RESUMO
Liver transplantation is the most common treatment for patients suffering from liver failure that is caused by congenital diseases, infectious agents, and environmental factors. Despite a high rate of patient survival following transplantation, organ availability remains the key limiting factor. As such, research has focused on the transplantation of different cell types that are capable of repopulating and restoring liver function. The best cellular mix capable of engrafting and proliferating over the long-term, as well as the optimal immunosuppression regimens, remain to be clearly well-defined. Hence, alternative strategies in the field of regenerative medicine have been explored. Since the discovery of induced pluripotent stem cells (iPSC) that have the potential of differentiating into a broad spectrum of cell types, many studies have reported the achievement of iPSCs differentiation into liver cells, such as hepatocytes, cholangiocytes, endothelial cells, and Kupffer cells. In parallel, an increasing interest in the study of self-assemble or matrix-guided three-dimensional (3D) organoids have paved the way for functional bioartificial livers. In this review, we will focus on the recent breakthroughs in the development of iPSCs-based liver organoids and the major drawbacks and challenges that need to be overcome for the development of future applications.
Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Fígado/citologia , Organoides/citologia , Diferenciação Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Transplante de Fígado , Modelos Biológicos , Técnicas de Cultura de Órgãos , Organoides/efeitos dos fármacos , Medicina RegenerativaRESUMO
Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.
Assuntos
Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Isoanticorpos/imunologia , Transferência Adotiva , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Portadores de Fármacos , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fator IXa/imunologia , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Fator X/imunologia , Feminino , Terapias Fetais , Terapia Genética , Hemofilia A/imunologia , Hemofilia A/terapia , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Imunoterapia Adotiva , Isoanticorpos/biossíntese , Tecido Linfoide/imunologia , Camundongos , Modelos Animais , Células Vegetais , Gravidez , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T Reguladores/transplanteRESUMO
Vitamin D (VD) deficiency (VDD) correlates to obesity, with VD a recognized mediator of metabolic diseases. From a previous proteomic study identifying adiponectin as a link between VDD and pediatric obesity, herein we analysed another protein (SSP2301) increased with VDD. A focused 2D-electrophoretic analysis identified 4 corresponding plasma proteins, with one predicted to be fetuin B (FETUB). FETUB was studied due to its emerging role in metabolic diseases and cytogenetic location (3q27.3) with adiponectin. Results were confirmed in obese children, where plasma FETUB was higher with VDD. A direct effect by 1α,25-(OH)2D3 on hepatocellular FETUB synthesis was observed, with a time and dose dependent reduction. Further, we demonstrated the VD-receptor (VDR) is key, with FETUB "released" with VDR silencing. Finally, VD supplementation (6weeks) to juvenile mice fed a standard diet, reduced plasma FETUB. Only at 22weeks did liver FETUB correspond to plasma FETUB, highlighting the contribution of other VD-responsive tissues. Overall, FETUB is a key protein linking VDD to pediatric obesity. With an emerging role in metabolic diseases, we demonstrate that VD/VDR directly regulate FETUB.