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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2020.tde-04092019-082714
Document
Author
Full name
Juçara Gastaldi Cominal
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Castro, Fabíola Attié de (President)
Antunes, Lusania Maria Greggi
Panepucci, Rodrigo Alexandre
Souza, Lucas Eduardo Botelho de
Machado Neto, João Agostinho
Orellana, Maristela Delgado
Title in Portuguese
Células estromais mesenquimais multipotentes em neoplasias mieloproliferativas: caracterização fenotípica, molecular e funcional
Keywords in Portuguese
Apoptose
Células estromais mesenquimais multipotentes
Microambiente medular
Neoangiogênese
Neoplasias mieloproliferativas
Oncoinflamação
Abstract in Portuguese
A policitemia vera (PV), trombocitemia essencial (TE) e mielofibrose (MF) são neoplasias mieloproliferativas (NMP) caracterizadas por proliferação exacerbada de células mieloides maduras e seus precursores na medula óssea e sangue periférico. A fisiopatologia das NMP está associada a presença de mutações iniciadoras nos genes JAK2, CALR e MPL, alterações epigenéticas e do microambiente medular. As células estromais mesenquimais multipotentes (MSC) são essenciais para a manutenção e desenvolvimento do microambiente medular. As MSC são capazes de secretar numerosas moléculas imunomodulatórias, fatores pró-angiogênicos e de crescimento. Pelo exposto, o presente trabalho teve como objetivos principais caracterizar e avaliar funcionalmente as MSC isoladas da medula óssea de pacientes com PV, TE e MF e determinar no microambiente medular desses pacientes o perfil de citocinas, quimiocinas e fatores pró-angiogênicos. Os resultados indicaram que as MSC de NMP são similares às MSC de indivíduos saudáveis quanto ao perfil imunofenotípico e multipotencialidade. Contudo, as MSC de pacientes com NMP se expandem mais lentamente e são de difícil estabelecimento in vitro em comparação com as MSC obtidas de medula óssea normais. Na PV, as MSC são mais resistentes à morte celular, apresentam níveis aumentados da expressão do gene antiapoptótico BIRC2 e menor potencial imunomodulatório. O microambiente medular dos pacientes com NMP apresentou perfil oncoinflamatório, caracterizado pela elevação dos níveis de citocinas, quimiocinas inflamatórias e fatores pró-angiogênicos, principalmente nos pacientes com PV. Em conjunto, os resultados obtidos indicam alteração do microambiente medular nas NMP. Estas alterações no nicho medular têm potencial para interferir no processo de hematopoese, neoangiogênese e na interação célula-célula/célula-estroma medular, contribuindo assim para o desenvolvimento de um microambiente pró-tumoral e na patogênese das NMP
Title in English
Multipotent mesechymal stromal cells from myeloproliferative neoplasms: phenotypic, molecular and functional characterization
Keywords in English
Apoptosis
Hematopoietic niche
Multipotent mesenchymal stromal cells
Myeloproliferative neoplasms
Neoangiogenesis
Oncoinflammation
Abstract in English
Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (PMF) are myeloproliferative neoplasms (MPN) characterized by an increased proliferation of mature myeloid cells and their precursors in the bone marrow and peripheral blood. The MPN's pathophysiology is associated with the presence of at least one of the driver mutations JAK2, CALR and MPL, and also with epigenetic deregulation and alterations in the bone marrow hematopoietic niche. Multipotent mesenchymal stromal cells (MSC) are an essential element for the maintenance and development of the hematopoietic niche and they secrete a large number of immunomodulatory molecules, pro-angiogenic and growth factors. The aims of this study were to characterize MSC from PV, ET and PMF patients, focusing on their phenotypic, molecular and functional properties and to determine the cytokines and chemokines profile of hematopoietic niche. The results indicated that MSC from MPN patients are similar to MSC from healthy individuals in regard to their immunophenotypic profile and multipotentiality. However, MSC from MPN patients are hard to establish in vitro and expand slower than normal MSC. MSC from PV patients are more resistant to cell death, they show an increased expression of the anti-apoptotic gene BIRC2 and less immunomodulatory properties in comparison to normal MSC. In NMP, the hematopoietic niche presented an oncoinflammatory profile characterized by elevated levels of inflammatory cytokines, chemokines and pro-angiogenic factors in comparison to the normal hematopoietic niche, mainly in PV patients. Taken together, our results indicate the deregulation of the hematopoietic niche in MPN. These alterations have potential to interfere in hematopoiesis, neoangiogenesis, cell-cell interactions and cell-stroma interactions in the bone marrow from MPN patients contributing to a pro-tumoral microenvironment and disease pathogenesis
 
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Release Date
2021-09-03
Publishing Date
2020-02-28
 
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