Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

Santos, Dino Matias; Tiscórnia, Gustavo

doi:10.3390/ijms18040888

Cited by 11 publications

(6 citation statements)

References 110 publications

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“…iPSC allowed new insights into many aspects of GD molecular and cellular pathology. Alterations in different cell mechanisms, including inflammatory response, autophagic flux, lysosomal activity, calcium signaling and α-synuclein accumulation were linked to GCase deficit and GluCer accumulation [ 15 ]. iPSC-derived macrophages were used as a platform to investigate typical GD cell features as the impaired ROS production, reduced chemotaxis [ 16 ] and production of high levels of cytokines, such as TNFα, IL-6 and IL-1β [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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

Messelodi

Bertuccio

Indio

et al. 2021

Cells

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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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Section: Discussionmentioning

confidence: 99%

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

Messelodi

Bertuccio

Indio

et al. 2021

Cells

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“…Nevertheless, iPSC were successfully developed and are valuable tools for personalized medicine approaches, as was demonstrated for single patient variants of sialidosis, 19 CLN5, 20 Gaucher disease (reviewed in Ref. 21), and many others 22–24 . Moreover, iPSC can be combined with simultaneous base editing, showing potential for future therapies based on autologous cell transplantation of in vitro‐corrected patient cells 13 .…”

Section: Cell Culture Modelsmentioning

confidence: 99%

Development of precision therapies for rare inborn errors of metabolism: Functional investigations in cell culture models

Didiasova,

Banning,

Tikkanen

2023

J of Inher Metab Disea

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Due to the low number of patients, rare genetic diseases are a special challenge for the development of therapies, especially for diseases that result from numerous, patient‐specific pathogenic variants. Precision medicine makes use of various kinds of molecular information about a specific variant, so that the possibilities for an effective therapy based on the molecular features of the variants can be elucidated. The attention to personalized precision therapies has increased among scientists and clinicians, since the “single drug for all patients” approach does not allow the classification of individuals in subgroups according to the differences in the disease genotype or phenotype. This review article summarizes some approaches of personalized precision medicine that can be used for a cost‐effective and fast development of therapies, even for single patients. We have focused on specific examples on inborn errors of metabolism, with special attention on drug repurposing. Furthermore, we provide an overview of cell culture models that are suitable for precision medicine approaches.

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“…Skin fibroblasts are also used as a genetic model of GD; however, these are not the primary cell type affected in nGD (Danes and Bearn, 1968 ). Nevertheless, it has been possible to obtain different cell types affected by the disease, such as osteoclasts (Panicker et al, 2018 ), macrophages (Panicker et al, 2012 , 2014 ; Aflaki et al, 2014 ; Messelodi et al, 2021 ), and neurons (Schöndorf et al, 2014 ) from induced pluripotent stem cells (iPSCs) derived from GD fibroblasts (Santos and Tiscornia, 2017 ). Furthermore, the immortalization of cortical neurons from GBA1 −/− mouse embryos provides a new tool for studying nGD (Westbroek et al, 2016 ).…”

Section: An Overview Of Animal and Cellular Models Of Gdmentioning

confidence: 99%

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

Arévalo

Lamaizon²,

Cavieres³

et al. 2022

Front. Mol. Neurosci.

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Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme β-glucocerebrosidase (β-GC). β-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of β-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.

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Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned?

Cited by 11 publications

References 110 publications

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

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

Development of precision therapies for rare inborn errors of metabolism: Functional investigations in cell culture models

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

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