Human Umbilical Cord Blood Treatment in a Mouse Model of ALS: Optimization of Cell Dose

Abstract

BackgroundAmyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (106 cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10×106, 25×106 and 50×106, were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice.Methodology/Principal FindingsOur results showed that a cell dose of 25×106 cells significantly increased lifespan of mice by 20–25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25×106 cells, although prevalent human Th1 cytokines were indicated in mice with 50×106 cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25×106 (mainly) and 10×106 cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25×106 cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25×106 cells.Conclusions/SignificanceThese results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response.

Human Skeletal Muscle Stem Cell Antiinflammatory Activity Ameliorates Clinical Outcome in Amyotrophic Lateral Sclerosis Models

“…In particular, the analysis of the levels of cytokines measured in vehicletreated ALS mice and in ALS mice receiving cells suggested that transplantation may favor the maintenance of Th-2 innate adaptive immune response by delaying the switch to the Th1-mediated pro -inflammatory response and therefore attenuating the clinical progression (9).…”

“…However, the lack of apparent cell migration to the side of injury (ventral horn of the Wr cervical spinal cord) and the absence of their differentiation toward motor neurons did not allow us to speculate that there is a cell replacement by SkmSCs. Whereas other MSC transplantation studies in ALS animal models demonstrate a motor efficacy improvement without grafts replacement, we have chosen to focus our investigation on the evaluation of the SkmSC pharmacological effects (9).…”

“…The potential of stem cell therapy has already been demonstrated in a familial model of ALS-the transgenic mutant superoxide dismutase 1 (SOD1) mouse (9).…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…In the earliest studies, a survival benefit was demonstrated in irradiated SOD1-G93A mice treated with human umbilical cord blood [93,94]. Follow-up studies also showed that transplanted human cord blood along with immunosuppression with cyclosporine delayed disease progression and that the transplanted cells were detected in the brain and spinal cord [25,26]. From these beginnings arose many strategies to harness the potential of stem cells for ALS.…”

Effects of Transplanted Human Cord Blood-Mononuclear Cells on Pulmonary Hypertension in Immunodeficient Mice and Their Distribution

“…In a recent study, it was shown that a single low dose (10 6 cells) of human umbilical cord blood-derived mononuclear cells (hUCBMNCs) administered intravenously to G93A mice with amyotrophic lateral sclerosis delayed symptom progression and modestly prolonged lifespan (6). It has been shown that human umbilical cord blood contains abundant with hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells that are able to differentiate into nerve cells and endothelial cells (7 -10).…”