Previously, we reported the successful regeneration of injured peripheral nerves using human dental pulp stem cells (DPSCs) or differentiated neuronal cells from DPSCs (DF-DPSCs) in a rat model. Here, we attempted to evaluate oxidative stress and supraspinal neuro-inflammation in rat brain after sciatic nerve injury (SNI). We divided our experimental animals into three SNI groups based on time. The expression of a microglial (Iba1) marker and reactive oxygen species (ROS) was lower in DPSCs and higher in DF-DPSCs. In contrast, the expression of an astroglial (GFAP) marker was higher in DPSCs and lower in DF-DPSCs at 2 weeks. However, the expression of ROS, Iba1 and GFAP gradually decreased at 8 and 12 weeks in the SNI DPSCs and DF-DPSCs groups compared to the SNI control. Furthermore, anti-inflammatory cytokine (IL-4 and TGF-β) expression was lower at 2 weeks, while it gradually increased at 8 and 12 weeks after surgery in the SNI DPSCs and DF-DPSCs groups. Similarly, SNI DPSCs had a high expression of pAMPK, SIRT1 and NFkB at the onset of SNI. However, 12 weeks after surgery, pAMPK and SIRT1 expression levels were higher and NFkB was down-regulated in both DPSCs and DF-DPSCs compared to the control group. Finally, we concluded that DPSCs responded early and more efficiently than DF-DPSCs to counterbalance peripheral nerve injury (PNI)-induced oxidative stress and supraspinal neuro-inflammation in rat brain.

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Background Although the immunomodulatory properties of mesenchymal stem cells (MSCs) have been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the disease-specific characteristics of MSCs derived from elderly RA patients are not well understood. Methods We established MSCs derived from synovial fluid (SF) from age-matched early (average duration of the disease: 1.7 years) and long-standing (average duration of the disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then analyzed the MSC characteristics such as stemness, proliferation, cellular senescence, in vitro differentiation, and in vivo immunomodulatory properties. Results The presence of MSC populations in the SF from RA patients was identified. We found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulatory properties, and attenuated anti-arthritic capacity in an RA animal model. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuated immunomodulatory properties similar to those of L-SF-MSC in an RA joint-mimetic milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to a long-term exposure to the chronic inflammatory milieu, cellular senescence, attenuated immunomodulatory properties, and the loss of anti-arthritic potentials were more often identified in SF-MSCs in a long-term RA than early RA. Conclusion We conclude that a chronic RA inflammatory milieu affects the MSC potential. Therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients. Graphical abstract

Following success of pancreatic islet transplantation in the treatment of Type I diabetes mellitus, there is a growing interest in using cell-based treatment approaches. However, severe shortage of donor islets-pancreas impeded the growth, and made researchers to search for an alternative treatment approaches. In this context, recently, stem cell-based therapy has gained more attention. The current study demonstrated that epigenetic modification improves the in vitro differentiation of Wharton's jelly mesenchymal stem cells (WJMSCs) into pancreatic endocrine-like cells. Here we used two histone deacetylase (HDAC) inhibitors namely trichostatin A (TSA) and TMP269. TSA inhibits both class I and II HDACs whereas TMP269 inhibits only class IIa HDACs. WJMSCs were differentiated using a multistep protocol in a serum-free condition with or without TSA pretreatment. A marginal improvement in differentiation was observed after TSA pretreatment though it was not significant. However, exposing endocrine precursor-like cells derived from WJMSCs to TMP269 alone has significantly improved the differentiation toward insulin-producing cells. Further, increase in the expression of paired box 4 (PAX4), insulin, somatostatin, glucose transporter 2 (GLUT2), MAF bZIP transcription factor A (MAFA), pancreatic duodenal homeobox 1 (PDX-1), and NKX6.1 was observed both at messenger RNA and protein levels. Nevertheless, TMP269-treated cells secreted higher insulin upon glucose challenge, and demonstrated increased dithizone staining. These findings suggest that TMP269 may improve the in vitro differentiation of WJMSCs into insulin-producing cells.

Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.