title: Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain.
abstract: BACKGROUND
  Preterm infants are at risk for hypoxic-ischemic encephalopathy. No therapy exists to treat this brain injury and subsequent long-term sequelae. We have previously shown in a well-established pre-clinical model of global hypoxia-ischemia (HI) that mesenchymal stem cells are a promising candidate for the treatment of hypoxic-ischemic brain injury. In the current study, we investigated the neuroprotective capacity of multipotent adult progenitor cells (MAPC®), which are adherent bone marrow-derived cells of an earlier developmental stage than mesenchymal stem cells and exhibiting more potent anti-inflammatory and regenerative properties.
  
  
  METHODS
  Instrumented preterm sheep fetuses were subjected to global hypoxia-ischemia by 25 min of umbilical cord occlusion at a gestational age of 106 (term ~147) days. During a 7-day reperfusion period, vital parameters (e.g., blood pressure and heart rate; baroreceptor reflex) and (amplitude-integrated) electroencephalogram were recorded. At the end of the experiment, the preterm brain was studied by histology.
  
  
  RESULTS
  Systemic administration of MAPC therapy reduced the number and duration of seizures and prevented decrease in baroreflex sensitivity after global HI. In addition, MAPC cells prevented HI-induced microglial proliferation in the preterm brain. These anti-inflammatory effects were associated with MAPC-induced prevention of hypomyelination after global HI. Besides attenuation of the cerebral inflammatory response, our findings showed that MAPC cells modulated the peripheral splenic inflammatory response, which has been implicated in the etiology of hypoxic-ischemic injury in the preterm brain.
  
  
  CONCLUSIONS
  In a pre-clinical animal model MAPC cell therapy improved the functional and structural outcome of the preterm brain after global HI. Future studies should establish the mechanism and long-term therapeutic effects of neuroprotection established by MAPC cells in the developing preterm brain exposed to HI. Our study may form the basis for future clinical trials, which will evaluate whether MAPC therapy is capable of reducing neurological sequelae in preterm infants with hypoxic-ischemic encephalopathy.
authors.affiliation: School of Mental Health and Neuroscience (MHENS), Maastricht University, Universiteitssingel 40, Maastricht, 6229, ER, The Netherlands. reint.jellema@maastrichtuniversity.nl.|Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. reint.jellema@maastrichtuniversity.nl.|Department of Pediatrics, Máxima Medical Center, PO Box 90052, 5600, PD, Veldhoven, The Netherlands. reint.jellema@maastrichtuniversity.nl.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.affiliation: School of Mental Health and Neuroscience (MHENS), Maastricht University, Universiteitssingel 40, Maastricht, 6229, ER, The Netherlands. d.ophelders@maastrichtuniversity.nl.|Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. d.ophelders@maastrichtuniversity.nl.
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. a.zwanenburg@maastrichtuniversity.nl.|Department of Biomedical Engineering, Maastricht University, PO Box 616, Maastricht, 6200, MD, The Netherlands. a.zwanenburg@maastrichtuniversity.nl.
authors.forename: Alex
authors.initials: A
authors.lastname: Zwanenburg
authors.affiliation: School of Mental Health and Neuroscience (MHENS), Maastricht University, Universiteitssingel 40, Maastricht, 6229, ER, The Netherlands. m.nikiforou@maastrichtuniversity.nl.|Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. m.nikiforou@maastrichtuniversity.nl.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. tammo.delhaas@maastrichtuniversity.nl.|Department of Biomedical Engineering, Maastricht University, PO Box 616, Maastricht, 6200, MD, The Netherlands. tammo.delhaas@maastrichtuniversity.nl.|School for Cardiovascular Diseases (CARIM), Maastricht University, PO Box 616, Maastricht, 6200, MD, The Netherlands. tammo.delhaas@maastrichtuniversity.nl.
authors.forename: Tammo
authors.initials: T
authors.lastname: Delhaas
authors.affiliation: Department of Pediatrics, Máxima Medical Center, PO Box 90052, 5600, PD, Veldhoven, The Netherlands. P.Andriessen@mmc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Andriessen
authors.affiliation: Regenerative Medicine, Athersys, Inc., 3201 Carnegie Avenue, Cleveland, OH, 44115-2634, USA. rwmays@athersys.com.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mays
authors.affiliation: Regenerative Medicine, Athersys, Inc., 3201 Carnegie Avenue, Cleveland, OH, 44115-2634, USA. rdeans@athersys.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Deans
authors.affiliation: School of Oncology and Developmental Biology (GROW), Maastricht University, Universiteitssingel 50, Maastricht, 6229, ER, The Netherlands. w.germeraad@maastrichtuniversity.nl.|Department of Internal Medicine, Division of Hematology, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. w.germeraad@maastrichtuniversity.nl.
authors.forename: Wilfred T V
authors.initials: WT
authors.lastname: Germeraad
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. tim.wolfs@maastrichtuniversity.nl.|School of Oncology and Developmental Biology (GROW), Maastricht University, Universiteitssingel 50, Maastricht, 6229, ER, The Netherlands. tim.wolfs@maastrichtuniversity.nl.
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
authors.affiliation: School of Mental Health and Neuroscience (MHENS), Maastricht University, Universiteitssingel 40, Maastricht, 6229, ER, The Netherlands. b.kramer@maastrichtuniversity.nl.|Department of Pediatrics, Maastricht University Medical Center, PO Box 5800, Maastricht, 6202, AZ, The Netherlands. b.kramer@maastrichtuniversity.nl.|School of Oncology and Developmental Biology (GROW), Maastricht University, Universiteitssingel 50, Maastricht, 6229, ER, The Netherlands. b.kramer@maastrichtuniversity.nl.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D053687:Adult Stem Cells / Q000637:transplantation*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005333:Fetus; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D047928:Premature Birth; D012756:Sheep