Publication: Papel de BMP9 en la patología hepática crónica: estudios "in vivo" e "in vitro"
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2018-01-11
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Universidad Complutense de Madrid
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Abstract
El hígado realiza numerosas funciones complejas implicadas en el mantenimiento de la homeostasis del organismo. Un aspecto muy característico es su elevada capacidad de regeneración después del daño hepático, que se lleva a cabo por las células parenquimáticas. Sin embargo, si se ve comprometida la capacidad de regeneración de estas células, como en una lesión crónica o en presencia de sustancias que inhiben la proliferación de los de hepatocitos (Falkowski et al. 2003; Marshall et al. 2005), las células progenitoras hepáticas (HPC) son activada para apoyar o asumir el proceso regenerativo. Las HPCs (que son más conocidas en ratones como células ovales) constituyen una población de células bipotenciales del hígado adulto. Durante la patología hepática crónica, se activan, se expanden en el parénquima hepático y se diferencian a colangiocitos y/o hepatocitos para compensar la pérdida celular y ayudar a mantener la homeostasis de hígado, contribuyendo así a la regeneración del hígado en diferentes enfermedades hepáticas (Riehle et al. 2011). Sin embargo, algunas evidencias recientes apoyen el papel pro-fibrogénico de estas células (Kuramitsu et al. 2013); lo que junto al hecho de que estas células pueden ser objeto de una conversión maligna y transformarse en células iniciadoras de tumores (Lee et al. 2009) contribuye a alimentar la polémica sobre cual es el papel real que juegan durante el daño hepático. Ciertamente, una adecuada regulación de estas células en el contexto de la patología hepática crónica podría ser un determinante importante en la respuesta a la lesión hepática y su posterior desenlace. Todo esto anima a estudiar los mecanismos moleculares implicados en el potencial pro-regenerativo o pro-tumorigénico de las HPC, aún poco conocidos. El factor de crecimiento hepático (HGF) y su receptor tirosina quinasa, c-Met son esenciales para promover una eficaz respuesta regenerativa después del daño hepático agudo y crónico, actuando en los hepatocitos así como en las HPC (Borowiak et al. 2004; Huh et al. 2004; Ishikawa et al. 2012). Este papel pro-regenerativo es la consecuencia de sus actividades anti-inflamatorias, anti-fibróticas y anti-apoptóticas. Es interesante destacar que la ausencia de c-Met tiene profundos efectos en las células ovales, afectando múltiples procesos celulares necesarios para la regeneración, incluyendo la proliferación, supervivencia, diferenciación y migración (Ishikawa et al. 2012)...
The liver performs many complex functions involved in maintaining the homeostasis of the organism. A very unique aspect is its high regenerative capacity after liver damage, which is carried out by parenchymal cells. However, if the regenerative capacity of these cells is compromised, such as in chronic injury states or in presence of substances inhibiting adult hepatocyte proliferation (Falkowski et al. 2003; Marshall et al. 2005), the hepatic progenitor cells (HPCs) are activated to support or take over the regenerative process. HPCs (better known as oval cells in rodents) constitute a bipotential cell population from adult liver. Under chronic liver disease (CLD), they become activated, expand into liver parenchyma and differentiate into cholangiocytes and/or hepatocytes to compensate for the cellular loss and to help maintain liver homeostasis; therefore contributing to sustain liver regeneration during several hepatic disorders (Riehle et al. 2011). However, recent evidence supports a pro-fibrogenic role for these cells (Kuramitsu et al. 2013); which together with the fact that they can also be target of malignant conversion and become tumor-initiating cells (Lee et al. 2009), adds to the confusion of which is their precise role during liver injury. Certainly, an appropriate regulation of these cells in the context of CLD could be a major determinant of the response to liver injury and its subsequent outcome. This encourages studying the molecular mechanisms involved in the pro-regenerative or pro-tumorigenic potential of the hepatic progenitor cells, still poorly understood. Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, has been demonstrated to be critical for a successful regenerative response after acute and chronic liver damage regulating both hepatocytes and progenitors population (Borowiak et al. 2004; Huh et al. 2004; Ishikawa et al. 2012). This pro-regenerative role is the consequence of its powerful anti-inflammatory, anti-fibrotic and anti-apoptotic activities. Interestingly, absence of c-Met has profound effects in oval cells, affecting multiple cellular processes required for regeneration, including proliferation, survival, differentiation and migration (Ishikawa et al. 2012)...
The liver performs many complex functions involved in maintaining the homeostasis of the organism. A very unique aspect is its high regenerative capacity after liver damage, which is carried out by parenchymal cells. However, if the regenerative capacity of these cells is compromised, such as in chronic injury states or in presence of substances inhibiting adult hepatocyte proliferation (Falkowski et al. 2003; Marshall et al. 2005), the hepatic progenitor cells (HPCs) are activated to support or take over the regenerative process. HPCs (better known as oval cells in rodents) constitute a bipotential cell population from adult liver. Under chronic liver disease (CLD), they become activated, expand into liver parenchyma and differentiate into cholangiocytes and/or hepatocytes to compensate for the cellular loss and to help maintain liver homeostasis; therefore contributing to sustain liver regeneration during several hepatic disorders (Riehle et al. 2011). However, recent evidence supports a pro-fibrogenic role for these cells (Kuramitsu et al. 2013); which together with the fact that they can also be target of malignant conversion and become tumor-initiating cells (Lee et al. 2009), adds to the confusion of which is their precise role during liver injury. Certainly, an appropriate regulation of these cells in the context of CLD could be a major determinant of the response to liver injury and its subsequent outcome. This encourages studying the molecular mechanisms involved in the pro-regenerative or pro-tumorigenic potential of the hepatic progenitor cells, still poorly understood. Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, has been demonstrated to be critical for a successful regenerative response after acute and chronic liver damage regulating both hepatocytes and progenitors population (Borowiak et al. 2004; Huh et al. 2004; Ishikawa et al. 2012). This pro-regenerative role is the consequence of its powerful anti-inflammatory, anti-fibrotic and anti-apoptotic activities. Interestingly, absence of c-Met has profound effects in oval cells, affecting multiple cellular processes required for regeneration, including proliferation, survival, differentiation and migration (Ishikawa et al. 2012)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, leída el 31-03-2017