From Neurogenic Niche to Site of Injury: Stem Cell-Mediated Biobridge for Brain Repair

Cell replacement and “bystander” effects of stem cells are currently the widely postulated mechanisms of stem cell-mediated repair. In a recent study, we reported efficacy of modified mesenchymal stromal cell (MSC) transplantation in animal models of traumatic brain injury (TBI), revealing data that corroborate the therapeutic potential of stem cell transplantation for brain injuries, and importantly, evidence that support another mechanism of action of transplanted stem cells. We found that intracerebrally administered SB623 cells (gene-modified human MSCs provided by SanBio Inc.) improved TBI-induced neurobehavioral deficits, via a unique mechanism of action involving the formation of a “biobridge” during the repair phase of TBI. Using immunohistochemistry and laser capture assay, we observed localization of this biobridge in an area between the neurogenic subventricular zone and the injured cortex. This stem cell-paved biobridge expressed high levels of extracellular matrix metalloproteinases (MMPs), which initially co-existed with a stream of transplanted MSCs, and later contained a few to non-detectable grafts and overgrown by newly recruited host cells. We advanced the concept that the biobridge facilitated the long-distance migration of host cells from the neurogenic niche to the injured brain site, representing a key regenerative process that highlights the potential of stem cell grafts to initiate endogenous repair mechanisms. Further studies on elucidating graft-host interaction will likely contribute to in-depth characterization of stem cell-paved biobridge, as a robust brain repair mechanism alongside cell replacement and trophic factor secretion, into a new treatment strategy for TBI and other neurological dysfunctions. In this chapter, we discuss the characteristics of stem cell paved-biobridges, the novel mechanism by which they promote neural repair in a rat model of TBI, and describe the clinical significance, challenges and opportunities of employing this novel stem cell-mediated brain repair concept for the treatment of other neurological disorders beyond TBI.