Predicting disease specific spinal motor neurons and glia in sporadic ALS

Dachet, Fabien; Liu, Jiangou; Ravits, John; Song, Fei

doi:10.1016/j.nbd.2019.104523

Cited by 11 publications

(12 citation statements)

References 32 publications

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“…Genes listed on the Y-axis can be found in Supplementary Fig. S1, or in the source publications, where they are named “MG/Mϕ1” genes (Dachet et al ., 2019) or “DAM” genes (Keren-Shaul et al ., 2017), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…To examine further the potential of the two different human iPSC-derived microglia differentiation methods under study to generate microglia that would provide disease-relevant experimental systems to investigate microglia involvement in ALS, we next compared the transcriptomes of Douvaras-microglia and McQuade-microglia to two previously described microglia gene signatures specific to sporadic ALS patients (Dachet et al ., 2019). This analysis revealed that both of these transcriptional signatures were significantly enriched in Douvaras-microglia, but not in McQuade-microglia (Fisher’s exact test for both ‘Dachet subtypes’: Bonferroni-corrected p-values with Douvaras-microglia = 0.00072 and 6.4×10 -6 ; both Bonferroni-corrected p-values with McQuade-microglia = 1) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, motor neuron degeneration in ALS is associated with pathological mechanisms in both the gray matter and white matter, which are populated by distinct microglia subtypes (Dachet et al, 2019;Maniatis et al, 2019;Cipollina et al, 2020). The future success of studies utilizing human iPSCderived microglia to model neurodegenerative diseases will depend in large part on the ability to generate, and study, those specific microglial subtypes that are relevant to the pathobiological questions under investigation.…”

Section: Discussionmentioning

confidence: 99%

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Comparing the potential of microglia preparations generated using different human iPSC-based differentiation methods to model microglia-mediated mechanisms of amyotrophic lateral sclerosis pathophysiology

Tang

Pulimood

Stifani

2022

Preprint

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Microglia are the resident immune cells of nervous system. In healthy conditions, microglia actively patrol neural tissues in a homeostatic state, which can rapidly change to an activated state in response to local injury/disease. Dysregulated microglia activation is a hallmark of disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The elucidation of the roles of microglia in human biology and disease has recently benefitted from the development of human induced pluripotent stem cell (iPSC)-based approaches to generate microglia-like cells. Microglia represent a heterogenous group of cells with spatial diversity in both health and disease. This situation poses a considerable challenge along the path towards establishing the most pathologically-relevant human iPSC-derived microglia preparations to investigate the complex roles of microglia in ALS and other neurological diseases. The success of these approaches must account for microglia diversity in different regions of the brain and spinal cord. In this study, we compared the transcriptomes of human iPSC-derived microglia generated using different methods to determine whether or not separate strategies can be used to generate microglia with distinct transcriptional signatures in vitro. We show that different derivation methods give rise to preparations comprising human microglia with distinct transcriptomic signatures resembling the gene profiles of specific microglia subpopulations in vivo. These findings suggest that a careful, and coordinated, implementation of multiple microglia differentiation methods from human iPSCs can be an effective approach towards the goal of generating multiple microglia subtypes that will offer enhanced model systems to account for microglia heterogeneity in vivo. Spatially-defined human iPSC-derived microglia would represent an enhanced tool to study the multiple levels of involvement of microglia in mechanisms of motor neuron degeneration in ALS, as well as other neurological diseases and disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparing the potential of microglia preparations generated using different human iPSC-based differentiation methods to model microglia-mediated mechanisms of amyotrophic lateral sclerosis pathophysiology

Tang

Pulimood

Stifani

2022

Preprint

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“…Although the pathogenesis of ALS is extremely intricate and remains largely unknown, inflammation and oxidative stress play a pivotal role in ALS pathogenesis and contribute to the vicious cycle of neurodegeneration in the lumbar spinal cord. There is growing evidence that activated microglia and reactive astrocytes increase in the spinal cord of ALS patients [4] and model mice [5]. Activation of glial cells in ALS is marked by the elevated production of neurotoxic mediators such as reactive oxygen species (ROS), proinflammatory cytokines, and inflammatory mediators [6].…”

Section: Introductionmentioning

confidence: 99%

“…Neuroinflammation is the activation of an immune response in the central nervous system by activated astrocytes and microglial cells. Activation of astrocytes and microglia is prominently observed in regions of degenerating motor neurons in ALS patients as well as in model mice [4,5,37,38]. A previous study conducted in our laboratory showed that the levels of spinal GFAP and Iba-1 expression were elevated in an age-dependent manner in G93A mice [17].…”

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confidence: 99%

Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

Kosuge

Kaneko

Nango

et al. 2020

Oxidative Medicine and Cellular Longevity

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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

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