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1.
Proc Natl Acad Sci U S A ; 116(45): 22624-22634, 2019 11 05.
Article in English | MEDLINE | ID: mdl-31636214

ABSTRACT

The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is, however, not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally, we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.


Subject(s)
Cell Proliferation , Cellular Senescence , Fibroblasts/cytology , Lysosomes/metabolism , Animals , Cell Division , Fibroblasts/metabolism , Gene Expression , Lysosomes/genetics , Oxidative Stress , Rats
2.
Biomed Opt Express ; 10(4): 1638-1648, 2019 Apr 01.
Article in English | MEDLINE | ID: mdl-31061760

ABSTRACT

We introduce a snapshot multi-wavelength quantitative polarization and phase microscope (MQPPM) for measuring spectral dependent quantitative polarization and phase information. The system uniquely integrates a polarized light microscope and a snap-shot quantitative phase microscope in a single system, utilizing a novel full-Stokes camera operating in the red, green, and blue (RGB) spectrum. The linear retardance and fast axis orientation of a birefringent sample can be measured simultaneously in the visible spectra. Both theoretical analysis and experiments have been performed to demonstrate the capability of the proposed microscope. Data from liquid crystal and different biological samples are presented. We believe that MQPPM will be a useful tool in measuring quantitative polarization and phase information of live cells.

3.
Cell Rep ; 20(13): 3223-3235, 2017 Sep 26.
Article in English | MEDLINE | ID: mdl-28954237

ABSTRACT

Quiescence is a non-proliferative cellular state that is critical to tissue repair and regeneration. Although often described as the G0 phase, quiescence is not a single homogeneous state. As cells remain quiescent for longer durations, they move progressively deeper and display a reduced sensitivity to growth signals. Deep quiescent cells, unlike senescent cells, can still re-enter the cell cycle under physiological conditions. Mechanisms controlling quiescence depth are poorly understood, representing a currently underappreciated layer of complexity in growth control. Here, we show that the activation threshold of a Retinoblastoma (Rb)-E2F network switch controls quiescence depth. Particularly, deeper quiescent cells feature a higher E2F-switching threshold and exhibit a delayed traverse through the restriction point (R-point). We further show that different components of the Rb-E2F network can be experimentally perturbed, following computer model predictions, to coarse- or fine-tune the E2F-switching threshold and drive cells into varying quiescence depths.


Subject(s)
Cellular Senescence/genetics , E2F Transcription Factors/genetics , Models, Biological , Retinoblastoma Protein/genetics , Animals , Cell Division , Cell Proliferation/genetics , E2F Transcription Factors/metabolism , Fibroblasts , Gene Regulatory Networks , Humans , Rats , Retinoblastoma Protein/metabolism
4.
Nat Commun ; 8(1): 321, 2017 08 22.
Article in English | MEDLINE | ID: mdl-28831039

ABSTRACT

Reactivating quiescent cells to proliferate is critical to tissue repair and homoeostasis. Quiescence exit is highly noisy even for genetically identical cells under the same environmental conditions. Deregulation of quiescence exit is associated with many diseases, but cellular mechanisms underlying the noisy process of exiting quiescence are poorly understood. Here we show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history before quiescence entry, and that such a memory is reflected in cell size at a coarse scale. The deterministic memory effects of preceding cell cycle, coupled with the stochastic dynamics of an Rb-E2F bistable switch, jointly and quantitatively explain quiescence-exit heterogeneity. As such, quiescence can be defined as a distinct state outside of the cell cycle while displaying a sequential cell order reflecting preceding cell growth and division variations.The quiescence-exit process is noisy even in genetically identical cells under the same environmental conditions. Here the authors show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history prior to quiescence entry.


Subject(s)
Algorithms , Cell Cycle/physiology , Cell Proliferation/physiology , Models, Biological , Animals , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Division/drug effects , Cell Division/genetics , Cell Division/physiology , Cell Line , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cell Size , Culture Media/pharmacology , Culture Media, Serum-Free/pharmacology , E2F Transcription Factors/genetics , E2F Transcription Factors/metabolism , Rats , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Time Factors
5.
Mol Cancer Ther ; 4(12): 1867-79, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16373702

ABSTRACT

To glean biological differences and similarities of peripheral T-cell lymphoma-not otherwise specified [PTCL-NOS] to diffuse large B-cell lymphoma (DLBCL), a transcriptosome analysis was done on five PTCL-NOS and four DLBCL patients and validated by quantitative real-time reverse transcription-PCR on 10 selected genes. Normal peripheral blood T cells, peripheral blood B cells, and lymph node were used as controls. The resultant gene expression profile delineated distinct "tumor profile signatures" for PTCL-NOS and DLBCL. Several highly overexpressed genes in both PTCL-NOS and DLBCL involve the immune network, stroma, angiogenesis, and cell survival cascades that make important contributions to lymphomagenesis. Inflammatory chemokines and their receptors likely play a central role in these complex interrelated pathways: CCL2 and CXCR4 in PTCL-NOS and CCL5 and CCR1 in DLBCL. Highly overexpressed oncogenes unique to PTCL-NOS are SPI1, STK6, alpha-PDGFR, and SH2D1A, whereas in DLBCL they are PIM1, PIM2, LYN, BCL2A1, and RAB13. Oncogenes common to both lymphomas are MAFB, MET, NF-kappaB2, LCK, and LYN. Several tumor suppressors are also down-regulated (TPTE, MGC154, PTCH, ST5, and SUI1). This study illustrates the relevance of tumor-stroma immune trafficking and identified potential novel prognostic markers and targets for therapeutic intervention.


Subject(s)
Gene Expression Profiling , Lymphoma, B-Cell/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Non-Hodgkin/genetics , Lymphoma, T-Cell/genetics , RNA, Messenger/genetics , Base Sequence , DNA Primers , Humans , Immunohistochemistry , Lymphoma, B-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Non-Hodgkin/pathology , Lymphoma, T-Cell/pathology , Oligonucleotide Array Sequence Analysis , Oncogenes , Reverse Transcriptase Polymerase Chain Reaction
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