BACKGROUND AND PURPOSERecombinant human erythropoietin (rHuEPO) is currently the mainstay of renal anaemia treatment. Recently, rHuEPO has been shown to provide pleiotrophic tissue protection in various pathological conditions. However, the benefits of rHuEPO beyond anaemia treatment are limited because it increases red blood cell mass. Carbamylated erythropoietin (CEPO) is the first rHuEPO derivative that lacks erythropoietic activity but retains tissue protection properties. Since carbamylation targets lysine residues on rHuEPo, we hypothesized that targeted lysine modifications of rHuEPO may result in a novel non-erythropoietic erythropoietin. EXPERIMENTAL APPROACHrHuEPO was subjected to various targeted lysine modifications. In vitro cytoprotection and apoptosis were evaluated using P19 and HEK293 cells. In vivo erythropoiesis was performed by administering the derivatives to animals for 2 weeks. Renoprotection was tested on an ischaemia/reperfusion (I/R) model. KEY RESULTSWe synthesized a novel derivative, a glutaraldehyde erythropoietin (GEPO). This construct abolished in vivo erythropoiesis. Biochemical characterization showed that GEPO was more electrostatically negative than rHuEPO. Immunoprecipitation experiments revealed that GEPO bound to the IL3RB/EPOR heterotrimeric receptor and ameliorated cellular apoptosis via the activation of Bcl-2. Notably, Bcl-2 activation was suppressed by the JAK2 inhibitor, tyrphostin AG490. In vivo experiments showed that GEPO also ameliorated kidney damage due to I/R injury both functionally and histologically.
Background: Angiogenesis is an essential mechanism for repairing any damaged target tissues or organs in cell therapy because the process can provide the supplements of nutrients, oxygen, and other repair factors. Many studies have revealed the ability of stem cells to induce angiogenesis of vessels in various organs. According to previous studies, We postulated that dental pulp stem cells (DPSCs) may improve angiogenesis for dental tissue repair and hence the outcome of regeneration. Objective: We would like to evaluate the potential of DPSCs to induce an angiogenesis for dental tissue repair and regeneration. Methods: In this study we employed endodontically treated teeth as a model to evaluate the angiogenesis properties of dental pulp stem cells. DPSCs were isolated from human third molar impacted tooth samples and reconstituted in basement membrane matrix scaffold (Matri-Gel 3D) and injected in the pulp chamber of the prepared endodontically treated teeth. Transplantation of experimental and control teeth was performed subcutaneously in the dorsum of immunocompromised mice (NOD-SCID). Results: The vascular numbers in subcutaneous connective tissues of 4 week experimental mice, DPSCs and Matri-Gel scaffolds appeared visibly greater than those in the control group with Matri-Gel transplantation alone. Similar appearance was also found in the section of H-E stain of soft tissues of experimental teeth. Conclusions: This may suggest that DPSCs can induce the regeneration of vascular dependent tissues such as dental pulp regeneration in necrotic pulp from diseases and may have implications in the regeneration of revital tooth.
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