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

Abstract

Neonatal stroke is a major cause of mortality and long-term morbidity in infants and children. Currently, very limited therapeutic strategies are available to protect the developing brain against ischemic damage and promote brain repairs for pediatric patients. Moreover, children who experienced neonatal stroke often have developmental social behavior problems. Cellular therapy using bone marrow mesenchymal stem cells (BMSCs) has emerged as a regenerative therapy after stroke. In the present investigation, neonatal stroke of postnatal day 7 (P7) rat pups was treated with noninvasive and brain-specific intranasal delivery of BMSCs at 6 h and 3 days after stroke (1 × 10 6 cells/animal). Prior to transplantation, BMSCs were subjected to hypoxic preconditioning to enhance their tolerance and regenerative properties. The effects on regenerative activities and stroke-induced sensorimotor and social behavioral deficits were specifically examined at P24 of juvenile age. The BMSC treatment significantly reduced infarct size and blood-brain barrier disruption, promoted angiogenesis, neurogenesis, neurovascular repair, and improved local cerebral blood flow in the ischemic cortex. BMSC-treated rats showed better sensorimotor and olfactory functional recovery than saline-treated animals, measured by the adhesive removal test and buried food finding test. In social behavioral tests, we observed functional and social behavioral deficits in P24 rats subjected to stroke at P7, while the BMSC treatment significantly improved the performance of stroke animals. Overall, intranasal BMSC transplantation after neonatal stroke shows neuroprotection and great potential as a regenerative therapy to enhance neurovascular regeneration and improve functional recovery observed at the juvenile stage of development.

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke

“…HP-BMSC-treated mice performed much better than N-BMSC- and vehicle-treated animals (Wei et al , 2013). Furthermore, we demonstrated in a neonatal stroke model of rats that intranasally delivered BMSCs showed beneficial effects on brain development after stroke and that rat pups receiving HP-BMSCs developed better sensorimotor activity, olfactory functional recovery, and performed better in social behavioral tests (Wei et al , 2015). Recently, we showed that intranasal delivery of HP-BMSCs enhanced neurogenesis and angiogenesis after intracerebral hemorrhagic stroke in mice (Sun et al , 2015).…”

“…4). The pro-survival and an enhanced homing to the ischemic brain were later demonstrated using BMSCs (Theus et al , 2008b; Wei et al , 2012; Wei et al , 2015; Yu et al , 2013). …”

“…The microenvironment of ischemic core several days and weeks after stroke provides certain cellular support, blood flow supply and strong trophic factor endorsements for cells to survive while the remaining and regenerating neurovascular infrastructure may be utilized as therapeutic targets for repairing damaged neurovascular unit and neuronal networks. With recent progress in priming transplanted cells using the preconditioning strategy, preconditioned cells are more tolerant and survive better even after transplantation into the ischemic core (Theus et al , 2008a; Wei et al , 2013; Wei et al , 2015). It appears that for the purpose of tissue repair, the development of transplanted cells with greater survival and regenerative properties will have the advantage of implanting cells into the brain area(s) where they are needed (Fig.…”

“…Investigations on transplantation of neural stem/progenitor cells at early and sub-acute phases after stroke report neuroprotective effects of reducing infarct volume (Takahashi et al , 2008; Wei et al , 2012; Wei et al , 2015). The infarct reducing effect can be observed in the acute phase after stroke.…”

Glial progenitor cell-based treatment of the childhood leukodystrophies

“…Among these, MSCs have enjoyed the most interest as therapeutic vectors. MSCs are stromal cells that can be isolated from bone marrow and human cord blood, which are able to differentiate along a variety of mesodermal lineages (Pittenger et al, 1999), and have been proposed as potential therapeutic agents for a wide variety of neural disorders, including neonatal brain injury (Donega et al, 2014; Wei et al, 2015), ischemic stroke (Gutierrez-Fernandez et al, 2013), and the neurodegenerative disorders (Castorina et al, 2015), as well as multiple sclerosis and the inflammatory myelin disorders (Ben-Hur and Goldman, 2008; Einstein and Ben-Hur, 2008). They are not, however, vectors for cell replacement, in that little credible evidence has yet supported the notion that genetically-unmodified MSCs might differentiate along neuroepithelial lineages.…”