Intranasal MSCs: Boosting regeneration of the neonatal injured brain

Abstract

Neonatal encephalopathy due to hypoxia-ischemia (HI) remains a major health issue worldwide. A HI-insult results in brain damage with subsequent development of motor and cognitive impairments like cerebral palsy and mental retardation. Currently, hypothermia is the only available treatment, but is only moderately neuroprotective and only effective in babies born at term if applied within 6 hours post-HI. Therefore, there is an urgent need for new treatment options. In this thesis we demonstrate that intranasal MSC treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Importantly, we also show that this effect is long-lasting, as we observed behavioral improvement and decreased lesion volume up to 14 months after HI. Our results show that MSCs reach the lesion site within 2 hours after intranasal administration, suggesting that MSCs migrate through blood vessels or the meningeal circulation. Furthermore, we show that it is unlikely that the MSCs engraft in the brain as we determined that the number of MSCs decrease over time, as it peaks at 12 hours after administration and decreases significantly at 72 hours. We found that MSCs induce lesion repair by stimulating endogenous neurogenesis rather than by having a neuroprotective effect. We observed that the number of neuronal cells increased within 5 days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18 days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC treatment resulted in resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype. Thus MSCs may induce lesion repair by stimulating endogenous neurogenesis and concomitantly decreasing scar formation, which is known to impair tissue repair following injury. Our results show that human MSCs also decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity following intranasal administration to neonatal HI mice. Importantly, we found no evidence of tumor formation or any lesion in the brain or other organs up to 14 months after HI. In conclusion, the results described in this thesis pave the way towards a novel therapeutic strategy not only for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.