Alterações imunológicas e metabólicas durante o desenvolvimento neonatal reprogramam a identidade e função do fígado

• Ano de defesa: 2022
• Autor(a) principal: Brenda Naemi Lanza Nakagaki
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais
• Palavras-chave em Português: Biologia Celular; Fígado; Animais Recém-Nascidos; Desmame; Microbioma Gastrointestinal; Desenvolvimento hepático pós-natal; Neonatos; Desmame prematuro; Imunologia hepática; Microbiota intestinal pós-natal
• Link de acesso: https://hdl.handle.net/1843/78376

Liver is the main hematopoietic site in embryos, becoming a crucial organ in both immunity and metabolism in adults. Although much is known about hepatic embryonic development and the chronology of hematopoiesis during the gestational phase, it is still largely elusive how the liver adapts both the immune system and enzymatic profile to react to a plethora of challenges that a newborn faces in the initial periods after birth. In fact, abrupt changes in both microbiota and diet are expected during this phase; thus, the transition from intra- to extra-uterine life may demand rapid, complex and well- orchestrated steps to ensure neonatal survival and adaptation. Given the importance of the postnatal period, known as neonatal window of opportunity, we aimed to characterize neonatal liver development and identify possible factors underlying this adaptation. We found that human and mouse newborns have a sharp different hepatic cellular composition and arrangement compared to adults. We also found that myeloid cells and B cells primarily compose the neonatal hepatic immune system. Although neonatal mice were more susceptible to infections, with reduced expression of genes related to bacterial recognition, phagocytosis and killing by Kupffer cells, a rapid evolution to an efficient immune response was observed. Concomitantly, newborns displayed a reduction of several macronutrient metabolic functions and normal expression level of enzymes belonging to lipid and carbohydrate metabolism was reached around the weaning period. Interestingly, in addition to altering the composition of the intestinal microbiota, early weaning profoundly disturbed the expression of several hepatic metabolic pathways, which persisted into adulthood, and caused a reduced ability to deal with infections. Lastly, we found that the gut microbiota is an important factor modulating bacterial catching by Kupffer cells and hepatic tolerance. In conclusion, our data provide a novel landscape of hepatic immune and metabolic development. The liver in neonates can be considered as a completely different organ from that in adults, which can be explained by the differences in the liver cell repertoire and phenotype. Also, dietary and antigen cues may be crucial to guide liver development during postnatal phase.