Dataset Information

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

ABSTRACT:

Background

Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated.

Methods

Instrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 10⁶ cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h.

Results

Antenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss.

Conclusion

In conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.

SUBMITTER: Neuen SML

PROVIDER: S-EPMC10990734 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature

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Publications

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

Neuen Sophie M L SML Ophelders Daan R M G DRMG Widowski Helene H Hütten Matthias C MC Brokken Tim T van Gorp Charlotte C Nikkels Peter G J PGJ Severens-Rijvers Carmen A H CAH Sthijns Mireille M J P E MMJPE van Blitterswijk Clemens A CA Troost Freddy J FJ LaPointe Vanessa L S VLS Jolani Shahab S Seiler Christof C Pillow J Jane JJ Delhaas Tammo T Reynaert Niki L NL Wolfs Tim G A M TGAM

Regenerative therapy 20240328

<h4>Background</h4>Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcome ...[more]

PMID: 38576851

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Project description: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.

Dataset Information

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

Background

Methods

Results

Conclusion

Publications

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

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