Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids

Çakır, Barış; Tanaka, Yoshiaki; Kiral, Ferdi Rıdvan; Xiang, Yangfei; Dağliyan, Onur; Wang, Juan; Lee, Maria; Greaney, Allison M.; Yang, Woo Sub; duBoulay, Catherine; Kural, Mehmet H.; Patterson, Benjamin; Zhong, Ming; Kim, Jonghun; Bai, Yalai; Wang, Min; Niklason, Laura E.; Patra, Prabir; Park, In‐Hyun

doi:10.1038/s41467-022-28043-y

Cited by 83 publications

(74 citation statements)

References 75 publications

(105 reference statements)

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“…Among the non-histone effects of HDACs and HATs are impact on protein aggregation, protein clearance/degradation, autophagy, DNA repair capabilities, oxidative stress, anti-inflammatory action, control of chaperone proteins, anti-viral roles, circadian rhythm, and other key cell functions (24,25,51). Beyond cancer, these acetylation modifiers have been shown to be impactful through their histone and non-histone action in cardiovascular health, especially related to development, hypertrophy/heart failure, metabolic state, and cardiac aging (52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Pressler

Horvath

Entcheva

2022

Front. Cardiovasc. Med.

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Development of safer drugs based on epigenetic modifiers, e.g., histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21–70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the acetylation modifiers may help explain their predominantly net-neutral effects on cardiac electrophysiology. ATP1A1, encoding for the Na/K pump, represented an outlier—with orthogonal regulation by the acetylation modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g., MEF2A and TBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+/-) mediatory role on ICs for NKX25 and TGF1B/KLF4, respectively, while RUNX1 exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of acetylation-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.

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Section: Discussionmentioning

confidence: 99%

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Pressler

Horvath

Entcheva

2022

Front. Cardiovasc. Med.

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“…For example, microglia are the tissue-resident macrophages of the brain that arise in the yolk sac and are involved in innate immune and homeostatic functions [ 106 ]. Incorporation of microglia into organoids via transplantation or induction of the PU.1 transcription factor expression in a subset of organoid cells [ 107 , 108 , 109 , 110 ] ( Figure 1 d) has been shown to attenuate DNA damage responses in organoids and to promote the maturation of neuronal activity.…”

Section: Reducing Stressmentioning

confidence: 99%

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

Nowakowski

Salama

2022

Cells

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The cerebral cortex forms early in development according to a series of heritable neurodevelopmental instructions. Despite deep evolutionary conservation of the cerebral cortex and its foundational six-layered architecture, significant variations in cortical size and folding can be found across mammals, including a disproportionate expansion of the prefrontal cortex in humans. Yet our mechanistic understanding of neurodevelopmental processes is derived overwhelmingly from rodent models, which fail to capture many human-enriched features of cortical development. With the advent of pluripotent stem cells and technologies for differentiating three-dimensional cultures of neural tissue in vitro, cerebral organoids have emerged as an experimental platform that recapitulates several hallmarks of human brain development. In this review, we discuss the merits and limitations of cerebral organoids as experimental models of the developing human brain. We highlight innovations in technology development that seek to increase its fidelity to brain development in vivo and discuss recent efforts to use cerebral organoids to study regeneration and brain evolution as well as to develop neurological and neuropsychiatric disease models.

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“…Recently, a protocol was developed for the generation of microglia-containing hCOs (mhCOs) via the overexpression of myeloid-specific transcription factor PU.1 in cortical organoids without co-culture. The mhCOs have become an efficient tool for functional investigation of microglia in neurodevelopmental and neurodegenerative disorders such as AD [ 108 ]. Given that microglia could not emerge natively inside organoids using the previous methods, this novel strategy has been a breakthrough for microglia generation in brain organoids.…”

Section: Future Perspectivesmentioning

confidence: 99%

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening

Seong

et al. 2022

Stem Cells International

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Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer’s disease (AD), Parkinson’s disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.

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Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids

Cited by 83 publications

References 75 publications

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Cerebral Organoids as an Experimental Platform for Human Neurogenomics

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening

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