At present, preclinical models of inflammatory bowel disease (IBD) are insufficient, limiting translation between research and new therapeutics. This is especially true for fistulising Crohn\'s disease (CD), as the severe lack of relevant models hinders research progression. To address this, we present in vitro human IBD mucosal models that recapitulate multiple pathological hallmarks of IBD simultaneously in one model system - immune cell infiltration, stromal remodelling and epithelial disruption. Stimulation of models induces epithelial aberrations common in IBD tissue including altered morphology, microvilli abnormalities, claudin gene expression changes and increased permeability. Inflammatory biomarkers are also significantly increased including cytokines and chemokines integral to IBD pathogenesis. Evidence of extracellular matrix remodelling, including upregulated matrix-metalloproteinases and altered basement membrane components, suggests the models simulate pathological stromal remodelling events that closely resemble fistulising CD. Importantly, MMP-9 is the most abundant MMP and mimics the unique localisation observed in IBD tissue. The inflamed models were subsequently used to elucidate the involvement of TNF-α and IFN- γ in intestinal stromal remodelling, in which TNF-α but not IFN- γ induced MMP upregulation, specifically of MMP-3 and MMP-9. Collectively, our results demonstrate the potential of the IBD models for use in preclinical research in IBD, particularly for fistulising CD.

The unprecedented rise in life expectancy observed in the last decades is leading to a global increase in the ageing population, and age-associated diseases became an increasing societal, economic, and medical burden. This has boosted major efforts in the scientific and medical research communities to develop and improve therapies to delay ageing and age-associated functional decline and diseases, and to expand health span. The establishment of induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells has revolutionised the modelling and understanding of human diseases. iPSCs have a major advantage relative to other human pluripotent stem cells as their obtention does not require the destruction of embryos like embryonic stem cells do, and do not have a limited proliferation or differentiation potential as adult stem cells. Besides, iPSCs can be generated from somatic cells from healthy individuals or patients, which makes iPSC technology a promising approach to model and decipher the mechanisms underlying the ageing process and age-associated diseases, study drug effects, and develop new therapeutic approaches. This review discusses the advances made in the last decade using iPSC technology to study the most common age-associated diseases, including age-related macular degeneration (AMD), neurodegenerative and cardiovascular diseases, brain stroke, cancer, diabetes, and osteoarthritis.

The availability of an appropriate and reliable research model is helpful for researchers to understand the occurrence and development of diseases. Historically, animal models have been beneficial in the study of intervertebral disc degenerative diseases, but intervertebral disc degeneration (IDD) is a precise and complex process that needs to appear and occur in a specific tissue microenvironment, and animal degeneration models cannot fully simulate these parameters. These challenges must be overcome, especially when animal models cannot fully generalise the complex pathology of humans. In the past few years, the research on the cell disease model has made important progress, and the construction of the nucleus pulposus cell (NPC) degeneration model has become an indispensable step in studying the occurrence and development of IDD. Here, several different methods of constructing NPC degeneration models and indicators for testing the effect of modelling are introduced. The practical applications of cell models constructed by different methods are enumerated to screen and evaluate effective methods of establishing degenerative cell models and explore the mechanism of IDD.

Placodes are embryonic structures originating from the rostral ectoderm that give rise to highly diverse organs and tissues, comprising the anterior pituitary gland, paired sense organs and cranial sensory ganglia. Their development, including the underlying gene regulatory networks and signalling pathways, have been for the most part characterised in animal models. In this Review, we describe how placode development can be recapitulated by the differentiation of human pluripotent stem cells towards placode progenitors and their derivatives, highlighting the value of this highly scalable platform as an optimal in vitro tool to study the development of human placodes, and identify human-specific mechanisms in their development, function and pathology.

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids (\"myelinoids\") and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination-both at the level of individual oligodendrocytes and globally across whole myelinoids-and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination.

Background: The Global Burden of Disease (GBD) approach estimates disease burden by combining fatal (years of life lost) and non-fatal burden prevalence-based years of life lived with disability (PYLDs) estimates. Although South Africa has data to estimate mortality, prevalence data to estimate non-fatal burden are sparse. PYLD estimates from the GBD study for South Africa can potentially be used. However, there is a divergence in mortality estimates for South Africa between the second South African National Burden of Disease (SANBD2) and 2013 GBD studies. Objective: We investigated the feasibility of utilising GBD PYLD estimates for stroke and diabetes by exploring different disease modelling scenarios. Method: DisMod II software-generated South African stroke and diabetes PYLDs for 2010 from models using local epidemiological parameters and demographic data for people 20-79 years old. We investigated the impact on PYLD estimates of 1) differences in the cause-of-death envelope, 2) differences in the cause-specific mortality estimates (increase/decrease by 15% for stroke and 30% for diabetes), and 3) difference using local disease parameters compared to other country or region parameters. Differences were expressed as ratios, average ratios and ratio ranges. Results: Using the GBD cause-of-death envelope (16% more deaths than SANBD2) and holding other parameters constant yielded age-specific ratios of PYLDs for stroke and diabetes ranging between 0.89 and 1.07 (average 0.98) for males. Similar results were observed for females. A 15% change in age-specific stroke mortality showed little difference in the ratio comparison of PYLDs (range 0.98-1.02) while a 30% change in age-specific diabetes mortality resulted in a ratio range of 0.96-1.07 for PYLDs depending on age. Conclusion: This study showed that GBD non-fatal burden estimates (PYLDs) can be used for stroke and diabetes non-fatal burden in the SANBD2 study.

The Russian Federation has very high cardiovascular disease (CVD) mortality rates compared with countries of similar economic development. This cross-sectional study compares the characteristics of CVD-free participants with and without recent primary care contact to ascertain their CVD risk and health status.
A total of 2774 participants aged 40-69 years with no self-reported CVD history were selected from a population-based study conducted in Arkhangelsk and Novosibirsk, Russian Federation, 2015-2018. A range of co-variates related to socio-demographics, health and health behaviours were included. Recent primary care contact was defined as seeing primary care doctor in the past year or having attended a general health check under the 2013 Dispansarisation programme.
The proportion with no recent primary care contact was 32.3% (95% CI 29.7% to 35.0%) in males, 16.3% (95% CI 14.6% to 18.2%) in females, and 23.1% (95% CI 21.6% to 24.7%) overall. In gender-specific age-adjusted analyses, no recent contact was also associated with low education, smoking, very good to excellent self-rated health, no chest pain, CVD 10-year SCORE risk 5+%, absence of hypertension control, absence of hypertension awareness and absence of care-intensive conditions. Among those with no contact: 37% current smokers, 34% with 5+% 10-year CVD risk, 32% untreated hypertension, 20% non-anginal chest pain, 18% problem drinkers, 14% uncontrolled hypertension and 9% Grade 1-2 angina. The proportion without general health check attendance was 54.6%.
Primary care and community interventions would be required to proactively reach sections of 40-69 year olds currently not in contact with primary care services to reduce their CVD risk through diagnosis, treatment, lifestyle recommendations and active follow-up.

Primary liver cancer, consisting predominantly of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), remains one of the most lethal malignancies worldwide. This high malignancy is related to the complex and dynamic interactions between tumour cells, stromal cells and the extracellular environment. Novel in vitro models that can recapitulate the tumour are essential in increasing our understanding of liver cancer. Herein, primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumour properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumour microenvironment. However, the extracellular component also plays a vital role in cancer progression and representation is lacking within current in vitro models. In this review, organoid technology is discussed in the context of liver cancer models through comparisons to other cell culture systems. In addition, the role of the tumour extracellular environment in primary liver cancer will be highlighted with an emphasis on its importance in in vitro modelling. Converging novel organoid-based models with models incorporating the native tumour microenvironment could lead to experimental models that can better recapitulate liver tumours in vivo.

High-throughput phenotypic screening enables the identification of new therapeutic targets even when the molecular mechanism underlying the disease is unknown. In the case of neurodegenerative disease, there is a dire need to identify new targets that can ameliorate, halt, or reverse degeneration. Stem cell-based disease models are particularly powerful tools for phenotypic screening because they use the same cell type affected in patients. Here, we describe the expansion of mouse stem cells and human induced pluripotent stem cells as well as the differentiation of these cells into neural lineages that, when exposed to neuroinflammatory stress, can be used for compound screening followed by hit identification, validation, and target deconvolution.