RESUMEN
OBJECTIVE: Glycosaminoglycans (GAG) are major components of bone marrow extracellular matrix because they have the property to interact with cells and growth factors in hematopoietic niches. In this study, we investigated the effect of two different chemically defined GAG mimetics on mobilization of hematopoietic stem and progenitor cells (HSPCs) in mice peripheral blood. MATERIALS AND METHODS: Mobilization was achieved by intraperitoneal injection of GAG mimetics. Mobilized cells were characterized phenotypically by reverse transcription polymerase chain reaction and fluorescence-activated cell sorting analysis and functionally by colony-forming cell, cobblestone area-forming cell and long-term culture-initiating cell assays in vitro. Radioprotection assays were performed to confirm the functionality of primitive hematopoietic cells in vivo. Involvement of stromal-derived factor-1 (SDF-1) and matrix metalloproteinase-9 (MMP-9) were investigated. RESULTS: GAG mimetics treatment induces hyperleukocytosis and mobilization of HSPC. They synergize with the effects of granulocyte colony-stimulating factor or AMD3100 on hematopoietic progenitors mobilization. Reconstitution of lethally irradiated recipient mice with peripheral blood mononuclear cells from GAG mimetic-treated donor mice improves engraftment and survival. BiAcore studies indicate that the mimetics interact directly with SDF-1. In addition, GAG mimetics-induced mobilization is associated with increased levels of pro- and active MMP-9 from bone marrow cells and increased level of SDF-1 in peripheral blood. Finally, mobilization is partially inhibited by co-injection with anti-SDF-1 antibody. CONCLUSION: This study demonstrates that GAG mimetics induce efficient mobilization of HSPCs, associated with an activation of pro-MMP-9 and a modification in the SDF-1 concentration gradient between bone marrow and peripheral blood. We suggest that structural features of GAGs can modify the nature of mobilized cells.
Asunto(s)
Materiales Biomiméticos/farmacología , Quimiocina CXCL12/sangre , Glicosaminoglicanos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/citología , Metaloproteinasa 9 de la Matriz/sangre , Animales , Fármacos Anti-VIH/agonistas , Fármacos Anti-VIH/farmacología , Bencilaminas , Médula Ósea/metabolismo , Ciclamas , Sinergismo Farmacológico , Glicosaminoglicanos/agonistas , Supervivencia de Injerto/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/agonistas , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Compuestos Heterocíclicos/agonistas , Compuestos Heterocíclicos/farmacología , Masculino , Ratones , Relación Estructura-Actividad , Trasplante HomólogoRESUMEN
El objetivo de la terapia frente al SIDA es disminuir la carga viral hasta hacerla indetectable y aumentar el recuento celular de linfocitos CD4+, el uso de tres sustancias combinadas, tan pronto como sea posible, ofrece la mejor posibilidad de conseguir tales respuestas virales y celulares en forma persistente por largo tiempo
