The human cell count and size distribution

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(39)

Опубликована: Сен. 18, 2023

Cell size and cell count are adaptively regulated intimately linked to growth function. Yet, despite their widespread relevance, the relation between has never been formally examined over whole human body. Here, we compile a comprehensive dataset of all major types, with data drawn from >1,500 published sources. We consider body representative male (70 kg), which allows further estimates female (60 kg) 10-y-old child (32 kg). build hierarchical interface for cellular organization body, giving easy access data, methods, sources (https://humancelltreemap.mis.mpg.de/). In total, estimate total counts ≈36 trillion cells in male, ≈28 female, ≈17 child. These reveal surprising inverse count, implying trade-off these variables, such that within given logarithmic class contribute an equal fraction body's biomass. also find coefficient variation is approximately independent mean size, existence cell-size regulation across types. Our serve establish holistic quantitative framework highlight large-scale patterns biology.

Язык: Английский

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RNA polymerase II dynamics and mRNA stability feedback scale mRNA amounts with cell size

Cell, Год журнала: 2023, Номер 186(24), С. 5254 - 5268.e26

Опубликована: Ноя. 1, 2023

Язык: Английский

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CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4062 - 4077.e5

Опубликована: Ноя. 1, 2023

Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent accumulation of p21. inhibitor washout results some entering S-phase. Overgrown experience replication resulting a second promotes G2 or subsequent G1. propose levels integrate signals overgrowth-triggered stresses determine fate. This model explains how hypertrophy can drive why inhibitors have long-lasting effects patients.

Язык: Английский

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Cell size homeostasis is tightly controlled throughout the cell cycle

PLoS Biology, Год журнала: 2024, Номер 22(1), С. e3002453 - e3002453

Опубликована: Янв. 5, 2024

To achieve a stable size distribution over multiple generations, proliferating cells require means of counteracting stochastic noise in the rate growth, time spent various phases cell cycle, and imprecision placement plane division. In most widely accepted model, is thought to be regulated at G1/S transition, such that smaller than critical pause end G1 phase until they have accumulated mass predetermined threshold, which point proceed through rest cycle. However, based solely on specific checkpoint G1/S, cannot readily explain why with deficient control mechanisms are still able maintain very distribution. Furthermore, model would not easily account for variation during subsequent anticipated G1/S. address questions, we applied computationally enhanced quantitative microscopy (ceQPM) populations cultured human lines, enables highly accurate measurement dry individual throughout From these measurements, evaluated factors contribute maintaining homeostasis any Our findings reveal accurately maintained, despite disruptions normal machinery or perturbations growth. Control generally confined regulation length. Instead imposed lines examined, find coefficient (CV) population begins decline well before transition continues S G2 phases. Among different types tested, detailed response growth differs. general, when it falls below exponential natural increase CV effectively constrained. We both mass-dependent cycle modulation reducing within population. Through interplay coordination 2 processes, emerges. Such previously unappreciated general principles cells. These same regulatory processes might also operative terminally differentiated Further dynamical studies should lead better understanding underlying molecular control.

Язык: Английский

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Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Abstract Aging of the brain vasculature plays a key role in development neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, genomic instability endothelial cells (EC) its potential effect on homeostasis is still largely unclear. We here investigated how aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human ECs an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, higher sprouting capacities due underlying dysregulation Dll4-Notch pathway. line, EC-KO mice showed more P21 + cells, augmented expression angiogenic markers, concomitant increase number pericytes. Moreover, leakage enhanced cell adhesion molecule accompanied peripheral immune infiltration into brain. These findings were confined white matter, suggesting regional susceptibility. Collectively, our results underline as driver impaired function, sprouting, migration brain, observed during process.

Язык: Английский

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Genome homeostasis defects drive enlarged cells into senescence

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4032 - 4046.e6

Опубликована: Ноя. 1, 2023

Cellular senescence refers to an irreversible state of cell-cycle arrest and plays important roles in aging cancer biology. Because is associated with increased cell size, we used reversible arrests combined growth rate modulation study how excessive affects proliferation. We find that enlarged cells upregulate p21, which limits progression. Cells re-enter the cycle encounter replication stress well tolerated physiologically sized but causes severe DNA damage cells, ultimately resulting mitotic failure permanent withdrawal. demonstrate fail recruit 53BP1 other non-homologous end joining (NHEJ) machinery sites robustly initiate damage-dependent p53 signaling, rendering them highly sensitive genotoxic stress. propose impaired response primes for persistent replication-acquired damage, leading division exit.

Язык: Английский

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Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4047 - 4061.e6

Опубликована: Ноя. 1, 2023

CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities healthy tissues. How they achieve this mechanistically is unclear. We show here specifically vulnerable to inhibition because during the arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cycle withdrawal by either preventing progression from or inducing genotoxic damage subsequent S-phase mitosis. Inhibiting reverting converge onto mTOR rescue excessive growth, DNA damage, exit cancer cells. Conversely, non-transformed these phenotypes sensitize inhibition. Together, demonstrates growth a synthetic lethal combination exploited tumor-specific toxicity.

Язык: Английский

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Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Molecular Cell, Год журнала: 2023, Номер 83(22), С. 4078 - 4092.e6

Опубликована: Ноя. 1, 2023

Tumor growth is driven by continued cellular and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs global gene expression makes it therefore an attractive target for cancer therapies. However, what cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear.Here, we address this question. We show that CDK7i, samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified active mTOR (mammalian of rapamycin) promotes samuraciclib-induced senescence. decreases samuraciclib sensitivity, increased mTOR-dependent correlates with sensitivity lines. Reverting growth-promoting mutation PIK3CA wild type CDK7i. Our work establishes enhanced alone CDK7i providing explanation why some cancers are more CDK than normally growing cells.

Язык: Английский

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The intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 27, 2023

Abstract Senescence, a state of irreversible cell-cycle withdrawal, is difficult to distinguish from quiescence, reversible withdrawal. This difficulty arises because quiescent and senescent cells are defined by overlapping biomarkers, raising the question whether these states truly distinct. To address this, we use single-cell time-lapse imaging slow-cycling that spend long periods in quiescence never cycle after recovery senescence-inducing treatments, followed staining for various senescence biomarkers. We find intensity multiple biomarkers graded rather than binary reflects duration per se. Together, our data show apparent nearly molecularly indistinguishable each other at snapshot time. suggests withdrawal itself binary, where intensities integrate past

Язык: Английский

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Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions

Developmental Cell, Год журнала: 2023, Номер 58(16), С. 1462 - 1476.e8

Опубликована: Июнь 19, 2023

Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how regulated the context remains poorly understood. Here, we introduce quantitative framework to elucidate growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, show that limiting rate of expansion creates confinement suppresses growth; however, this does not directly affect cycle. This leads uncoupling between rates division epithelia and, thereby, reduces volume. Division becomes arrested at minimal volume, which consistent across diverse vivo. nucleus approaches minimum volume capable packaging genome. Loss cyclin D1-dependent cell-volume regulation results an abnormally high nuclear-to-cytoplasmic ratio DNA damage. Overall, demonstrate by interplay regulation.

Язык: Английский

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