Transplantation of Cryopreserved Human Bone Marrow-derived Multipotent Adult Progenitor Cells for Neonatal Hypoxic-Ischemic Injury: Targeting the Hippocampus

There is currently no treatment for neonatal hypoxic-ischemic (HI) injury. Although limited clinical trials of stem cell therapy have been initiated in a number of neurological disorders, the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. Stem cell therapy, via stimulation of endogenous stem cells or transplantation of exogenous stem cells, has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has also been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents a highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor-secreting features, the hippocampus stands as an appealing target for stem cell therapy. In the present study, we investigated the efficacy of intrahippocampal transplantation of multipotent adult progenitor cells (MAPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day old Sprague-Dawley rats were initially subjected to unilateral HI injury, that involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI injury, animals received stereotaxic hippocampal injections of vehicle or cryopreserved MAPCs (thawed just prior to transplantation) derived either from Sprague-Dawley rats (syngeneic) or Fisher rats (allogeneic). All animals were treated with daily immunosuppression throughout the survival period. Behavioral tests were conducted on post-transplantation days 7 and 14 using the elevated body swing test and the rotarod to reveal general and coordinated motor functions. MAPC-transplanted animals exhibited reduced motor asymmetry and longer time spent on the rotarod than those that received the vehicle infusion. Syngeneic and allogeneic MAPC-transplanted injured animals did not significantly differ in their behavioral improvements at both test periods. Immunohistochemical evaluations of graft survival after behavioral testing at day 14 post-transplantation revealed that syngeneic and allogeneic transplanted MAPCs survived in the hippocampal region. These results demonstrate for the first time that transplantation of MAPCs ameliorated motor deficits associated with HI injury. The similar degree of behavioral recovery produced by syngeneic and allogeneic MAPC grafts indicates that allogeneic transplantation is a feasible and efficacious cell replacement strategy that could be considered for clinical use. Moreover, the hippocampus is a highly potent target area for stem cell therapy in treating HI injury.