3D engineered tissue models for studying human-specific infectious viral diseases DOI Creative Commons

Kyeong Seob Hwang,

Eun U Seo,

Nakwon Choi

et al.

Bioactive Materials, Journal Year: 2022, Volume and Issue: 21, P. 576 - 594

Published: Sept. 22, 2022

Viral infections cause damage to various organ systems by inducing organ-specific symptoms or systemic multi-organ damage. Depending on the infection route and virus type, infectious diseases are classified as respiratory, nervous, immune, digestive, skin infections. Since these can widely spread in community their catastrophic effects severe, identification of causative agent mechanisms underlying pathogenesis is an urgent necessity. Although infection-associated have been studied two-dimensional (2D) cell culture models animal models, they shown limitations human-associated pathogenesis, development a human-organ-mimetic system required. Recently, three-dimensional (3D) engineered tissue which present human organ-like physiology terms 3D structure, utilization human-originated cells, recapitulation physiological stimuli, tight cell–cell interactions, were developed. Furthermore, recent studies that recapitulate pathologies. In this review, we summarized advances mimic viral First, briefly described current 2D recapitulating human-specific pathology. Next, provided overview recently reported focusing particularly Finally, future perspective must be pursued reconstitute more presented.

Language: Английский

The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder DOI Creative Commons
Sheetal Sreeram, Fengchun Ye, Yoelvis García‐Mesa

et al.

Trends in Immunology, Journal Year: 2022, Volume and Issue: 43(8), P. 630 - 639

Published: July 12, 2022

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% HIV-1-infected patients receiving ART exhibit neuroinflammation symptoms HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that emergence from latency microglia underlies both CNS progression HAND. Recent molecular studies cellular silencing mechanisms show can be reversed proinflammatory cytokines signals damaged neurons, potentially creating intermittent cycles reactivation brain. posit anti-inflammatory agents also block reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for treatment

Language: Английский

Citations

52
Revolutionizing Disease Modeling: The Emergence of Organoids in Cellular Systems DOI Creative Commons

Rita Silva-Pedrosa,

António J. Salgado, Pedro Eduardo Ferreira

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(6), P. 930 - 930

Published: March 18, 2023

Cellular models have created opportunities to explore the characteristics of human diseases through well-established protocols, while avoiding ethical restrictions associated with post-mortem studies and costs researching animal models. The capability cell reprogramming, such as induced pluripotent stem cells (iPSCs) technology, solved complications embryonic (hESC) usage. Moreover, iPSCs made significant contributions for medicine, in diagnosis, therapeutic regenerative medicine. two-dimensional (2D) allowed monolayer cellular culture vitro; however, they were surpassed by three-dimensional (3D) system. 3D provides higher cell–cell contact a multi-layered culture, which more closely respects morphology polarity. It is tightly able resemble conditions vivo closer approach architecture tissues, organoids. Organoids are structures that mimic function native tissues. They generated vitro from or differentiated cells, epithelial neural used study organ development, disease modeling, drug discovery. become powerful tool understanding molecular mechanisms underlying physiology, providing new insights into pathogenesis cancer, metabolic diseases, brain disorders. Although organoid technology up-and-coming, it also has some limitations require improvements.

Language: Английский

Citations

38
Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids DOI Creative Commons
Weili Kong, Julie Frouard, Guorui Xie

et al.

PNAS Nexus, Journal Year: 2024, Volume and Issue: 3(5)

Published: April 29, 2024

Abstract Despite the success of combination antiretroviral therapy (ART) for individuals living with HIV, mild forms HIV-associated neurocognitive disorder (HAND) continue to occur. Brain microglia form principal target HIV infection in brain. It remains unknown how these cells leads neuroinflammation, neuronal dysfunction, and/or death observed HAND. Utilizing two different inducible pluripotent stem cell-derived brain organoid models (cerebral and choroid plexus [ChP] organoids) containing microglia, we investigated pathogenic changes associated infection. Infection was a sharp increase CCL2 CXCL10 chemokine gene expression activation many type I interferon stimulated genes (MX1, ISG15, ISG20, IFI27, IFITM3 others). Production proinflammatory chemokines persisted at low levels after treatment cell cultures ART, consistent persistence HAND following clinical introduction ART. Expression multiple members S100 family inflammatory sharply increased measured by single-cell RNA-seq. However, not limited but also detected more broadly uninfected stromal cells, mature immature ChP neural progenitor importantly bystander neurons suggesting propagation response cells. Neurotransmitter transporter declined neurons, accompanied promoting cellular senescence death. Together, studies underscore an generated HIV-infected is propagated ultimately resulting dysfunction neurons.

Language: Английский

Citations

17
iPSC-derived three-dimensional brain organoid models and neurotropic viral infections DOI Open Access

Michael Swingler,

Martina Donadoni, Anna Bellizzi

et al.

Journal of NeuroVirology, Journal Year: 2023, Volume and Issue: 29(2), P. 121 - 134

Published: April 1, 2023

Language: Английский

Citations

19
Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids DOI Creative Commons
Andrew J. Boreland, Alessandro C. Stillitano, Hsin‐Ching Lin

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(5), P. 109628 - 109628

Published: March 28, 2024

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) affects up to half of people living with HIV-1 and causes long term neurological consequences. The pathophysiology HIV-1-induced glial neuronal functional deficits in humans remains enigmatic. To bridge this gap, we established a model simulating infection the central nervous system using human induced pluripotent stem cell (iPSC)-derived microglia combined sliced neocortical organoids. Incubation two replication-competent macrophage-tropic strains (JRFL YU2) elicited productive inflammatory activation. RNA sequencing revealed significant sustained activation type I interferon signaling pathways. Incorporating into organoids extended effects aberrant neural context. Collectively, our results illuminate role for persistent HIV-1-infected model, suggesting its potential significance pathogenesis HAND.

Language: Английский

Citations

7
Modeling HIV-1 infection and NeuroHIV in hiPSCs-derived cerebral organoid cultures DOI Creative Commons
Martina Donadoni,

Senem Çakır,

Anna Bellizzi

et al.

Journal of NeuroVirology, Journal Year: 2024, Volume and Issue: 30(4), P. 362 - 379

Published: April 10, 2024

The human immunodeficiency virus (HIV) epidemic is an ongoing global health problem affecting 38 million people worldwide with nearly 1.6 new infections every year. Despite the advent of combined antiretroviral therapy (cART), a large percentage HIV (PWH) still develop neurological deficits, grouped into term HIV-associated neurocognitive disorders (HAND). Investigating neuropathology important for understanding mechanisms associated cognitive impairment seen in PWH. major obstacle studying neuroHIV lack suitable vitro culture models that could shed light HIV-CNS interactions. Recent advances induced pluripotent stem cell (iPSC) and 3D brain organoid systems have allowed generation 2D methods possess potential to serve as model neurotropic viral diseases, including HIV. In this study, we first generated characterized several hiPSC lines from healthy donor skin fibroblast cells. hiPSCs were then used microglia-containing cerebral organoids (hCOs). Once fully characterized, hCOs infected HIV-1 presence absence cART regimens infection was studied by cellular, molecular/biochemical, virological assays. Our results revealed productively evident p24-ELISA media, RT-qPCR RNAscope analysis RNA, well ddPCR proviral genomic DNA samples. More interestingly, replication gene expression also greatly suppressed early 7 days post-infections. suggest derived support may unique platform better understand brain.

Language: Английский

Citations

7
A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders DOI Creative Commons

Ana Rubio,

L. L. Hamilton,

Marcel Bausch

et al.

Journal of Neuroimmune Pharmacology, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 22, 2025

Most current information about neurological disorders and diseases is derived from direct patient animal studies. However, studies in many cases do not allow replication of the early stages disease and, therefore, offer limited opportunities to understand progression. On other hand, although use models allows us study mechanisms disease, they present significant limitations developing drugs for humans. Recently, 3D-cultured vitro human pluripotent stem cells have surfaced as a promising system. They potential connect findings with those models. In this comprehensive review, we discuss their application modeling neurodevelopmental conditions such Down Syndrome or Autism, neurodegenerative Alzheimer's Parkinson's, viral like Zika virus HIV. Furthermore, will different used prenatal exposure abuse, well challenges that must be met transform landscape research on brain disorders.

Language: Английский

Citations

1
Gene expression in organoids: an expanding horizon DOI Creative Commons
Artem Smirnov, Gerry Melino, Eleonora Candi

et al.

Biology Direct, Journal Year: 2023, Volume and Issue: 18(1)

Published: March 25, 2023

Abstract Recent development of human three-dimensional organoid cultures has opened new doors and opportunities ranging from modelling in vitro to personalised cancer therapies. These systems are opening horizons the classic understanding disease. However, complexity heterogeneity these models requires cutting-edge techniques capture trace global changes gene expression enable identification key players uncover underlying molecular mechanisms. Rapid sequencing approaches made possible transcriptome analyses epigenetic profiling. Despite challenges culture handling, now being adapted embrace organoids derived a wide range tissues. Here, we review current state-of-the-art multi-omics technologies, such as single-cell transcriptomics chromatin accessibility assays, employed study model for platform precision medicine.

Language: Английский

Citations

14
HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology DOI Open Access

Landon John-Patrick Thompson,

Jessica Genovese,

Zhenzi Hong

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4697 - 4697

Published: April 25, 2024

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with continue experience HIV-associated neurocognitive disorder (HAND). HAND is associated impairment, including motor and memory loss. has been detected brain within 8 days of estimated exposure mechanisms for this early entry are being actively studied. Once having entered into central nervous system (CNS), degrades blood-brain barrier through production its gp120 Tat proteins. These proteins directly toxic endothelial cells neurons, propagate inflammatory cytokines by activation immune dysregulation tight junction The BBB breakdown progression disease. One main hurdles treatment latent pool cells, which insensitive cART prolong inflammation harboring provirus long-lived that can reactivate, causing damage. Multiple strategies studied combat HAND; however, clinically, these approaches have insufficient require further revisions. goal paper aggregate known challenges HAND.

Language: Английский

Citations

6
Shock and kill within the CNS: A promising HIV eradication approach? DOI Creative Commons
Marieke M. Nühn, Stephanie B. H. Gumbs, Ninée V. E. J. Buchholtz

et al.

Journal of Leukocyte Biology, Journal Year: 2022, Volume and Issue: 112(5), P. 1297 - 1315

Published: Sept. 23, 2022

Abstract The most studied HIV eradication approach is the “shock and kill” strategy, which aims to reactivate latent reservoir by latency reversing agents (LRAs) allowing elimination of these cells immune-mediated clearance or viral cytopathic effects. CNS an anatomic compartment in (persistent) plays important role HIV-associated neurocognitive disorder. Restriction blood–brain barrier for maintenance homeostasis microenvironment, includes CNS-specific cell types, expression transcription factors, altered immune surveillance. Within predominantly myeloid such as microglia perivascular macrophages are thought be a persistent infection. Nevertheless, infection T astrocytes might also impact CNS. Genetic adaptation this microenvironment results genetically distinct, compartmentalized populations with differences profiles. Because profiles, LRAs have different effects within compared periphery. Moreover, reactivation brain complex could detrimental consequences. Finally, independent activity on HIV, themselves can adverse neurologic We provide extensive overview current knowledge strategy. Subsequently, we reflect promise strategy

Language: Английский

Citations

20