Nature Protocols, Journal Year: 2022, Volume and Issue: 18(2), P. 490 - 529
Published: Nov. 9, 2022
Language: Английский
Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)
Published: Dec. 10, 2021
Organoids-cellular aggregates derived from stem or progenitor cells that recapitulate organ function in miniature-are of growing interest developmental biology and medicine. Organoids have been developed for organs tissues such as the liver, gut, brain, pancreas; they are used surrogates to study a wide range questions basic biology, genetic disorders, therapies. However, many organoids reported date cultured Matrigel, which is prepared secretion Engelbreth-Holm-Swarm mouse sarcoma cells; Matrigel complex poorly defined. This complexity makes it difficult elucidate Matrigel-specific factors governing organoid development. In this review, we discuss promising Matrigel-free methods generation maintenance use decellularized extracellular matrix (ECM), synthetic hydrogels, gel-forming recombinant proteins.
Language: Английский
Citations
261
Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 561 - 572
Published: July 19, 2023
Disease modeling and target identification are the most crucial initial steps in drug discovery, influence probability of success at every step development. Traditional is a time-consuming process that takes years to decades usually starts an academic setting. Given its advantages analyzing large datasets intricate biological networks, artificial intelligence (AI) playing growing role modern identification. We review recent advances focusing on breakthroughs AI-driven therapeutic exploration. also discuss importance striking balance between novelty confidence selection. An increasing number AI-identified targets being validated through experiments several AI-derived drugs entering clinical trials; we highlight current limitations potential pathways for moving forward.
Language: Английский
Citations
149
Cell, Journal Year: 2022, Volume and Issue: 185(23), P. 4428 - 4447.e28
Published: Oct. 31, 2022
Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define dynamic trajectories each type, revealing major reconfiguration prenatal-to-postnatal transition in all types followed continuous adulthood identifying regulatory networks guiding developmental programs, states, functions. We uncover links between milestones, characterize diverse timing when cells acquire adult-like identify convergence distinct origins. further their regulators implicated neurological disorders. Finally, using this reference, benchmark identities maturation states organoid models. Together, captures landscape cortical development.
Language: Английский
Citations
130
Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2756 - 2769
Published: July 1, 2022
For decades, insight into fundamental principles of human biology and disease has been obtained primarily by experiments in animal models. While this allowed researchers to understand many biological processes great detail, some developmental mechanisms have proven difficult study due inherent species differences. The advent organoid technology more than 10 years ago established laboratory-grown organ tissues as an additional model system recapitulate human-specific aspects biology. use 3D organoids, well other advances single-cell technologies, revealed unprecedented insights mechanisms, especially those that distinguish humans from species. This review highlights novel with a focus on how generated better understanding development disease.
Language: Английский
Citations
103
Nature, Journal Year: 2024, Volume and Issue: 635(8039), P. 690 - 698
Published: Nov. 20, 2024
Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the covered by existing protocols, has been difficult quantitatively assess organoid variation fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated cell atlas totalling more than 1.7 million cells1–26. Mapping developing references27–30 shows primary types states that have estimates similarity between counterparts across protocols. We provide a programmatic interface browse query new datasets, showcase power annotate evaluate Finally, show can be used as diverse control cohort compare models disease, identifying genes pathways may underlie pathological mechanisms with models. The will fidelity, characterize perturbed diseased facilitate protocol development. A integrating counterparts, showing potential fidelity
Language: Английский
Citations
26
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: May 14, 2024
Abstract Human hippocampal organoids (hHOs) derived from human induced pluripotent stem cells (hiPSCs) have emerged as promising models for investigating neurodegenerative disorders, such schizophrenia and Alzheimer’s disease. However, obtaining the electrical information of these free-floating in a noninvasive manner remains challenge using commercial multi-electrode arrays (MEAs). The three-dimensional (3D) MEAs developed recently acquired only few neural signals due to limited channel numbers. Here, we report cyborg organoid (cyb-organoid) platform coupling liquid metal-polymer conductor (MPC)-based mesh neuro-interface with hHOs. MPC (mMPC) integrates 128-channel multielectrode distributed on small surface area (~2*2 mm). Stretchability (up 500%) flexibility mMPC enable its attachment Furthermore, show that under Wnt3a SHH activator induction, hHOs produce HOPX + PAX6 progenitors ZBTB20 PROX1 dentate gyrus (DG) granule neurons. transcriptomic signatures reveal high similarity developing hippocampus. We successfully detect activities via this cyb-organoid. Compared traditional planar devices, our non-invasive offers an adaptor recording 3D models.
Language: Английский
Citations
19
Neurocritical Care, Journal Year: 2021, Volume and Issue: 35(S1), P. 68 - 85
Published: July 1, 2021
Abstract Background/Objective For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source hope frustration. Almost all clinical trials in DoC have limited by small sample sizes, lack placebo groups, use heterogeneous outcome measures. As result, few strong evidence to support use; amantadine is only therapy recommended current guidelines, specifically caused severe traumatic brain injury. To foster advance development consciousness-promoting DoC, Curing Coma Campaign convened Science Work Group perform gap analysis. Methods We consider five classes therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; (5) regenerative. each class therapy, we summarize state science, identify gaps knowledge, suggest future directions development. Results Knowledge therapeutic can be attributed of: unifying conceptual framework evaluating mechanisms action; large-scale randomized controlled trials; pharmacodynamic biomarkers that measure subclinical effects early-phase trials. address these gaps, propose precision medicine approach which selectively enroll based upon physiological receptivity targeted therapies, are measured complementary behavioral, neuroimaging, electrophysiologic endpoints. Conclusions This personalized realized through rigorous trial design international collaboration, both will essential advancing ultimately improving lives DoC.
Language: Английский
Citations
102
Dialogues in Clinical Neuroscience, Journal Year: 2020, Volume and Issue: 22(3), P. 207 - 222
Published: Sept. 30, 2020
The endocannabinoid system (ECS) is a highly versatile signaling within the nervous system. Despite its widespread localization, functions context of distinct neural processes are very well discernable and specific. This remarkable, question remains as to how such specificity achieved. One key player in ECS cannabinoid type 1 receptor (CB1), G protein–coupled characterized by complexity cell-specific expression, cellular subcellular adaptable regulation intracellular cascades. CB1 receptors involved different synaptic plasticity brain's bioenergetics context-specific manner. CB2 also important several neurons, glial cells, immune cells brain. As polymorphisms components, external impacts stress metabolic challenges, can both lead dysregulated activity subsequently possible neuropsychiatric disorders, pharmacological intervention targeting promising therapeutic approach. Understanding neurobiology depth will aid optimal design interventions, minimizing unwanted side effects.
Language: Английский
Citations
82
Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15
Published: Nov. 3, 2021
Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological psychiatric symptoms, differing in etiology, onset severity. Such symptoms include mental delay, cognitive language impairments, or restrictions to adaptive social behavior. Nevertheless, all have common that critical milestones brain development disrupted, leading functional deficits the central nervous system clinical manifestation child- adulthood. To approach how different development-associated neuropathologies can occur which risk factors processes involved provoking higher susceptibility for diseases, a detailed understanding mechanisms underlying proper formation is required. NDDs rely on neuronal identity, proportion function, whereby defective cerebral cortex, seat functions, implicated numerous disorders. be provoked genetic environmental during corticogenesis. Thereby, epigenetic act an interface between external stimuli genome, since they known responsive also cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, well regulatory non-coding RNAs regulate aspects development, alterations epigenomic marks been associated varying phenotypes. Here, we provide overview essential steps mammalian corticogenesis, discuss role assumed contribute pathophysiological NDDs, when being disrupted.
Language: Английский
Citations
60
The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(17)
Published: Aug. 2, 2022
Organoids enable in vitro modeling of complex developmental processes and disease pathologies. Like most 3D cultures, organoids lack sufficient oxygen supply therefore experience cellular stress. These negative effects are particularly prominent models, such as brain organoids, can affect lineage commitment. Here, we analyze organoid fetal single-cell RNA sequencing (scRNAseq) data from published new datasets, totaling about 190,000 cells. We identify a unique stress signature the all samples, but not samples. demonstrate that cell is limited to defined subpopulation cells does neuronal specification or maturation. have developed computational algorithm, Gruffi, which uses granular functional filtering remove stressed any scRNAseq dataset an unbiased manner. validated our method using six additional datasets different protocols early brains, show its usefulness other systems including retinal organoids. Our adverse be corrected by bioinformatic analysis for improved delineation trajectories resemblance vivo data.
Language: Английский
Citations
45