O PAPEL DA QUIMIOCINA CXCL12 NA DIFERENCIAÇÃO E AUTORRENOVAÇÃO DE CÉLULAS-TRONCO HEMATOPOÉTICAS

• Ano de defesa: 2021
• Autor(a) principal: Sabrina do Nascimento
• Orientador(a): Luciana Cavalheiro Marti
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Faculdade Israelita de Ciências da Saúde Albert Einstein
• Programa de Pós-Graduação: Acadêmico em Ciências da Saúde
• País: Brasil
• Palavras-chave em Português: Células-tronco hematopoéticas; Células-tronco mesenquimais; Quimiocina CXCL12
• Palavras-chave em Inglês: Hematopoietic stem cells; Mesenchymal stem cells; Quimiocina CXCL12
• Link de acesso: https://repositorio.einstein.br/publicacao/163519

Introduction: Hematopoietic stem cells are the only cells that are capable of producing all blood cell lines throughout a lifetime. In the bone marrow, there is a strictly controlled local microenvironment or niche that regulates the quiescence, proliferation, and differentiation of hematopoietic stem cells. Previous studies have shown that mesenchymal stem cells can regulate the hematopoietic stem cell niche. Although the mechanisms are not fully understood, these cells express genes associated with the maintenance of hematopoietic stem cells and their retention in the niche, including those encoding the chemokine CXCL12 and the stem cell factor. Purpose: This study aimed to determine the role of CXCL12 in multipotency, self-renewal, and differentiation of human hematopoietic stem cells, and also correlate the effects of aging of mesenchymal stem cells in a mouse transplantation model. Methods: Treatment of CXCL12 in the cultivation of hematopoietic stem cells was used and after 3 and 7 days immunophenotypic and gene expression analyses related to differentiation, self-renewal, and ß-catenin were performed. For the analysis of silencing of CXCL12 in stromal cells the silencing method using the siRNA and the shRNA was used. For the study in animal models, we used the spinal flush technique and compared the immunophenotypic profile of hematopoietic stem cells in young and older mice, and isolated stromal cells from animals. We also investigated the influence of co-cultivation of hematopoietic stem cells with mesenchymal stem cells on gene expression of differentiation, multipotency, and the ß-catenin protein. Results: Our results showed that hematopoietic stem cells cultured in the presence of CXCL12 led to an upregulation of genes associated with multipotency, a downregulation of genes involved in lineage differentiation, and to an increased protein expression of ß-catenin. We have also initiated experiments in animal models and analyzed bone marrow from young and old mice. Younger mice expressed significantly higher percentages of Lin-cKit+Sca1+ cells compared to the older mice. Conclusion: Treatment with CXCL12 may contribute to multipotency and pool maintenance as well as to their undifferentiated phenotype with hematopoietic stem cells. In accordance with the human findings, the older mice showed a reduced pool of hematopoietic stem cells in the bone marrow.