Use of Human Umbilical Cord Blood Mononuclear Cells to Prevent Perinatal Brain Injury: A Preclinical Study

Abstract

Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury of the developing brain. Major brain lesions associated with CP are white matter damage (WMD) in preterm infants and cortico-subcortical lesions in term newborns. Cell therapy is considered promising for the repair of brain damage. Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a rich source of various stem cells that could be of interest in repairing perinatal brain damage. Our goal was to investigate the potential of hUCB-MNCs to prevent or repair brain lesions in an animal model of excitotoxic brain injury. We induced neonatal brain lesions using intracranial injections of ibotenate, a glutamate agonist, in 5-day-old rat pups. hUCB-MNCs were injected either intraperitoneally (i.p.) or intravenously (i.v.) soon or 24 h after ibotenate injection, and their neurological effects were assessed using histology and immunohistochemistry. hUCB-MNCs injected i.p. did not reach the systemic circulation but high amounts induced a significant systemic inflammatory response and increased the WMD induced by the excitotoxic insult. This effect was associated with a significant 40% increase in microglial activation around the white matter lesion. hUCB-MNCs injected i.v. soon or 24 h after the excitotoxic insult did not affect lesion size, microglial activation, astroglial cell density, or cell proliferation within the developing white matter or cortical plate at any concentration used. We demonstrated that hUCB-MNCs could not integrate into the developing brain or promote subsequent repair in most conditions tested. We found that the intraperitoneal injection of high amounts of hUCB-MNCs aggravated WMD and was associated with systemic inflammation.

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

“…Intravenously transplanted MSCs do not cross the blood brain barrier, and are trafficked not only in the pulmonary capillaries but also in other organs, such as the liver, spleen, and kidney (38). Moreover, human umbilical mononuclear cells given intravenously did not attenuate excitotoxic white matter injury, and even aggravated white matter lesion following intraperitoneal administration (39). Overall, these findings indicate that local intratracheal route might be more efficient than the systemic intravenous route for MSC transplantation in an animal model of combining developing lung and brain injuries, simulating BPD and white matter damage in preterm infants.…”

Cell-Based Therapies in Neonatal Stroke

“…Some studies demonstrate that a higher dose is more beneficial [14,38,39], while a study does not confirm it [67].…”

“…Five studies have reported the effects of cell-based therapies in rodent models with excitotoxicity, in which brain lesions are induced by intracerebral injection of excitotoxic compounds such as a glutamate analogue [63][64][65][66][67]. Those studies are summarized in Table 17.3.…”

“…Dalous et al, in the same group as Titomanlio, examined the effects of hUCBMNCs [67]. When MNCs were administered intraperitoneally either immediately or 24 h after the insult, a low-cell dose (1 × 10 6 cells) ameliorated the lesion size in the cortex, but a high-cell dose (1 × 10 7 cells) exacerbated the lesion size in the white matter at 5 days after the insult.…”

“…Comi et al reported NSC transplantation at 2 days, but not 7 days, after CCAO is beneficial [16]. Two studies in an excitotoxicity model showed no time-dependent effects comparing 4 h versus 72 h after insult [66] and immediate versus 24 h after insult [67]. Another study showed no difference in characteristics of grafted mutlipotent astrocytic stem cells between 24 h and 5 days after HI injury [28].…”