A Novel Immunomodulatory Mechanism Dependent on Acetylcholine Secreted by Human Bone Marrow-derived Mesenchymal Stem Cells

BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are used to treat autoimmune or inflammatory diseases. Our aim was to determine the immunomodulatory mechanisms elicited by MSCs during inflammation. METHODS AND RESULTS: We cocultured MSCs with peripheral blood mononuclear cells for a mixed lymphocyte reaction or stimulated them by phytohemagglutinin. Morphological changes of MSCs and secretion of acetylcholine (ACh) from MSCs were measured. The effects of an ACh antagonist and ACh agonist on lymphocyte proliferation and proinflammatory-cytokine production were determined. The inflammatory milieu created by immune-cell activation caused MSCs to adopt a neuronlike phenotype and induced them to release ACh. Additionally, nicotinic acetylcholine receptors (nAChRs) were upregulated in activated peripheral blood mononuclear cells. We observed that ACh bound to nAChR on activated immune cells and led to the inhibition of lymphocyte proliferation and of proinflammatory-cytokine production. MSC-mediated immunosuppression through ACh activity was reversed by an ACh antagonist called α-bungarotoxin, and lymphocyte proliferation was inhibited by an ACh agonist, ACh chloride. CONCLUSIONS: Our findings point to a novel immunomodulatory mechanism in which ACh secreted by MSCs under inflammatory conditions might modulate immune cells. This study may provide a novel method for the treatment of autoimmune diseases by means of MSCs.

Molecular Characterization of Neurally Differentiated Human Bone Marrow-derived Clonal Mesenchymal Stem Cells

Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent, with the ability to differentiate into different cell types. Additionally, the immunomodulatory activity of MSCs can downregulate inflammatory responses. The use of MSCs to repair injured tissues and treat inflammation, including in neuroimmune diseases, has been extensively explored. Although MSCs have emerged as a promising resource for the treatment of neuroimmune diseases, attempts to define the molecular properties of MSCs have been limited by the heterogeneity of MSC populations. We recently developed a new method, the subfractionation culturing method, to isolate homogeneous human clonal MSCs (hcMSCs). The hcMSCs were able to differentiate into fat, cartilage, bone, neuroglia, and liver cell types. In this study, to better understand the properties of neurally differentiated MSCs, gene expression in highly homogeneous hcMSCs was analyzed. Neural differentiation of hcMSCs was induced for 14 days. Thereafter, RNA and genomic DNA was isolated and subjected to microarray analysis and DNA methylation array analysis, respectively. We correlated the transcriptome of hcMSCs during neural differentiation with the DNA methylation status. Here, we describe and discuss the gene expression profile of neurally differentiated hcMSCs. These findings will expand our understanding of the molecular properties of MSCs and contribute to the development of cell therapy for neuroimmune diseases.

Erratum: Mesenchymal Stem Cell Lines Isolated by Different Isolation Methods Show Variations in the Regulation of Graft-versus-host Disease

Typographical error has been detected in acknowledgements.

Mesenchymal Stem Cell Lines Isolated by Different Isolation Methods Show Variations in the Regulation of Graft-versus-host Disease

Since the discovery of the immunomodulation property of mesenchymal stem cells (MSCs) about a decade ago, it has been extensively investigated whether MSCs can be used for the treatment of immune-related diseases, such as graft-versus-host disease (GvHD). However, how to evaluate the efficacy of human MSCs for the clinical trial is still unclear. We used an MHC-mismatched model of GvHD (B6 into BALB/c). Surprisingly, the administration of the human MSCs (hMSCs) could reduce the GvHD-related mortality of the mouse recipients and xenogeneically inhibit mouse T-cell proliferation and IFN-gamma production in vitro. We recently established a new protocol for the isolation of a homogeneous population of MSCs called subfractionation culturing methods (SCM), and established a library of clonal MSC lines. Therefore, we also investigated whether MSCs isolated by the conventional gradient centrifugation method (GCM) and SCM show different efficacy in vivo. Intriguingly, clonal hMSCs (hcMSCs) isolated by SCM showed better efficacy than hMSCs isolated by GCM. Based on these results, the MHC-mismatched model of GvHD may be useful for evaluating the efficacy of human MSCs before the clinical trial. The results of this study suggest that different MSC lines may show different efficacy in vivo and in vitro.

Gluteal Compartment Syndrome and Lumbosacral Plexus Injury Associated with Rhabdomyolysis: A Case Report

Gluteal compartment syndrome is a rare disorder which often occurs in conjunction with prolonged immobility after an overdose of sedative. Signs of sciatic nerve compression frequently occur, and rhabdomyolysis may be associated with the syndrome. We recently encountered a patient with lumbosacral plexopathy, complicated by gluteal compartment syndrome. A 42-year-old man presented with weakness and swelling in the right lower extremity and gluteal area after an overdose of antipsychotic drug, accompanied by prolonged immobilization. Serum creatine phosphokinase and urinary myoglobin were markedly elevated, and a T2-weighted pelvis MRI showed hyperintensities and swelling in the gluteal muscles. An electrodiagnosis study showed incomplete lumbosacral plexopathy. The patient received medical treatment and rehabilitation. Six months later, his right lower limb weakness had improved and he could walk independently. Lumbosacral plexus injury with rhabdomyolysis is a rare but debilitating disorder. Therefore, early diagnosis and treatment are crucial for prevention of neurologic deterioration.

Gustatory Change after Sympathetic Ganglion Block in Complex Regional Pain Syndrome Type I Patient: A case report

Some reports provide conclusive evidence of close interactive regulation between the taste receptor and sympathetic nervous system. We report a middle-aged male patient with gustatory change after cervical sympathetic ganglion block (CSGB) who had been suffering from hypersensitivity to sour taste since developing complex regional pain syndrome (CRPS) type 1, diagnosed according to the revised CRPS criteria. Despite receiving two high doses of prednisolone therapy, he experienced the recurrence of CRPS symptoms. We attempted other therapy treatments, including pamidronate intravenous infusion, non-steroidal anti-inflammatory drugs, opioids, tricyclic antidepressants, and CSGB. Following each CSGB administration, the patient reported decreased hypersensitivity to sour-tasting foods, such as kimchi and oranges, with decreased pain and reduction of dysautonomic symptoms. This case demonstrates that overactivation of the sympathetic nervous system may influence sensitivity and regulation of gustatory receptors; therefore, a patient demonstrating CRPS symptoms, including taste alterations, may respond positively to CSGB therapy.

Assessment of Quality of Life in Parents of Childrenwith Cerebral Palsy

OBJECTIVE: To evaluate the quality of life and psychologic status in parents of children with cerebral palsy (CP). METHOD: We studied 94 parents of children with cerebral palsy (case) and 60 parents of normal children (control). The functional level of CP was determined based on the gross motor functional classification system (GMFCS), and type of CP was classified by clinical features. We collected the data through questionnaires obtained from the parents, which consisted of Short Form Health Survey-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Family APGAR score. The data were statistically analyzed. RESULTS: The mean scores of SF-36 in parents of CP children was significantly lower than controls (60.09<67.38, p< 0.001). BDI (p<0.001) and BAI (p=0.002) scores of parents of CP children were significantly higher than control group, and familial APGAR score was lowered in the CP group compared to the control group. There were no differences in the scores of SF-36 in parents according to the severity of CP (p=0.844). CONCLUSION: The quality of life of parents of children with CP was significantly lower than that of control parents. Also psychologic status and familial function were poorer in parents of CP. It is necessary to evaluate and support for parent's psychologic status and quality of life in the comprehensive rehabilitation of CP.

Expression of Vascular Endothelial Growth Factor in Diabetic Frozen shoulder / 대한정형외과연구학회지

PURPOSE: To investigate the expression of Vascular Endothelial Growth Factor (VEGF) in diabetic frozen shoulders. MATERIALS AND METHODS: We preformed arthroscopic adhesiolysis on 9 diabetic frozen shoulder patients, and observed the arthroscopic findings. Also, we examined the potential role of VEGF by using samples of synovial tissues from 5 patients, and 2 normal synovial tissues. Immunohistochemical staining and Western blotting were performed using polyclonal antibodies against VEGF. RESULTS: There was hyperemic synovitis in the 9 diabetic frozen shoulder patients. In the 5 patients' tissue samples, there was strong immunostaining and expression to VEGF, but there was little staining and expression in the control group. CONCLUSION: We postulate that VEGF is synthesized and secreted in the synovium of diabetic frozen shoulders and that secreted VEGF binds specific receptors on the endothelial cells of nearby small blood vessels, and leads to the subsequent development of frozen shoulders in diabetic patients.