Amelioration of Ischemic Brain Injury in Rats with Human Umbilical Cord Blood Stem Cells: Mechanisms of Action

Abstract

Despite the high prevalence and devastating outcome, there remain a few options for treatment of ischemic stroke. Currently available treatments are limited by a short time window for treatment and marginal efficacy when used. We have tested a human umbilical cord blood-derived stem cell line that has been shown to result in a significant reduction in stroke infarct volume as well as improved functional recovery following stroke in the rat. In the present study we address the mechanism of action and compared the therapeutic efficacy of high- versus low-passage nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs). Using the middle cerebral arterial occlusion (MCAo) model of stroke in Sprague-Dawley rats, we administered nh-UCBSC by intravenous (IV) injection 2 days following stroke induction. These human cells were injected into rats without any immune suppression, and no adverse reactions were detected. Both behavioral and histological analyses have shown that the administration of these cells reduces the infarct volume by 50% as well as improves the functional outcome of these rats following stroke for both high- and low-passaged nh-UCBSCs. Flow cytometry analysis of immune cells present in the brains of normal rats, rats with ischemic brain injury, and ischemic animals with nh-UCBSC treatment confirmed infiltration of macrophages and T cells consequent to ischemia and reduction to normal levels with nh-UCBSC treatment. Flow cytometry also revealed a restoration of normal levels of microglia in the brain following treatment. These data suggest that nh-UCBSCs may act by inhibiting immune cell migration into the brain from the periphery and possibly by inhibition of immune cell activation within the brain. nh-UCBSCs exhibit great potential for treatment of stroke, including the fact that they are associated with an increased therapeutic time window, no known ill-effects, and that they can be expanded to high numbers for, and stored for, treatment.

Cellular therapy for traumatic neurological injury

“…These bone marrow mononuclear cells have similar characteristics to umbilical cord blood mononuclear cells and both cell populations have proven efficacious in proof of concept studies treating TBI (15,17). Similar work, with parallel results, have been done in stroke with both cell types (18)(19)(20). ESC-derived NSC or oligodendrocyte stem cell/OPC.…”

Human Umbilical Cord Mesenchymal Stem Cells Preserve Adult Newborn Neurons and Reduce Neurological Injury after Cerebral Ischemia by Reducing the Number of Hypertrophic Microglia/Macrophages

“…However, it should be stressed that hUC-MSCs may ameliorate ischemic brain injury by inhibiting both immune cell activation within the brain and immune cell migration into the brain from the periphery. 42 …”

From cord to caudate: characterizing umbilical cord blood stem cells and their paracrine interactions with the injured brain

“…Several different routes have been trialed in preclinical studies using stem cell transplantation for brain injury. These include intraventricular, intraperitoneal, intravenous, intrathecal, intranasal, and intraparenchymal injections into the cerebral cortex (82)(83)(84)(85)(86)(87)(88)(89). One study examined the difference between intravenous and intraparenchymal transplantation of UCB MSCs in treating cerebral hypoxic injury.…”