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

Authors :
Daria Messelodi
Salvatore Nicola Bertuccio
Valentina Indio
Silvia Strocchi
Alberto Taddia
Salvatore Serravalle
Jessica Bandini
Annalisa Astolfi
Andrea Pession
Source :
Cells, Vol 10, Iss 11, p 2822 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
20734409
Volume :
10
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.2a5a4b5bba184e2a9a0967caa254cf87
Document Type :
article
Full Text :
https://doi.org/10.3390/cells10112822