Differential expression of retinoic acid alpha and beta receptors in neuronal progenitors generated from human embryonic stem cells in response to TTNPB (a retinoic acid mimetic)

Das, Madhurima; Pethe, Prasad

doi:10.1016/j.diff.2021.08.001

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…In addition, we further estimated the potential therapeutic drugs targeting AD patients with different risks using the CMap analysis and found that arachidonyltrifluoromethane and TTNPB may exert most effective therapeutic efficacy for AD patients in low-risk and high-risk groups, respectively. As a retinoic acid mimetic, TTNPB has been shown to promote neuronal differentiation via reinforcing the activities of RARα and RARγ, thus exerting neuroprotective effects ( 69 ). Arachidonyltrifluoromethane, a cPLA2 inhibitor, plays a vital role in attenuating lysosomal membrane permeabilization, inhibition of autophagy, and neuron death, eventually providing neuroprotective and anti-neuroinflammatory effects ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

Integration of bulk RNA sequencing and single-cell analysis reveals a global landscape of DNA damage response in the immune environment of Alzheimer’s disease

Lai

Lin²,

Chen³

et al. 2023

Front. Immunol.

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BackgroundWe developed a novel system for quantifying DNA damage response (DDR) to help diagnose and predict the risk of Alzheimer’s disease (AD).MethodsWe thoroughly estimated the DDR patterns in AD patients Using 179 DDR regulators. Single-cell techniques were conducted to validate the DDR levels and intercellular communications in cognitively impaired patients. The consensus clustering algorithm was utilized to group 167 AD patients into diverse subgroups after a WGCNA approach was employed to discover DDR-related lncRNAs. The distinctions between the categories in terms of clinical characteristics, DDR levels, biological behaviors, and immunological characteristics were evaluated. For the purpose of choosing distinctive lncRNAs associated with DDR, four machine learning algorithms, including LASSO, SVM-RFE, RF, and XGBoost, were utilized. A risk model was established based on the characteristic lncRNAs.ResultsThe progression of AD was highly correlated with DDR levels. Single-cell studies confirmed that DDR activity was lower in cognitively impaired patients and was mainly enriched in T cells and B cells. DDR-related lncRNAs were discovered based on gene expression, and two different heterogeneous subtypes (C1 and C2) were identified. DDR C1 belonged to the non-immune phenotype, while DDR C2 was regarded as the immune phenotype. Based on various machine learning techniques, four distinctive lncRNAs associated with DDR, including FBXO30-DT, TBX2-AS1, ADAMTS9-AS2, and MEG3 were discovered. The 4-lncRNA based riskScore demonstrated acceptable efficacy in the diagnosis of AD and offered significant clinical advantages to AD patients. The riskScore ultimately divided AD patients into low- and high-risk categories. In comparison to the low-risk group, high-risk patients showed lower DDR activity, accompanied by higher levels of immune infiltration and immunological score. The prospective medications for the treatment of AD patients with low and high risk also included arachidonyltrifluoromethane and TTNPB, respectively,ConclusionsIn conclusion, immunological microenvironment and disease progression in AD patients were significantly predicted by DDR-associated genes and lncRNAs. A theoretical underpinning for the individualized treatment of AD patients was provided by the suggested genetic subtypes and risk model based on DDR.

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Section: Discussionmentioning

confidence: 99%

Integration of bulk RNA sequencing and single-cell analysis reveals a global landscape of DNA damage response in the immune environment of Alzheimer’s disease

Lai

Lin²,

Chen³

et al. 2023

Front. Immunol.

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“…Some offtarget biological GO terms were significantly enriched in samples treated with TTNPB, such as nervous system development (GO:0007399). A recent study demonstrated that addition of 1µM TTNPB can improve the generation of neuronal progenitors from hESCs (69), an effect that should be avoided in the RAPID-E protocol with an addition of only 100nM TTNPB. Furthermore, samples treated at day 11 showed high expression of RARβ, which has been showed to negatively regulate neuronal differentiation (69).…”

Section: Discussionmentioning

confidence: 99%

Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis

Humphreys

Woods

Bates

et al. 2023

Preprint

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Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but are still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development. Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

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“…To determine how RA might transcriptionally regulate expression of genes involved in neurogenesis identified in the spatial transcriptomic analysis, we first used a transcription factor DNA binding prediction algorithm (LASAGNA) 43 to identify DNA binding sites for RA receptor RAR upstream of genes in the Notch pathway and Sox2 (-1000 base pairs upstream to +200 base pairs downstream relative to transcription start sites). We opted to study RAR as it is the main receptor in neural progenitors 44,45 . We used Rarb as a positive control as it is known to be regulated by RA via direct binding of RAR [46][47][48] , this showed a high score for RAR binding, 94.08 (p-value = 2.5E-5, chromosomal location: chr14:16728769-16729905).…”

Section: Ra-rar Directly Regulates Expression Of the Long Noncoding ...mentioning

confidence: 99%

Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2

Como,

O’Rourke,

Winkler

et al. 2024

Preprint

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The meninges act as a regulator of brain development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meningeal-derived retinoic acid (RA) promotes neocortical neural progenitor cell cycle exit; however, the underlying molecular mechanism is unknown. Here, we used spatial transcriptomics and profiling of retinoic-acid receptor-α (RARα) DNA binding in Foxc1-mutant embryos that lack meninges-derived ligands to identify the neurogenic transcriptional mechanisms of RA signaling in telencephalic neural progenitors. We determined that meningeal-derived RA controls neurogenesis by suppressing progenitor self-renewal pathways Notch signaling and the transcription factor Sox2. We show that RARα binds in the Sox2ot promoter, a long non-coding RNA that regulates Sox2 expression, and RA promotes Sox2ot expression in neocortical progenitors. Our findings elucidate a previously unknown mechanism of how meningeal RA coordinates neocortical development and insight into how defects in meningeal development may cause neurodevelopmental disorders.

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Differential expression of retinoic acid alpha and beta receptors in neuronal progenitors generated from human embryonic stem cells in response to TTNPB (a retinoic acid mimetic)

Cited by 8 publications

References 47 publications

Integration of bulk RNA sequencing and single-cell analysis reveals a global landscape of DNA damage response in the immune environment of Alzheimer’s disease

Integration of bulk RNA sequencing and single-cell analysis reveals a global landscape of DNA damage response in the immune environment of Alzheimer’s disease

Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis

Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2

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