Systemic multipotent adult progenitor cells protect the cerebellum after asphyxia in fetal sheep

Ruth Gussenhoven, Daan R. M. G. Ophelders, Jeroen Dudink, Kay Pieterman, Martin Lammens, Robert W. Mays, Luc J. Zimmermann, Boris W. Kramer, Tim G. A. M. Wolfs, Reint K. Jellema*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

Involvement of the cerebellum in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) in preterm infants is increasingly recognized. We aimed to assess the neuroprotective potential of intravenously administered multipotent adult progenitor cells (MAPCs) in the preterm cerebellum. Instrumented preterm ovine fetuses were subjected to transient global hypoxia-ischemia (HI) by 25 minutes of umbilical cord occlusion at 0.7 of gestation. After reperfusion, two doses of MAPCs were administered intravenously. MAPCs are a plastic adherent bone-marrow-derived population of adult progenitor cells with neuroprotective potency in experimental and clinical studies. Global HI caused marked cortical injury in the cerebellum, histologically indicated by disruption of cortical strata, impeded Purkinje cell development, and decreased dendritic arborization. Furthermore, global HI induced histopathological microgliosis, hypomyelination, and disruption of white matter organization. MAPC treatment significantly prevented cortical injury and region-specifically attenuated white matter injury in the cerebellum following global HI. Diffusion tensor imaging (DTI) detected HI-induced injury and MAPC neuroprotection in the preterm cerebellum. This study has demonstrated in a preclinical large animal model that early systemic MAPC therapy improved structural injury of the preterm cerebellum following global HI. Microstructural improvement was detectable with DTI. These findings support the potential of MAPC therapy for the treatment of HIE and the added clinical value of DTI for the detection of cerebellar injury and the evaluation of cell-based therapy.

Original languageEnglish
Pages (from-to)57-67
Number of pages11
JournalStem Cells Translational Medicine
Volume10
Issue number1
Early online date28 Sep 2020
DOIs
Publication statusPublished - Jan 2021

Keywords

  • asphyxia
  • cerebellum
  • hypoxic-ischemic encephalopathy
  • MAPC
  • stem cells
  • LIPID-PEROXIDATION
  • BRAIN-INJURY
  • PRETERM
  • CASPASE-3
  • ISCHEMIA
  • CORTEX
  • MRI

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