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Delivering Human Umbilical Cord Blood Cells after Hypothermia Augments Neuroprotection after Severe Brain Injury in the Vannucci seven day old Rat Model

Presented at the Neonatal Society 2017 Spring Meeting.

Thoresen M1,3, Falck M1,2, Maes E1, Fjerdingstad HB1,2, Sabir H1, Glover J1,2, Kurtzberg J4, Cotton M4, Wood T1

1 Div. For Physiology, Inst. Basic Medical Sciences, Univ. of Oslo, Norway
2 Oslo Univ. Hospitals, Norway
3 Neonatal Neuroscience, School of Clinical Medicine, Univ of Bristol, UK
4 Pediatric Blood and Marrow Transplant Program and Department of Pediatrics, Duke University, US

Background: After severe injury in the Vannucci neonatal rat unilateral hypoxic-ischaemic (HI) brain injury model, 5h of immediate postinsult hypothermia (TH) is not neuroprotective (1,2). Recently, human umbilical cord blood cells (hUBCs) have been proposed as a neuroprotective therapy for HI brain injury with the potential to extend the therapeutic window and stimulate repair processes. hUBC delivered by direct injection into the brain has shown added neuroprotection in neonatal rats (3). Direct intracerebral injection of hUBC is however not feasible in a clinical setting. We hypothesize that delivering hUBC intraperitoneally starting after the postinsult hypothermic period will reduce severe brain injury when hypothermia alone do not.

Methods: Postnatal-day-7 (N=130, n=27-35) Wistar rats-pups underwent ligation of the left carotid artery followed by subsequent hypoxia (8% oxygen). After HI, pups were immediately randomised to either NT (37ºC) or TH (32ºC) for 5h, followed by an i.p. injection of hUBCs (2×107cells/kg in 10ml/kg; NTCell and THCell groups) or an equivalent volume of vehicle (NTVeh and THVeh). Brains were harvested on P14 and processed for H&E and immunohistochemistry. Relative (ligated vs unligated) hemispheric area loss was calculated, and hippocampal pyramidal cell numbers were counted in the CA1 region. The project was funded by The Norwegian Research Council, The University of Oslo, Norway, Duke University, US, and the German Research Council (travel fund HS).

Results: A severe insult was confirmed by the presence of a median (interquartile range) 58.6% (12.7-64.9%) hemispheric area loss in the NT+V group (1). Neither hUBCs alone (NT+Cell) nor TH alone (TH+Veh) reduced hemispheric area loss significantly (NT+Cell: 54.8% (14.3-66.2%), TH+Veh: 48.2% (8.1-58.0%)). However, significant neuroprotection (median 37.5% (3.4-54.9%) area loss) was seen in the TH+Cell group (p=0.02). The median (interquartile range) number of NeuN positive cells in the CA1 hippocampal region was also higher in the TH+Cell (74.5 (15.5-123)) group compared to the both the NT+Veh (7 (0-64)) and NT+Cell (8 (0-89)) groups (p<0.05 for both).

Conclusion: The combination of peripheral delivery of hUBCs after 5h of TH is the first treatment that results in significant neuroprotection in severe HI brain injury in the neonatal rat, where TH alone or hUBC at Normothermia did not offer neuroprotection. We aim to develop cell-based treatments combined with TH to reduce inflammation and promote long-term cellular repair and regeneration.

Corresponding author: marianne.thoresen@medisin.uio.no

References
1. Sabir H et Stroke 2012;43(12):3364-3370 doi: 10.1161/STROKEAHA.112.674481
2. Wood T et al Scientifc Reports srep23430 DOI: 10.1038/srep234303)
3. Park, W. S. et al. PloS one 10, (2015)

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