Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells1,2. The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors2, indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified3. We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.
Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.
Paraquat (PQ) is a redox cycling herbicide known for its acute toxicity in humans. Airway parenchymal cells have been identified as primary sites for PQ accumulation, tissue inflammation and cellular injury. However, the role of immune cells in PQ induced tissue injury is largely unknown. To explore this further, primary cultures of human CD34+ stem cell derived macrophages (MC cd34 ) and dendritic cells (DC cd34 ) were established and characterised using RNA-Seq profiling. The impact of PQ on DC cd34 and MC cd34 cytotoxicity revealed increased effect within DC cd34 cultures. PQ toxicity mechanisms were examined using sub-cytotoxic concentrations and TempO-seq transcriptomic assays. Comparable increases for several stress response pathway (NFE2L2, NF-kB and HSF) dependent genes were observed across both cell types. Interestingly, PQ induced unfolded protein response (UPR), p53, Irf and DC maturation genes in DC cd34 but not in MC cd34 . Further exploration of the immune modifying potential of PQ was performed using the common allergen house dust mite (HD). Co-treatment of PQ and HD resulted in enhanced inflammatory responses within MC cd34 but not DC cd34 . These results demonstrate immune cell type differential responses to PQ, that may underlie aspects of acute toxicity and susceptibility to inflammatory disease.
Myeloid cells form an essential component of initial responses to environmental hazards and toxic exposures. The ability to model these responses in vitro is central to efforts tasked with identifying hazardous materials and understanding mechanisms of injury and disease. Induced pluripotent stem cell (iPSC) derived cells have been suggested as alternatives to more established primary cell testing systems for these purposes. iPSC derived macrophage and dendritic like cells were compared to CD34+ haematopoietic stem cell derived populations using transcriptomic analysis. Using single cell sequencing-based characterisation of iPSC derived myeloid cells, we identified transitional, mature and M2 like macrophages as well as dendritic like antigen presenting cells and fibrocytes. Direct transcriptomic comparisons between iPSC and CD34+ cell derived populations revealed higher expression of myeloid differentiation genes such as MNDA, CSF1R and CSF2RB in CD34+ cells, while iPSC populations had higher fibroblastic and proliferative markers. Exposure of differentiated macrophage populations to nanoparticle alone or in combination with dust mite, resulted in differential gene expression on combination only, with responses markedly absent in iPSC compared to CD34+ derived cells. The lack of responsiveness in iPSC derived cells may be attributable to lower levels of dust mite component receptors CD14, TLR4, CLEC7A and CD36. In summary, iPSC derived myeloid cells display typical characteristics of immune cells but may lack a fully mature phenotype to adequately respond to environmental exposures.
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