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iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death

Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are...

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Autores principales: Messelodi, Daria, Bertuccio, Salvatore Nicola, Indio, Valentina, Strocchi, Silvia, Taddia, Alberto, Serravalle, Salvatore, Bandini, Jessica, Astolfi, Annalisa, Pession, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616237/
https://www.ncbi.nlm.nih.gov/pubmed/34831047
http://dx.doi.org/10.3390/cells10112822
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author Messelodi, Daria
Bertuccio, Salvatore Nicola
Indio, Valentina
Strocchi, Silvia
Taddia, Alberto
Serravalle, Salvatore
Bandini, Jessica
Astolfi, Annalisa
Pession, Andrea
author_facet Messelodi, Daria
Bertuccio, Salvatore Nicola
Indio, Valentina
Strocchi, Silvia
Taddia, Alberto
Serravalle, Salvatore
Bandini, Jessica
Astolfi, Annalisa
Pession, Andrea
author_sort Messelodi, Daria
collection PubMed
description Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease.
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spelling pubmed-86162372021-11-26 iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death Messelodi, Daria Bertuccio, Salvatore Nicola Indio, Valentina Strocchi, Silvia Taddia, Alberto Serravalle, Salvatore Bandini, Jessica Astolfi, Annalisa Pession, Andrea Cells Article Gaucher disease is a lysosomal storage disorder characterized by β-glucosidase enzyme deficiency and substrate accumulation, especially in cells of the reticuloendothelial system. Typical features of the disease are the unrestrained activation of inflammatory mechanisms, whose molecular pathways are still unclear. To investigate biological mechanisms underlying the macrophage activation in GD, we derived iPSCs from a healthy donor and a GD patient line and differentiated them into hematopoietic progenitors. While GD iPSCs are able to efficiently give rise to CD33+/CD45+ myeloid progenitors, the maturation towards the CD14+/CD163+ monocyte/macrophages fate resulted enhanced in the GD lines, that in addition displayed a decreased growth potential compared to control cells either in semisolid or in liquid culture. The GD lines growth impairment was associated with a significant upregulation of RIPK3 and MLKL, two key effectors of necroptosis, the inflammation related cell death pathway. The activation of necroptosis, which has already been linked to neuronopathic GD, may play a role in the disease proinflammatory condition and in the identified cell growth defects. Understanding the GD macrophage role in the alteration of mechanisms linked to cellular metabolism imbalance, cell death and inflammation are crucial in identifying new ways to approach the disease. MDPI 2021-10-21 /pmc/articles/PMC8616237/ /pubmed/34831047 http://dx.doi.org/10.3390/cells10112822 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Messelodi, Daria
Bertuccio, Salvatore Nicola
Indio, Valentina
Strocchi, Silvia
Taddia, Alberto
Serravalle, Salvatore
Bandini, Jessica
Astolfi, Annalisa
Pession, Andrea
iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title_full iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title_fullStr iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title_full_unstemmed iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title_short iPSC-Derived Gaucher Macrophages Display Growth Impairment and Activation of Inflammation-Related Cell Death
title_sort ipsc-derived gaucher macrophages display growth impairment and activation of inflammation-related cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616237/
https://www.ncbi.nlm.nih.gov/pubmed/34831047
http://dx.doi.org/10.3390/cells10112822
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