Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms

Sabogal‐Guáqueta, Angélica Maria; Marmolejo-Garza, Alejandro; Pádua, Vítor Passos de; Eggen, Bart J. L.; Boddeke, Erik; Dolga, Amalia M.

doi:10.1016/j.pneurobio.2020.101805

Cited by 45 publications

(36 citation statements)

References 197 publications

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“…In the aging and diseased CNS, the stiffness of CNS tissue often decreases (Hiscox et al, 2018). Our results are compatible with the notion that those changes of mechanobiological properties may contribute to an altered functional and activation state of microglia, including a chronically activated phenotype, and a failure to shut down activation as known from neurodegenerative disorders (for recent reviews see Sabogal-Guáqueta et al, 2020;Webers et al, 2020).…”

Section: Discussionsupporting

confidence: 89%

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Blaschke

Demir

König

et al. 2020

Front. Cell. Neurosci.

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Microglia-the brain's primary immune cells-exert a tightly regulated cascade of proand anti-inflammatory effects upon brain pathology, either promoting regeneration or neurodegeneration. Therefore, harnessing microglia emerges as a potential therapeutic concept in neurological research. Recent studies suggest that-besides being affected by chemokines and cytokines-various cell entities in the brain relevantly respond to the mechanical properties of their microenvironment. For example, we lately reported considerable effects of elasticity on neural stem cells, regarding quiescence and differentiation potential. However, the effects of elasticity on microglia remain to be explored.Under the hypothesis that the elasticity of the microenvironment affects key characteristics and functions of microglia, we established an in vitro model of primary rat microglia grown in a polydimethylsiloxane (PDMS) elastomer-based cell culture system. This way, we simulated the brain's physiological elasticity range and compared it to supraphysiological stiffer PDMS controls. We assessed functional parameters of microglia under "resting" conditions, as well as when polarized towards a pro-inflammatory phenotype (M1) by lipopolysaccharide (LPS), or an anti-inflammatory phenotype (M2) by interleukin-4 (IL-4). Microglia viability was unimpaired on soft substrates, but we found various significant effects with a more than twofold increase in microglia proliferation on soft substrate elasticities mimicking the brain (relative to PDMS controls). Furthermore, soft substrates promoted the expression of the activation marker vimentin in microglia. Moreover, the M2-marker CD206 was upregulated in parallel to an increase in the secretion of Insulin-Like Growth Factor-1 (IGF-1). The upregulation of CD206 was abolished by blockage of stretch-dependent chloride channels. Our data suggest that the cultivation of microglia on substrates of brain-like elasticity promotes a basic anti-inflammatory activation state via stretch-dependent chloride

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Section: Discussionsupporting

confidence: 89%

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Blaschke

Demir

König

et al. 2020

Front. Cell. Neurosci.

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“…For example, yolk sac-derived monocytes migrate to the brain and differentiate into resident microglia, which thereafter comprise a lifelong self-sustained cell population (Fig. 1) [58]. Microglia are responsible for many of aspects of central nervous system homeostasis, including neuronal synapse pruning.…”

Section: Hematopoietic Contributions To Neurodegenerative Diseasementioning

confidence: 99%

“…Microglia are responsible for many of aspects of central nervous system homeostasis, including neuronal synapse pruning. Microglia have been recently recognized to play important roles in neuropsychiatric and neurodegenerative diseases [58,59].…”

Section: Hematopoietic Contributions To Neurodegenerative Diseasementioning

confidence: 99%

“…The iPSC technology may be particularly important in modeling neurodegenerative disease, given difficulty in accessing patient tissue and given key differences between human microglia and those in animal models [60]. Several protocols exist to differentiate iPSCs into microglia, with ramifications for cellular remyelinating therapy [61] and microglia-associated disease modeling [58]. For example, gene-edited iPSCs recently demonstrated that Triggering receptor expression on myeloid cells 2 (TREM2) and Phospholipase C g2 (PLCG2) participate in a common pathway to mediate microglial cell survival, phagocytosis, and lipid metabolism [60].…”

Section: Hematopoietic Contributions To Neurodegenerative Diseasementioning

confidence: 99%

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Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

Thom

Chou

French

2020

Preprint

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Human induced pluripotent stem cell (iPSC)-based model systems can be used to produce blood cells for the study of both hematologic and non-hematologic disorders. This commentary discusses recent advances that have utilized iPSC-derived red blood cells, megakaryocytes, myeloid cells, and lymphoid cells to model hematopoietic disorders. In addition, we review recent studies that have defined how microglial cells differentiated from iPSC-derived monocytes impact neurodegenerative disease. Related translational insights highlight the utility of iPSC models for studying pathologic anemia, bleeding, thrombosis, autoimmunity, immunodeficiency, blood cancers, and neurodegenerative disease such as Alzheimer’s.

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“…In an effort to understand the contribution of non-neuronal cells to C9orf72 ALS/FTD, we generated a human in vitro cell culture model by differentiating C9orf72 ALS/FTD patient derived induced pluripotent stem cell (iPSCs) into microglia. While the use of a human iPSC-microglia (iPSC-MG) culture technique has only recently been developed, several studies have implemented this technology to study the role of microglia in neurodegenerative diseases, in particular Alzheimer's disease (42)(43)(44)(45)(46)(47)(48). To our knowledge, the intrinsic properties of microglia carrying a C9orf72 HRE, and their role in C9orf72 ALD/FTD neurodegeneration, have yet to be examined.…”

Section: Introductionmentioning

confidence: 99%

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

Lorenzini

Alsop

Levy

et al. 2020

Preprint

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Background: A mutation in the C9orf72 gene is the most common genetic mutation of familial and sporadic ALS, as well as familial FTD. While prior studies have focused on elucidating the mechanisms of neuronal dysfunction and neurodegeneration associated with this genetic mutation, the contribution of microglia to disease pathogenesis in the ALS/FTD disease spectrum remains poorly understood. Methods: Here, we generated a new disease model consisting of cultured C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG). We used this model to study the intrinsic cellular and molecular phenotypes of microglia triggered by the C9orf72 gene mutation. Results: We show that C9orf72 ALS/FTD iPSC-MG have a similar transcriptional profile compared to control iPSC-MG, despite the presence of C9orf72-associated phenotypes including reduced C9orf72 protein levels and dipeptide-repeat protein translation. Interestingly, C9orf72 ALS/FTD iPSC-MG exhibit intrinsic dysfunction of phagocytic activity upon exposure to Aβ or brain synaptoneurosomes and display a heightened inflammatory response. Detailed analysis of the endosomal and lysosomal pathways revealed altered expression of endosomal marker early endosome antigen 1 and lysosomal associated membrane protein 1 in C9orf72 ALS/FTD iPSC-MG, which was confirmed in patient postmortem tissues. Conclusions: These findings demonstrate that unstimulated C9orf72 iPSC-MG mono-cultures share a largely similar transcriptome profile with control microglia, despite the presence of C9orf72 disease phenotypes. The dysfunction of the endosomal-lysosomal pathway as demonstrated by aberrant microglia phagocytosis and engulfment of cellular debris and brain pathogens suggests that disease-related microglia phenotypes are not intrinsic but instead require microglia to be activated. In summary, the C9orf72 iPSC-MG culture system provides a novel human disease model to study the role of microglia in C9orf72 ALS/FTD disease pathogenesis.

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Microglia alterations in neurodegenerative diseases and their modeling with human induced pluripotent stem cell and other platforms

Cited by 45 publications

References 197 publications

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Substrate Elasticity Exerts Functional Effects on Primary Microglia

Mechanistic and Translational Advances Using iPSC-Derived Blood Cells

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

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