Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

Lazzeri, Elena; Angelotti, Maria Lucia; Conte, Carolina; Anders, Hans‐Joachim; Romagnani, Paola

doi:10.1016/j.molmed.2019.02.006

Cited by 69 publications

(84 citation statements)

References 110 publications

(208 reference statements)

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“…In the past several years, an increasing number of examples of polyploidy have been observed not only in insects and plants, but also in vertebrate species, including zebrafish, mice and human tissue cell types (Gjelsvik et al, 2019). Polyploid cells are frequently generated in response to stress and/ or injury and are now recognized to offer an alternative tissue-growth strategy that can prevent acute organ failure (Lazzeri et al, 2019). Genotoxic stress is known to accumulate with age and has been observed in the mammalian cornea endothelium (Joyce et al, 2011), in which multinucleated polyploid cells are generated in response to damage or age-associated diseases (Ikebe et al, 1986, 1988; Losick et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Regeneration is limited for many organs due to the lack of a resident stem cell or progenitor cell population. As result, when injury or damage occur, organ failure may be delayed by the growth of cells through polyploidy (Lazzeri et al, 2019). Polyploidy is the more than doubling of the genome of a cell and frequently arises during organogenesis, tissue repair and disease (Gjelsvik et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Wound-induced polyploidization is driven by Myc and supports tissue repair in the presence of DNA damage

et al. 2019

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Tissue repair usually requires either polyploid cell growth or cell division, but the molecular mechanism promoting polyploidy and limiting cell division remains poorly understood. Here, we find that injury to the adult Drosophila epithelium causes cells to enter the endocycle through the activation of Yorkie-dependent genes ( Myc and E2f1 ). Myc is even sufficient to induce the endocycle in the uninjured post-mitotic epithelium. As result, epithelial cells enter S phase but mitosis is blocked by inhibition of mitotic gene expression. The mitotic cell cycle program can be activated by simultaneously expressing the Cdc25-like phosphatase String ( stg ), while genetically depleting APC/C E3 ligase fizzy-related ( fzr ) . However, forcing cells to undergo mitosis is detrimental to wound repair as the adult fly epithelium accumulates DNA damage, and mitotic errors ensue when cells are forced to proliferate. In conclusion, we find that wound-induced polyploidization enables tissue repair when cell division is not a viable option.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wound-induced polyploidization is driven by Myc and supports tissue repair in the presence of DNA damage

et al. 2019

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“…It has long been known that some parts of mammalian kidneys such as proximal tubule undergo cellular regeneration after acute kidney injury (AKI) (Witzgall et al, 1994). The S3 segment of proximal tubule is often damaged in cases of acute kidney injury elicited by ischemia, sepsis, trauma or other mechanisms (Lazzeri et al, 2019). However, it has been controversial as to whether tubular stem cells or progenitor cells contribute to regeneration.…”

Section: Discussionmentioning

confidence: 99%

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

Wang

Spradling

2019

Preprint

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Adult Drosophila Malpighian tubules have low rates of cell turnover but are vulnerable to damage caused by stones, like their mammalian counterparts, kidneys. We show that Drosophila renal stem cells (RSCs) comprise a unique, unipotent regenerative compartment. RSCs respond only to loss of nearby principal cells (PCs), cells critical for maintaining ionic balance. Perhaps due to the large size of PCs they are outnumbered by RSCs, which replace each lost cell with multiple PCs of lower ploidy. RSCs share a developmental origin with highly active intestinal stem cells (ISCs), and like ISCs generate daughters by asymmetric Notch signaling, yet RSCs remain quiescent in the absence of damage. Nevertheless, the capacity for RSC-mediated repair extends the lifespan of flies carrying kidney stones. We propose that abundant, RSC-like stem cells exist in other tissues with low rates of turnover where they may have been mistaken for differentiated tissue cells.

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“…An alternative pathophysiological interpretation of cell cycle events after acute injury has recently been proposed [95,96]. Indeed, several studies have recently pointed toward the existence of a scattered population of undifferentiated, self-renewing, renal progenitors with the ability to regenerate fully differentiated TECs rather than acquire a dedifferentiation state [97,98,99,100,101,102].…”

Section: Pathophysiology Of the Aki-to-ckd Transitionmentioning

confidence: 99%

“…Polyploidization increases the gene copy number in response to the need to quickly support increased functional requests for a higher metabolic output while persistently maintaining differentiated and specialized cell functions. This permits hypertrophy and function recovery [95,96].…”

Section: Pathophysiology Of the Aki-to-ckd Transitionmentioning

confidence: 99%

Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View

Guzzi

Cirillo

Roperto

et al. 2019

IJMS

Self Cite

107

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Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.

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Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

Cited by 69 publications

References 110 publications

Wound-induced polyploidization is driven by Myc and supports tissue repair in the presence of DNA damage

Wound-induced polyploidization is driven by Myc and supports tissue repair in the presence of DNA damage

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View

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