Cell fate decisions: emerging roles for metabolic signals and cell morphology

Tatapudy, Sumitra; Aloisio, Francesca; Barber, Diane L.; Nystul, Todd

doi:10.15252/embr.201744816

Cited by 89 publications

(69 citation statements)

References 171 publications

(216 reference statements)

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“…4f). This metabolic switch is often observed in cellular differentiation processes 44 . The activated cell states and Krt8+ cells were also characterized by increased ribosomal content, ElF2 signaling components, and N-Myc target genes, suggesting that these cells had reentered the cell cycle ( Fig.…”

Section: A Sky Dive Into Epithelial Cell Fate Transitionsmentioning

confidence: 89%

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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Lung disease is a major health burden accounting for one in six deaths globally 1 . The lung's large surface area is exposed to a great variety of environmental and microbial insults causing injuries to its epithelium that require a regenerative response mediated by tissue-resident stem and progenitor Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ bird's-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ~30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To 'sky dive' into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of TNF-alpha/NFkappaB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven switch towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

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Section: A Sky Dive Into Epithelial Cell Fate Transitionsmentioning

confidence: 89%

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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“…pH homeostasis is a crucial biological process that is linked to several cellular pathways and is a plausible candidate [16][17][18]. pH homeostasis is a crucial biological process that is linked to several cellular pathways and is a plausible candidate [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

pH‐controlled histone acetylation amplifies melanocyte differentiation downstream of MITF

et al. 2019

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Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF. This involves the rapid and selective induction of melanocyte maturation genes, while concomitantly the expression of other effector genes is maintained. In this study, using cell-based and zebrafish model systems, we report on a pH-mediated feed-forward mechanism of epigenetic regulation that enables selective amplification of the melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of the enzyme carbonic anhydrase 14 (CA14). Nuclear localization of CA14 leads to an increase of the intracellular pH, resulting in the activation of the histone acetyl transferase p300/CBP. In turn, enhanced H3K27 histone acetylation at selected differentiation genes facilitates their amplified expression via MITF. CRISPR-mediated targeted missense mutation of CA14 in zebrafish results in the formation of immature acidic melanocytes with decreased pigmentation, establishing a central role for this mechanism during melanocyte differentiation in vivo. Thus, we describe an epigenetic control system via pH modulation that reinforces cell fate determination by altering chromatin dynamics.

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“…Rapidly induced changes in fundamental cellular features such as cell shape, subcellular organization and cell bioenergetics can drive adaptive regulatory mechanisms ensuring cell survival. These changes also impact whether a cell undergoes cell proliferation or acquires a specialized function (Basson, 2012;McBeath et al, 2004;Paluch and Heisenberg, 2009;Tatapudy et al, 2017). Cell fusion, an essential process during regeneration and development, is a remarkable example of how cellular morphogenesis arising from the merging of two or more cells influences cell fate determination (Ogle et al, 2005;Oren-Suissa and Podbilewicz, 2007;Zhou and Platt, 2011), but whether the cellular changes in response to cell fusion are sufficient to promote a transcriptional program which supports the new differentiated state remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

Feliciano

Espinosa-Medina

Weigel

et al. 2019

Preprint

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Developing cells divide and differentiate, and in many tissues, such as bone, muscle, and placenta, cells fuse acquiring specialized functions. While it is known that fused-cells are differentiated, it is unclear what mechanisms trigger the programmatic-change, and whether cell-fusion alone drives differentiation. To address this, we employed a fusogen-mediated cell-fusion system involving undifferentiated cells in tissue culture. RNA-seq analysis revealed cell-fusion initiates a dramatic transcriptional change towards differentiation. Dissecting the mechanisms causing this reprogramming, we observed that after cell-fusion plasma-membrane surface area decreases through increased endocytosis. Consequently, glucose-transporters are internalized, and cytoplasmic-glucose and ATP transiently decrease. This low-energetic state activates AMPK, which inhibits YAP1, causing cell-cycle arrest. Impairing either endocytosis or AMPK prevents YAP1 inhibition and cell-cycle arrest after fusion. Together these data suggest that cell-fusion-induced differentiation does not need to rely on extrinsiccues; rather the plasma-membrane diminishment forced by the geometrictransformations of cell-fusion cause transient cell-starvation that induces differentiation. GLUCOSE [GLUC] AMPK [ATP] YAP1 NON-FUSED CELLS PROLIFERATIVE STATE Proliferation genes GLUCOSE [GLUC] [ATP] YAP1-P SYNCYTIUM DIFFERENTIATED STATE Differentiation genes GLUCOSE [GLUC] AMPK [ATP] LOW ENERGY STATE / REMODELING YAP1 CME Proliferation genes CELL FUSION Figure 8. Feliciano et al.

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Cell fate decisions: emerging roles for metabolic signals and cell morphology

Cited by 89 publications

References 171 publications

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

pH‐controlled histone acetylation amplifies melanocyte differentiation downstream of MITF

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

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