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

doi:10.3390/cells10112822

Cited by 7 publications

(7 citation statements)

References 28 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In another study, GD-iMphs (2D-F) modeled necroptosis, a pathway implicated in the development of GD-associated neuroinflammation. Specifically, iMphs generated from healthy donors and treated with GBA1 inhibitor or derived from GD patient displayed an altered growth potential and an increased expression of necroprosis-associated genes RIPK3 and MLKL [ 52 ].…”

Section: Hereditary Disease Modelingmentioning

confidence: 99%

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Lyadova

Vasiliev

2022

Cell Biosci

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs) represent a valuable cell source able to give rise to different cell types of the body. Among the various pathways of iPSC differentiation, the differentiation into macrophages is a recently developed and rapidly growing technique. Macrophages play a key role in the control of host homeostasis. Their dysfunction underlies many diseases, including hereditary, infectious, oncological, metabolic and other disorders. Targeting macrophage activity and developing macrophage-based cell therapy represent promising tools for the treatment of many pathological conditions. Macrophages generated from human iPSCs (iMphs) provide great opportunities in these areas. The generation of iMphs is based on a step-wise differentiation of iPSCs into mesoderm, hematopoietic progenitors, myeloid monocyte-like cells and macrophages. The technique allows to obtain standardizable populations of human macrophages from any individual, scale up macrophage production and introduce genetic modifications, which gives significant advantages over the standard source of human macrophages, monocyte-derived macrophages. The spectrum of iMph applications is rapidly growing. iMphs have been successfully used to model hereditary diseases and macrophage-pathogen interactions, as well as to test drugs. iMph use for cell therapy is another promising and rapidly developing area of research. The principles and the details of iMph generation have recently been reviewed. This review systemizes current and prospective iMph applications and discusses the problem of iMph safety and other issues that need to be explored before iMphs become clinically applicable.

show abstract

Section: Hereditary Disease Modelingmentioning

confidence: 99%

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Lyadova

Vasiliev

2022

Cell Biosci

View full text Add to dashboard Cite

show abstract

“…Two of the iPSC lines employed in this study have been generated from the peripheral blood mononuclear cells (PBMCs) of a healthy donor (CTRL) and a GD type 1 patient (GD-1) carrying a compound heterozygous condition for the N370S and L444P mutations 76 . Briefly, after blood collection, mononuclear cells have been isolated through Ficoll (Lymphoprep) gradient centrifugation, and infected with Sendai vectors encoding for the reprogramming factors: Klf4, cMyc, Sox2, and Oct4 from the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher) according to the manufacturer instructions.…”

Section: Methodsmentioning

confidence: 99%

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

et al. 2023

Self Cite

View full text Add to dashboard Cite

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.

show abstract

“…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.

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 7 publications

References 28 publications

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

Contact Info

Product

Resources

About