Transplantation of bone marrow mononuclear cells prolongs survival, delays disease onset and progression and mitigates neuronal loss in pre-symptomatic, but not symptomatic ALS mice

Abstract

Cell-based therapy provides a novel strategy to restore lost neurons or modulate the degenerating microenvironment in amyotrophic lateral sclerosis (ALS). This study verified the therapeutic potential of bone marrow mononuclear cells (BMMCs) in SOD1 mice. BMMCs were obtained from enhanced green fluorescent protein (EGFP) transgenic C57BL/6 mice (BMMCs) or from SOD1 transgenic mice (BMMCs) and given to mice at the pre-symptomatic or late symptomatic stage. Survival, body weight and motor performance data were recorded. DNA integrity was evaluated using the alkaline comet assay. The spinal cords were collected to assess motoneuron preservation and cell migration. BMMCs andBMMCs transplantation to pre-symptomatic SOD1 mice prolonged survival and delayed disease progression. The effects were more significant for the BMMC-transplanted mice. In late symptomatic mice,BMMCs promoted a discrete increase in survival, without other clinical improvements. DNA from BMMCs andBMMCs was found in the spinal cords of transplanted animals. DNA damage was not modified by BMMCs in any of the studied groups. Despite positive behavioral effects observed in our study, the limited results we observed for late transplanted mice call for caution before clinical application of BMMCs in ALS.

Enhancing the Therapeutic Efficacy of Bone Marrow-Derived Mononuclear Cells with Growth Factor-Expressing Mesenchymal Stem Cells for ALS in Mice

“…Previous reports have shown that BMT preserved motor function and prolonged the survival time of SOD1tg mice (Ohta et al, 2011;Silani et al, 2004;Venturin et al, 2016). BMT has been experimentally used for the treatment of patients with ALS in conjunction with total body irradiation (Appel et al, 2008).…”

“…Despite recent advances in stem cell therapies, ALS remains non-curable and clinical remission or reversal remains to be achieved. Although bone marrow or MSCs transplantation has already been attempted in ALS mice and patients, their efficacy has been limited (Appel et al, 2008;Kim et al, 2010;Mazzini et al, 2010Mazzini et al, , 2012Ohta et al, 2011;Silani et al, 2004;Venturin et al, 2016;Zhang et al, 2009). Therefore, to improve the therapeutic effects, we demonstrated a new therapeutic approach that combines MNCs and MSCs with the overexpression of growth factors such as HGF, GDNF, and IGF, whose efficacy has been reported for ALS (Dodge et al, 2008;Kaspar et al, 2003;Sun et al, 2002;Wang et al, 2002).…”

Emprego de riluzol, tempol e células-tronco mesenquimais no tratamento da esclerose lateral amiotrófica em camundongos SOD1G93A

“…Vários estudos sugerem que as MSCs possam exercer papel protetor para os neurônios motores em animais SOD1 G93A , modificando o ambiente inflamatório na medula espinal (Boido, Piras et al 2014) Apesar de diversos estudos já terem demonstrado resultados positivos com a terapia celular usando diferentes tipos de MSC em diferentes doses e vias de aplicação (Kim, Lee et al 2014, Gubert, Decotelli et al 2016, Venturin, Greggio et al 2016, Sironi, Vallarola et al 2017 Pensando na transposição clínica dos nossos resultados e baseados em resultados da literatura que demonstraram sucesso terapêutico quando células foram injetadas em períodos assintomáticos (Gubert, Decotelli et al 2016, Venturin, Greggio et al 2016, sugerimos uma alternativa de tratamento (Figura 48: A e B). Assim, empregando-se a mesma quantidade de células e o mesmo método de aplicação utilizado no presente estudo, iniciando a intervenção no estágio inicial dos sintomas (14° semana) e repetindo uma ou até duas aplicações, é possível potencializar os efeitos já observados.…”