Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Jin, Yinhua; Anbarchian, Teni; Wu, Peng; Sarkar, Abby; Fish, Matt; Nusse, Roel

doi:10.1101/2021.10.15.464616

Cited by 3 publications

(6 citation statements)

References 52 publications

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“…Previous studies have demonstrated that Tbx3 regulates division of hepatoblasts during embryonic liver development by repressing cell cycle inhibitors (Suzuki et al 2008). In an accompanying manuscript, we show that Tbx3 is required for hepatocyte cell division during postnatal development (Jin et al 2021). To determine if Tbx3 plays a role in IF-induced hepatocyte proliferation, we genetically depleted Tbx3 in hepatocytes and traced expansion of Axin2+ GFP-labeled cells after .…”

Section: Endocrine Fgf15-b-klotho Signaling Is Required For Hepatocyte Proliferation During Intermittent Fastingmentioning

confidence: 52%

“…Pericentral hepatocyte proliferation ensures replacement of lost cellular mass through increases in overall cell numbers. Together with the work in an accompanying paper (Jin et al 2021) we propose our current working model in which paracrine WNT and endocrine FGF pathways work together to push hepatocytes through different phases of the cell cycle. Specifically, the general role of FGF in cell proliferation observed in our studies suggest that this signal initiates S-phase, whereas WNT through TBX3 permits progression through Mphase by repressing cell division inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver

Sarkar

Jin

Anbarchian

et al. 2021

Preprint

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Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary change influences cell proliferation in the liver. Here, we show that intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF elicits intestinal production of endocrine FGF15, which activates the b- KLOTHO receptor on hepatocytes to induce proliferation. Furthermore, IF-induced proliferation is locally controlled in hepatocytes by WNT signaling and the WNT target gene Tbx3. IF induces hepatocyte proliferation to re-establish a constant liver-to-body-mass ratio during periods of fasting and re-feeding and maintain the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and identifies both systemic FGF and local WNT as regulators of this process.

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Section: Endocrine Fgf15-b-klotho Signaling Is Required For Hepatocyte Proliferation During Intermittent Fastingmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver

Sarkar

Jin

Anbarchian

et al. 2021

Preprint

Self Cite

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“…To circumvent these challenges, we sought to specifically measure RB protein concentrations in proliferating isolated primary hepatocytes. To do this, we used a 2D primary hepatocyte culture protocol 31,32 (Figure 3A). In these cultures, primary hepatocytes actively enter the cell cycle, and we can detect RB protein using immunfluorescence because the autofluorescence is significantly reduced in the isolated hepatocytes compared to those in the mouse liver (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

“…The protocol for 2D culture of primary hepatocytes was kindly shared by Yinhua Jin from Dr. Roeland Nusse's lab at Stanford University 31,32 . Briefly, primary hepatocytes from Rb1 flx/flx ; Rosa26-CreER2; Fucci2 mouse were isolated by two-step collagenase perfusion.…”

Section: Primary Hepatocyte 2d Culturementioning

confidence: 99%

The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver

Zhang

Zatulovskiy

Arand

et al. 2022

Preprint

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Every type of cell in an animal maintains a specific size, which likely contributes to its ability to perform its physiological functions. While some cell size control mechanisms are beginning to be elucidated through studies of cultured cells, it is unclear if and how such mechanisms control cell size in an animal. For example, it was recently shown that RB, the retinoblastoma protein, was diluted by cell growth in G1 to promote size-dependence of the G1/S transition. However, it remains unclear to what extent the RB-dilution mechanism controls cell size in an animal. We therefore examined the contribution of RB-dilution to cell size control in the mouse liver. The RB-dilution model has two requirements. First, manipulations changing RB concentration drive corresponding changes in cell size, and second, the endogenous RB concentration decreases with cell size in G1. We found that both these requirements were met. Genetic perturbations decreasing RB protein concentrations through inducible shRNA expression or through liverspecific Rb1 knockout reduced hepatocyte size, while perturbations increasing RB protein concentrations in an Fah−/− mouse model increased hepatocyte size. Moreover, RB concentration decreased in larger G1 hepatocytes while the concentrations of the cell cycle activators Cyclin D1 and E2f1 remained relatively constant. Lastly, we tested how Rb1 manipulations affected G1/S cell size control in primary hepatocytes using live cell imaging. Loss of Rb1 weakened cell size control, i.e., reduced the inverse correlation between how much cells grew in G1 and how large they were at birth. Taken together, our results show that an RB- dilution mechanism contributes to cell size control in the mouse liver by linking cell growth to the G1/S transition.

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“…To circumvent these challenges, we sought to specifically measure RB protein concentrations in proliferating isolated primary hepatocytes. To do this, we used a 2D primary hepatocyte culture protocol ( Peng et al, 2018 ; Jin et al, 2021 ) ( Figure 3A ). In these cultures, primary hepatocytes actively enter the cell cycle, and we can detect RB protein using immunfluorescence because the autofluorescence is significantly reduced in the isolated hepatocytes compared to those in the mouse liver.…”

Section: Resultsmentioning

confidence: 99%

The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver

Zhang

Zatulovskiy

Arand

et al. 2022

Front. Cell Dev. Biol.

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Every type of cell in an animal maintains a specific size, which likely contributes to its ability to perform its physiological functions. While some cell size control mechanisms are beginning to be elucidated through studies of cultured cells, it is unclear if and how such mechanisms control cell size in an animal. For example, it was recently shown that RB, the retinoblastoma protein, was diluted by cell growth in G1 to promote size-dependence of the G1/S transition. However, it remains unclear to what extent the RB-dilution mechanism controls cell size in an animal. We therefore examined the contribution of RB-dilution to cell size control in the mouse liver. Consistent with the RB-dilution model, genetic perturbations decreasing RB protein concentrations through inducible shRNA expression or through liver-specific Rb1 knockout reduced hepatocyte size, while perturbations increasing RB protein concentrations in an Fah−/− mouse model increased hepatocyte size. Moreover, RB concentration reflects cell size in G1 as it is lower in larger G1 hepatocytes. In contrast, concentrations of the cell cycle activators Cyclin D1 and E2f1 were relatively constant. Lastly, loss of Rb1 weakened cell size control, i.e., reduced the inverse correlation between how much cells grew in G1 and how large they were at birth. Taken together, our results show that an RB-dilution mechanism contributes to cell size control in the mouse liver by linking cell growth to the G1/S transition.

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Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling

Cited by 3 publications

References 52 publications

Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver

Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver

The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver

The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver

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