Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories

Gonzales, Kevin Andrew Uy; Polak, Lisa; Matos, Irina; Tierney, Matthew; Gola, Anita; Wong, Edmund; Infarinato, Nicole R.; Nikolova, Maria; Luo, Shijing; Liu, Siqi; Novak, Jesse; Lay, Kenneth; Pasolli, H. Amalia; Fuchs, Elaine

doi:10.1126/science.abh2444

Cited by 69 publications

(75 citation statements)

References 61 publications

(63 reference statements)

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“…Although stem cell mechanical memory and cellular reprogramming had previously been shown ( 5, 20, 29 ), our findings reveal that such memory can be encoded into the ECM. In stem cells, cardiac cells and breast cancer cells, mechanical priming can result in chromatin remodeling ( 30–32 ), causing epigenetic modifications and potentially mechanical memory.…”

Section: Discussioncontrasting

confidence: 47%

Mechanically primed cells transfer memory to fibrous matrices for persistent invasion

Almeida

Mathur

Lee

et al. 2022

Preprint

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In disease and development, cells sense and migrate across mechanically dissimilar environments. We investigated whether mechanical memory of past environments empowers cells to navigate new, three-dimensional environments. Here, we show that cells primed by stiff matrices apply higher forces, compared to soft-primed cells, to accumulate and align collagen fibers towards sustained invasion. This priming advantage persists in dense or stiffened collagen. Through an energy-minimization model, we elucidate how memory-laden cells overcome mechanosensing of softer or challenging environments via a cell-matrix transfer of memory. Consistent with model predictions, depletion of α-catenin and YAP hamper coordinated forces and cellular memory required for collagen remodeling before invasion. We release tension in collagen fibers via laser ablation and disable fiber remodeling by lysyl-oxidase inhibition; both of which disrupt cell-to-matrix transfer of memory and reduce invasion. These results have implications for cancer, fibrosis, and aging, where potential matrix memory may generate prolonged cellular response.One-Sentence SummaryCell invasion across mechanically dissimilar environments is mediated by force-based storage and extraction of cell and matrix memory.

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Section: Discussioncontrasting

confidence: 47%

Mechanically primed cells transfer memory to fibrous matrices for persistent invasion

Almeida

Mathur

Lee

et al. 2022

Preprint

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“…First, cells cycling among states impacts mutation and epigenetic alterations and their penetrance, and NWD1 decreased Lgr5 hi cell mutation accumulation while increasing mutational burden from the expanded Bmi1+ cell population (Li et al, 2019a; Li et al, 2019b). Second, epigenetic “history” of a cell dictates its future course and responses to signals (Gonzales et al, 2021). Third, impact of onco- and tumor suppressor genes and key regulators are always context dependent, with major differences in the role and regulation of such genes among tissues and lineages in both normal functioning and as drivers of disease.…”

Section: Discussionmentioning

confidence: 99%

Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

Choi

Zhang

et al. 2022

Preprint

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NWD1, a mouse purified western diet uniquely relevant to human nutritional exposures elevating risk for human sporadic colon cancer rapidly and reversibly altered the stem cell signature and transcriptome of Lgr5hi intestinal stem cells. Down-regulated Ppargc1a expression altered mitochondrial structure and function, metabolically reprogramming Lgr5hi cells, suppressing developmental maturation of their progeny as they progress through progenitor cell compartments. This recruited Bmi1+, Ascl2 cells, remodeling the mucosa, including cell adaptation to the altered nutritional environment and elevated pathways of antigen processing and presentation, especially in mature enterocytes, a pathogenic mechanism in human Inflammatory Bowel Disease resulting in chronic low-level pro-tumorigenic inflammation. Plasticity of intestinal cells to function as stem-like cells encompasses a physiological and continual response to changing nutritional environments, supporting historic concepts of tissue homeostasis as a process of continual adaptation to the environment, with important consequences for mechanisms establishing probability for tumor development. The data emphasize importance of better reflecting human nutritional exposures in mouse models of development and disease.

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“…While the capacity of cells in other organs to retain memory of previous insults has been previously established (Kisseleva et al , 2012; Naik et al , 2017; Gonzales et al , 2021; Larsen et al , 2021), whether the lung mesenchyme possesses the capacity to retain memory has remained relatively unexplored. Our findings that the lung mesenchyme retains fibrotic-relevant memory following fibrogenic injury resolution demonstrates a new and unappreciated role of these cells in the amplified response to repetitive injury.…”

Section: Discussionmentioning

confidence: 99%

“…Nearly a decade ago it was shown that a portion of hepatic stellate cells that are activated by liver injury undergo deactivation after successful resolution of fibrotic injury but retain an altered state that accelerates subsequent in vitro activation (Kisseleva et al , 2012). More recently, epithelial stem cells of the skin have been shown to retain epigenetic memory of prior tissue injury and inflammation (Naik et al , 2017; Gonzales et al , 2021; Larsen et al , 2021). In both cases, such memory is thought to provide an evolutionary advantage and protective role by accelerating wound repair following a second tissue insult.…”

Section: Introductionmentioning

confidence: 99%

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

Jones

Caporarello

Meridew

et al. 2022

Preprint

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The lungs have a remarkable capacity to repair. However, repetitive injury can lead to progressive fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multi-modal analyses on isolated lung mesenchyme during the initiation, progression and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrogenic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme retains specific epigenetic traits (memory) of prior activation, resulting in amplified induction of a fibrogenic program upon re-injury. We identify Runx1 as a critical driver of both fibrogenic activation and epigenetic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that Runx1 is spontaneously activated in standard culture conditions, previously masking these roles of Runx1. Genetic and pharmacological targeting of Runx1 dampens fibrogenic mesenchymal cell activation in cell and tissue models, confirming its functional importance. Finally, publicly available scRNAseq data reveal selective expression of Runx1 in the fibrogenic cell subpopulations that emerge in mouse and human fibrotic lung tissue. Collectively, our findings implicate Runx1 in both the initiation and memory of fibrogenic mesenchymal cell activation that together prime amplified mesenchymal cell responses upon repeated injury.

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Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories

Cited by 69 publications

References 61 publications

Mechanically primed cells transfer memory to fibrous matrices for persistent invasion

Mechanically primed cells transfer memory to fibrous matrices for persistent invasion

Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

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