Evaluations of Intravenous Administration of CD34⁺ Human Umbilical Cord Blood Cells in a Mouse Model of Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

Several cell therapies have been explored as novel therapeutic strategies for neonatal encephalopathy because the benefits of current treatments are limited. We previously reported that intravenous administration of human umbilical cord blood (hUCB) CD34⁺ cells (hematopoietic stem cells/endothelial progenitor cells) at 48 h after insult exerts therapeutic effects in neonatal mice with stroke, i.e., permanent middle cerebral artery occlusion. Although neonatal stroke and hypoxic-ischemic encephalopathy (HIE) are grouped under the term “neonatal encephalopathy,” their pathogenesis differs. However, little is known about the differences in the effects of the same treatment between these 2 diseases. In this study, we investigated whether the same treatment protocol exerts therapeutic effects in neonatal mice with HIE. The treatment significantly ameliorated the decreased cerebral blood flow in the ischemic penumbra. Although the cylinder and rotarod tests showed a trend of amelioration of behavioral impairments from the treatment, these were not statistically significant. Morphological brain injuries were not altered by treatment. The cell administration did not cause any adverse effects apart from hyperactivity in the open-field test. Some of these findings are consistent with the results obtained in our previous study using a stroke model, but others are not. This study suggests that the treatment protocol needs to be optimized for each pathological condition.

Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety

“…In the literature, almost all preclinical studies on neonatal brain injuries examined the effects of UCBC administration at only one timepoint. Many such studies reported beneficial effects of UCBC administration at 24 or 48 hours after brain injury 11,12,15,17,18,22,24,25,35 . Preclinical studies on other types of cells and/or in other models have demonstrated that early administration, i.e., a few hours after brain injury is not as beneficial as later administration, such as 24-72 hours after brain injury 36 .…”

“…Our research group, named the Neonatal Encephalopathy Consortium Japan, conducted preclinical studies before translating UCBC therapy to the clinic. We demonstrated that the intravenous infusion of human CD34 + cells (haematopoietic stem/endothelial progenitor cells) at 48 hours after brain injury partially ameliorated the damage in mouse models of neonatal stroke 18 and neonatal HIE 22 . Additionally, we have demonstrated that intraperitoneal infusion of the MNC fraction of human UCBCs at 6 hours after brain injury partially ameliorates the damage in a rat model of neonatal HIE 19 .…”

“…Several preclinical studies on the systemic administration of UCBCs for neonatal HIE have been published thus far [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] . Most of these preclinical studies used the mononuclear cell (MNC) fraction of human UCBCs, and the cells were transfused either intraperitoneally or intravenously.…”

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

“…even one week after hypoxia-ischemia. However, some groups have reported that intravenous administration of human UCBCs 24 or 48 hours after hypoxia-ischemia in rodent models leads to no significant improvement in either brain injuries or motor function (de Paula et al , 2009; Ohshima et al , 2016). Thus, a number of parameters, such as optimal dose, timing, administration route, duration of therapy, and immunosuppression, still need to be further investigated in order to provide better guidance for the full translation to clinical applications.…”

Bone Morphogenetic Protein (BMP)-3b Gene Depletion Causes High Mortality in a Mouse Model of Neonatal Hypoxic-Ischemic Encephalopathy

“…Forelimb functional impairment was evaluated in cylinder tests 7 days after the surgery (P19), as previously described ( 20 ). We placed each mouse in a transparent cylinder (14 cm inner diameter and 30 cm high) and video recorded its behavior until it reared and touched the cylinder wall with its forepaw(s) a minimum of 20 times.…”