs or saline at gestational day 127. Circulating inflammation markers were measured. Fetal brains were examined immuno-histochemically post-mortem at gestational day 132. Fetal plasma IL-6 levels were elevated significantly 24 h after LPS administration. In utero systemic MAPC treatment after LPS exposure increased Annexin A1 (ANXA1) expression in the cerebrovascular endothelium, indicating enforcement of BBB integrity, and increased the number of leukocytes at brain barriers throughout the brain. Further characterisation of brain barrier-associated leukocytes showed that monocyte/choroid plexus macrophage (IBA-1⁺/CD206⁺) and neutrophil (MPO⁺) populations predominantly contributed to the LPS-MAPC-induced increase of CD45⁺cells. In the choroid plexus, the percentage of leukocytes expressing the proresolving mediator ANXA1 tended to be decreased after LPS-induced antenatal inflammation, an effect reversed by systemic MAPC treatment. Accordingly, expression levels of ANXA1 per leukocyte were decreased after LPS and restored after subsequent MAPC treatment. Increased expression of ANXA1 by the cerebrovasculature and immune cells at brain barriers following MAPC treatment in an infectious setting indicate a MAPC driven early defence mechanism to protect the neonatal brain against infection-driven inflammation and potential additional pro-inflammatory insults in the neonatal period.

Keywords: Antenatal inflammation; Immunomodulation; Neuro-immune axis; Stem cell therapy.