Mannitol-enhanced delivery of stem cells and their growth factors across the blood-brain barrier

Abstract

Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood-brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy.

Figure 1

Mannitol facilitation of peripheral delivery of stem cells. (A) The blood–brain barrier (BBB) ordinarily prevents the entry of stem cells and therapeutic drugs from migrating into the brain. (B) BBB breakdown proceeds after stroke, permitting a small number of stem cells to penetrate the brain. (C) BBB leakage in combination with mannitol creates a conducive opening in the barrier that allows many stem cells to enter the brain and consequently abrogate the stroke pathology. (D) Ideal opening in the BBB selectively allows stem cells to breach the barrier but prevents access to the proinflammatory cells, therefore aiding the brain repair process while reducing the contribution of systemic inflammation associated with stroke and other neurological disorders.