Factors derived from human exfoliated deciduous teeth stem cells reverse neurological deficits in a zebrafish model of Parkinson's disease.

Background/purpose: Mesenchymal stem cells exhibit therapeutic efficacy for brain injury. This study examined the effect of mesenchymal stem cells derived from human exfoliated deciduous teeth (SHED) on alleviating symptoms of Parkinson's disease (PD). Materials and methods: SHED were isolated to examine the biosafety and bioavailability of stem cells derived from human exfoliated deciduous teeth-derived conditioned medium (SHED-CM) for the alleviation of PD symptoms in a 6-hydroxydopamine (6-OHDA)-induced PD zebrafish model. Results: SHED-CM administration did not induce neurological, skin or muscle toxicity in control zebrafish at any dose, and estrogen equivalent testing showed no chronic toxicants. Induction of PD with 6-OHDA suppressed zebra SHED-CM was administered to zebrafish treated with 6-OHDA to induce PD symptoms. Similar to nomifensine, a drug with proven anti-PD potential, SHED-CM repaired the motor deficiencies in the zebrafish PD model. Conclusion: Our results indicate the biosafety of SHED-CM and its therapeutic potential in treating PD in a zebrafish model.

Erratum: Chen, Y.-R., et al. Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease. Int. J. Mol. Sci. 2020, 21, 3807.

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Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased α-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor 1 (TGF-1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.

Parathyroid hormone gene-activated matrix with DFDBA/collagen composite matrix enhances bone regeneration in rat calvarial bone defects.

BACKGROUND: Gene-activated matrix (GAM) induces sustained local production of growth factors to promote tissue regeneration. GAM contains a plasmid DNA (pDNA) encoding target proteins that is physically entrapped within a biodegradable matrix carrier. GAM with a pDNA encoding the first 34 amino acids of parathyroid hormone (PTH 1-34) and a collagen matrix enhances bone regeneration in long bone defects. Demineralized freeze-dried bone allograft (DFDBA) is a widely used osteoinductive bone graft. The present study determined the osteogenic effects of PTH-GAM with a collagen or DFDBA/collagen composite (D/C) matrix for treating craniofacial bone defects. METHODS: We constructed a pDNA encoding human PTH 1-34 and performed cyclic AMP ELISA to verify the bioactivity of PTH 1-34. Next, we generated a D/C matrix and PTH-GAMs containing a collagen matrix (PTH-C-GAM) or D/C matrix (PTH-D/C-GAM). Rats with critical-sized calvarial bone defects were divided into four groups, namely, untreated rats (sham group) and rats grafted with D/C matrix, PTH-C-GAM, or PTH-D/C-GAM (D/C, PTH-C-GAM, or PTH-D/C-GAM groups, respectively). PTH expression was determined by performing immunohistochemical staining after 4 and 8 weeks. New bone formation was evaluated by performing radiography, dual-energy X-ray absorptiometry, microcomputed tomography, and histological examination. RESULTS: PTH pDNA-transfected cells secreted bioactive PTH 1-34. Moreover, PTH was expressed at 4 and 8 weeks after the surgery in rats in the PTH-C-GAM group but not in rats in the D/C group. New bone formation in the calvarial bone defects, from more to less, was in the order of PTH-D/C-GAM, PTH-C-GAM, D/C, and sham groups. CONCLUSION: Our results indicate that PTH-GAM with a collagen matrix promotes local PTH production for at least 8 weeks and bone regeneration in craniofacial bone defect. Moreover, our results indicate that replacement of the collagen matrix with the D/C matrix improves the osteogenic effects of PTH-GAM.

Human Beta-Defensin-2 and -3 Mitigate the Negative Effects of Bacterial Contamination on Bone Healing in Rat Calvarial Defect.

Bacterial contamination during the healing of bone defects frequently compromises the effects of bone regenerative therapy. Human beta-defensin-2 (hBD2) and -3 (hBD3) are antimicrobial peptides of human innate immune system with a broad antibacterial spectrum and rare bacterial resistance. The purpose of this study was to determine the effect of hBD2 and hBD3 on the healing of bacteria-contaminated bone defects. Rat bone marrow stromal cells (BMSCs) were infected with adenovirus to overexpress hBD2 or hBD3. Treatment with the conditioned medium derived from the BMSCs overexpressing defensins could concentration dependently reduce the viable Staphylococcus aureus numbers in the colony formation assay. In addition, the antimicrobial effect of BMSCs overexpressing defensins was verified with a diffusion chamber model in rats. Furthermore, we established a S. aureus-contaminated rat calvarial defect model and demonstrated that S. aureus contamination significantly compromised the bone regenerative effect after treatment with wild-type BMSCs. When defensin-overexpressing BMSCs were implanted into the S. aureus-contaminated defect, the viable S. aureus numbers were dramatically reduced and the negative effects of S. aureus contamination on bone healing were significantly mitigated. In conclusion, application of hBD2 or hBD3 promotes the healing of S. aureus-contaminated bone defects.

Cell Therapy With G-CSF-Mobilized Stem Cells in a Rat Osteoarthritis Model.

G-CSF-mobilized peripheral blood stem cells (gm-PBSCs) offer a convenient cell source for treatment of hematopoietic and vascular disorders. Whether gm-PBSCs provide beneficial effects on skeleton diseases, such as osteoarthritis (OA), remains unknown. This study was undertaken to address the hypothesis that gm-PBSCs promote articular regeneration in OA. Here we studied the effect of single-dose intra-articular injection of gm-PBSCs from male donors delivered in hyaluronic acid (HA) on papain-induced OA in the knee joints of female Sprague-Dawley (SD) rats. Contralateral OA knee joints received single-dose HA alone and served as vehicle controls. We evaluated the histologic changes in glycosaminoglycan, type II collagen, type X collagen, modified Mankin score, and cell apoptosis rate in the articular cartilage of rat knees. We demonstrated that gm-PBSCs were mobilized to the peripheral blood via G-CSF infusion for 5 days in SD rats with increasing CD34(+) percentage up to 55-fold. We showed that gm-PBSCs inhibit progression of papain-induced OA via reducing articular surface irregularity, fibrillation, and erosion, preventing cellular necrosis and loss of chondrogenic proteins, such as glycosaminoglycan and type II collagen, at both 3 and 6 weeks after treatment. Moreover, gm-PBSCs reduced modified Mankin scores and cellular apoptosis rates compared with HA alone. Our findings demonstrate that HA plus gm-PBSCs, rather than HA alone, inhibits progression of OA in rats in vivo. Thus, intra-articular injection of gm-PBSCs is a convenient protocol for treating OA with consistent beneficial effects.