The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients

Abstract

In a previous study, we reported that intrathecal injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 transgenic mice. In this study, we found that intrathecal MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide dismutase1 transgenic). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (T reg ; CD4and the mRNA expression of several cytokines (IFN-c, TNF-a, IL-17, IL-4, IL-10, IL-13, and TGF-b). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 or 72 h. Based on a fluorescence-activated cell sorting analysis, we found that co-culture with MSCs increased the T reg /total T-lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-c and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFNc mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-c mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-b were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor mRNA, in both HC and ALS PBMCs cocultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase in T reg induction. These findings of T reg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients.

Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO

“…For example, IDO acts as a pivotal molecule controlling the functional status of Tregs following TLR9 ligation [41]. When MSCs are cocultured with peripheral blood mononuclear cells from patients of amyotrophic lateral sclerosis, IDO levels in the co-cultured MSCs are correlated with the increase in Treg induction [42]. In the present study, we showed that Treg levels were significantly increased in splenocytes after ASCs treatment.…”

Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection

“…Treatment with MSCs was also shown to boost positive adaptive immune responses in ALS, leading to increased infiltration of immune cells into the spinal cord in the animal model [96]. In human beings with ALS or MS, concomitant intrathecal and iv treatment with autologous MSCs led to increased numbers of circulating Treg cells (assessed as CD4+ CD25+ T cells) [97].…”

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

“…Jovicic et al also identified several genes related to rRNA biogenesis (e.g., efg1 and nsr1 ) as significant modifiers of poly(PR) toxicity [17]. Additionally, poly(PR) and poly(GR) peptides colocalize with nucleoli, the site of rRNA synthesis [62]. Although the dysregulation of ribogenesis has been associated with c9orf72 HRE in multiple studies, the mechanism remains poorly understood.…”