Opportunities for organoids as new models of aging

Hu, Jennifer L.; Todhunter, Michael E.; LaBarge, Mark A.; Gartner, Zev J.

doi:10.1083/jcb.201709054

Cited by 52 publications

(50 citation statements)

References 144 publications

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“…There is potential for organoids to be used as models for aging 9 ; however, whether in vitro culture conditions alter or reset aging profiles for SI or colon, thereby minimizing detection of age-associated functional changes, is not clear.…”

Section: Dna Methylation Age Deceleration Of Human Small Intestine Ismentioning

confidence: 99%

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DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

Lewis

Nachun

Martı́n

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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We found that human intestinal organoids maintain the age of the patient from whom they are derived, as measured by the epigenetic clock. Unexpectedly, we found that crypts and spheroids derived from small intestine showed striking epigenetic age reduction, relative to the colon. BACKGROUND & AIMS:The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating agerelated changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylationbased aging profiles associated with the tissues and crypts from which they were derived. METHODS:To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids. RESULTS:We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon. CONCLUSIONS:Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro. (Cell Mol Gastroenterol Hepatol 2020;9:527-541; https://doi.

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Section: Dna Methylation Age Deceleration Of Human Small Intestine Ismentioning

confidence: 99%

“…7 In addition, mouse colon organoids aged in vitro show global methylation changes similar to those seen in the aging mouse colon. 8 However, although there is potential for organoids to be used as models for aging, 9 the degree to which organoids faithfully recapitulate aging has yet to be determined.…”

mentioning

confidence: 99%

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

Lewis

Nachun

Martı́n

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…In recent years, the use of murine and human 3‐dimensional (3D) in vitro models has increased as a result of the growing number of differentiation protocols available and the precise characterisation of these tissue models 16 . More specifically, 3D tissue organoids aim to recreate the morphology, structural complexity and primitive functions of murine and human organs, allowing us to study in vitro pared‐down versions of complex environments 17,18 …”

Section: Introductionmentioning

confidence: 99%

Comparison of two human organoid models of lung and intestinal inflammation reveals Toll‐like receptor signalling activation and monocyte recruitment

et al. 2020

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Objectives. The activation of immune responses in mucosal tissues is a key factor for the development and sustainment of several pathologies including infectious diseases and autoimmune diseases. However, translational research and personalised medicine struggle to advance because of the lack of suitable preclinical models that successfully mimic the complexity of human tissues without relying on in vivo mouse models. Here, we propose two in vitro human 3D tissue models, deprived of any resident leucocytes, to model mucosal tissue inflammatory processes. Methods. We developed human 3D lung and intestinal organoids differentiated from induced pluripotent stem cells to model mucosal tissues. We then compared their response to a panel of microbial ligands and investigated their ability to attract and host human primary monocytes. Results. Mature lung and intestinal organoids comprised epithelial (EpCAM + ) and mesenchymal (CD73 + ) cells which responded to Toll-like receptor stimulation by releasing pro-inflammatory cytokines and expressing tissue inflammatory markers including MMP9, COX2 and CRP. When added to the organoid culture, primary human monocytes migrated towards the organoids and began to differentiate to an 'intermediate-like' phenotype characterised by increased levels of CD14 and CD16. Conclusion. We show that human mucosal organoids exhibit proper immune functions and successfully mimic an immunocompetent tissue microenvironment able to host patient-derived immune cells. Our experimental set-up provides a novel tool to tackle the complexity of immune responses in mucosal tissues which can be tailored to different human pathologies.

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“…A range of in vitro ageing approaches has been developed over the past decades, including the use of cultured cells, organoids and modelling [40][41][42]. In particular, HU and D-galactose have been used to induce accelerated ageing in mice models, and have been shown to cause systemic effects such as neurological and behavioural changes [43,44] and loss of muscle strength [45], which are consistent with ageing outcomes.…”

Section: Discussionmentioning

confidence: 99%

Examining Cardiomyocyte Dysfunction Using Acute Chemical Induction of an Ageing Phenotype

Masoud

McDonald

Bister

et al. 2019

IJMS

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Much effort is focussed on understanding the structural and functional changes in the heart that underlie age-dependent deterioration of cardiac performance. Longitudinal studies, using aged animals, have pinpointed changes occurring to the contractile myocytes within the heart. However, whilst longitudinal studies are important, other experimental approaches are being advanced that can recapitulate the phenotypic changes seen during ageing. This study investigated the induction of an ageing cardiomyocyte phenotypic change by incubation of cells with hydroxyurea for several days ex vivo. Hydroxyurea incubation has been demonstrated to phenocopy age- and senescence-induced changes in neurons, but its utility for ageing studies with cardiac cells has not been examined. Incubation of neonatal rat ventricular myocytes with hydroxyurea for up to 7 days replicated specific aspects of cardiac ageing including reduced systolic calcium responses, increased alternans and a lesser ability of the cells to follow electrical pacing. Additional functional and structural changes were observed within the myocytes that pointed to ageing-like remodelling, including lipofuscin granule accumulation, reduced mitochondrial membrane potential, increased production of reactive oxygen species, and altered ultrastructure, such as mitochondria with disrupted cristae and disorganised myofibres. These data highlight the utility of alternative approaches for exploring cellular ageing whilst avoiding the costs and co-morbid factors that can affect longitudinal studies.

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Opportunities for organoids as new models of aging

Abstract: Hu et al. discuss challenges in studying aging and offer a perspective on the use of organoids as a model to understand the biology of aging.

Cited by 52 publications

References 144 publications

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

Comparison of two human organoid models of lung and intestinal inflammation reveals Toll‐like receptor signalling activation and monocyte recruitment

Examining Cardiomyocyte Dysfunction Using Acute Chemical Induction of an Ageing Phenotype

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