Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury

Abstract

Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site. HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin, Doublecortin, NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time. MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2h after intranasal administration. At 12h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72h. The number of DCX(+) cells increased 1 to 3days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX(+) expression increased 3 to 5days after MSC-treatment. The number of NeuN(+) cells increased within 5days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC-treatment resulted in the 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. In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis.

Intranasal delivery of bone marrow stromal cells to spinal cord lesions

“…Furthermore, accord ing to Donega et al, 11 BDNF and NGF mRNA expression from MSCs significantly increases after co-culture with hypoxicischemic brain extract.…”

Stem cell therapy in intracerebral hemorrhage rat model

“…Not only intranasal administration is simple and noninvasive, but also avoids potentially dangerous systemic interactions [148][149][150][151] . Positive results were reported following the delivery of growth factors [152][153][154] and MSCs [155][156][157][158] following experimentallyinduced ischemic stroke in rodents. To our knowledge to date, no intranasal delivery trials were conducted on the treatment of ICH using MSCs.…”

Intranasal Delivery of Bone Marrow Mesenchymal Stem Cells Improved Neurovascular Regeneration and Rescued Neuropsychiatric Deficits after Neonatal Stroke in Rats

“…However, most preclinical and all clinical studies have been performed on adult animals or humans, and only a few reports have studied stem cell therapy in neonatal stroke models (52,56,59,61). Those laboratories show great promise for cellular therapy using core blood stem cells or BMSCs to provide enhanced trophic support and an enriched microenvironment in the damaged developing brain (11,32,57).…”