Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain

Abstract

BackgroundPreterm 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.MethodsInstrumented 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.ResultsSystemic 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.ConclusionsIn 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.

Multipotent Adult Progenitor Cells Enhance Recovery After Stroke by Modulating the Immune Response from the Spleen

“…Enrollment into a double‐blind, placebo controlled clinical trial of MAPC, for the treatment of ischemic stroke has recently been completed . Prior studies have demonstrated that MAPC are not immunogenic and have the capacity to exert potent immunomodulatory effects ; however, the impact of MAPC modulating splenic activation and immune responses after ischemic stroke remain largely unknown. In the present study, using a clinically relevant rat surgical model of focal ischemic stroke, we performed tissue microarray analyses to query the impact of ischemic injury and MAPC treatment upon gene expression and identified significant ischemia‐induced enrichment of genes related to inflammation and immune responses that were suppressed in animals treated with MAPC.…”

Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period

“…IL-1β expression was increased in blood up to 24 h after exposure to repetitive umbilical cord occlusions and microglia counts were increased in the white matter and hippocampus at 24 h [ 55 ]. Other studies also demonstrated the central activation of microglia associated with systemic inflammation and the influx of neutrophils into the brain after 25 min of umbilical cord occlusion in fetal sheep [ 56 , 57 , 58 , 59 ].…”

Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key

“…In preterm fetal sheep, global HI caused a potent neuroinflammatory response, characterized by excessive microglial activation, from 3 h [ 59 ] until 21 days post-HI [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. This was associated with acute loss of pre-OLs at 72 h after the insult, and restoration of pre-OL numbers at seven days and 14 days post-reperfusion, in association with the increased restorative proliferation of oligodendrocyte progenitors [ 63 , 74 , 75 ].…”