Intrathecal Delivery of Mesenchymal Stromal Cells Protects the Structure of Altered Perineuronal Nets in SOD1 Rats and Amends the Course of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder resulting in a lethal outcome. We studied changes in ventral horn perineuronal nets (PNNs) of superoxide dismutase 1 (SOD1) rats during the normal disease course and after the intrathecal application (5 × 105 cells) of human bone marrow mesenchymal stromal cells (MSCs) postsymptom manifestation. We found that MSCs ameliorated disease progression, significantly improved motor activity, and prolonged survival. For the first time, we report that SOD1 rats have an abnormal disorganized PNN structure around the spinal motoneurons and give different expression profiles of chondroitin sulfate proteoglycans (CSPGs), such as versican, aggrecan, and phosphacan, but not link protein-1. Additionally, SOD1 rats had different profiles for CSPG gene expression (Versican, Hapln1, Neurocan, and Tenascin-R), whereas Aggrecan and Brevican profiles remained unchanged. The application of MSCs preserved PNN structure, accompanied by better survival of motorneurons. We measured the concentration of cytokines (IL-1α, MCP-1, TNF-α, GM-CSF, IL-4, and IFN-γ) in the rats' cerebrospinal fluid and found significantly higher concentrations of IL-1α and MCP-1. Our results show that PNN and cytokine homeostasis are altered in the SOD1 rat model of ALS. These changes could potentially serve as biological markers for the diagnosis, assessment of treatment efficacy, and prognosis of ALS. We also show that the administration of human MSCs is a safe procedure that delays the loss of motor function and increases the overall survival of symptomatic ALS animals, by remodeling the recipients' pattern of gene expression and having neuroprotective and immunomodulatory effects. Stem Cells 2014;32:3163–3172

A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1G93A Rats

“…In our previous study, we reported a prolonged lifespan and an improved neurological outcome in the SOD1 rats treated with hMSC in one single injection into cisterna magna at the onset of the disease. The animals survived on average 13.5 days longer than the PBS treated rats and no grafted cells were found 2 weeks after the application . The lifespan extension observed in our study was 18 and 19 days respectively for SC + M and SC groups.…”

“…Overall, this evidence suggests that necroptosis plays an important role in the development of ALS . We have previously reported the positive effect of a single application of hMSC into cisterna magna of SOD1 transgenic rats . In this study, we aimed to investigate the effect of repeated intrathecal applications of hMSC in a SOD1 transgenic rat model of ALS.…”

Label-Free LC–MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis

“…Pathological ECM alterations have been described for ALS 94 and ALS model systems 95 . Our results showed consistent decreases in levels of ECM proteins, including tenascin R, agrin, and cell adhesion molecule 3.…”

The effects of grafted mesenchymal stem cells labeled with iron oxide or cobalt-zinc-iron nanoparticles on the biological macromolecules of rat brain tissue extracts

“…Adherent cells during subsequent passages were differentiated into adipoblasts, osteoblasts, and chondroblasts. 12,13 Flow cytometry revealed strong positivity for CD90 and weak positivity for CD105, but cells were negative for CD3, CD34, CD45RA, and CD73 (Turnovcova, unpublished data, 2015). In culture, the cells were positive for CD90 and fibronectin and negative for CD11b and CD45.…”