Asunto(s)
Sistemas CRISPR-Cas/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Leucemia/genética , Osteonectina/genética , Animales , Progresión de la Enfermedad , Edición Génica/métodos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Xenoinjertos , Humanos , Leucemia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Microambiente Tumoral/genéticaRESUMEN
Normal placentation relies on an efficient maternal adaptation to pregnancy. Within the decidua, natural killer (NK) cells and dendritic cells (DC) have a critical role in modulating angiogenesis and decidualization associated with pregnancy. However, the contribution of these immune cells to the placentation process and subsequently fetal development remains largely elusive. Using two different mouse models, we here show that optimal placentation and fetal development is sensitive to disturbances in NK cell relative abundance at the fetal-maternal interface. Depletion of NK cells during early gestation compromises the placentation process by causing alteration in placental function and structure. Embryos derived from NK-depleted dams suffer from intrauterine growth restriction (IUGR), a phenomenon that continued to be evident in the offspring on post-natal day 4. Further, we demonstrate that IUGR was accompanied by an overall reduction of global DNA methylation levels and epigenetic changes in the methylation of specific hepatic gene promoters. Thus, temporary changes within the NK cell pool during early gestation influence placental development and function, subsequently affecting hepatic gene methylation and fetal metabolism.
Asunto(s)
Células Dendríticas/citología , Epigénesis Genética , Células Asesinas Naturales/citología , Animales , Metilación de ADN , Células Dendríticas/inmunología , Femenino , Retardo del Crecimiento Fetal , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Placenta/patología , Placentación , Embarazo , Útero/patologíaRESUMEN
Transforming growth factor-ßs (TGF-ßs) are secreted from cells as latent complexes and the activity of TGF-ßs is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-ß1 and TGF-ß2 play important roles in regulating these processes. Pregnancy-specific ß-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-ß1 and TGF-ß2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS)-induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the number of T regulatory cells. The PSG1-mediated protection was greatly inhibited by the coadministration of neutralizing anti-TGF-ß antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-ß and identify PSG1 as one of the few known biological activators of TGF-ß2.