Mechanisms, Hallmarks, and Implications of Stem Cell Quiescence

Cho, Inchul J.; Lui, Prudence PokWai; Obajdin, Jana; Riccio, Federica; Stroukov, Wladislaw; Willis, Thea L; Spagnoli, Francesca M.; Watt, Fiona M.

doi:10.1016/j.stemcr.2019.05.012

Cited by 115 publications

(110 citation statements)

References 105 publications

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“…Both pathways are typically active in stem cells, suggesting that multiple small clones may be present and spread throughout the PT and composed of cancer stem cells. This fits well with the cancer stem cell hypothesis, which assumes that small groups of relatively quiescent cancer cells that have acquired stem cell characteristics are present in tumor tissue (1,38,39). Both pathways are generally thought to play an important role in governing metastatic behavior and therapy resistance of cancer stem cells, another hallmark of cancer (1).…”

Section: Within Tumor Heterogeneity Of Signaling Pathway Activitysupporting

confidence: 76%

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Inda

Swinderen

Brussel

et al. 2020

Preprint

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BackgroundTargeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated.MethodsActivity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFβ, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four “quadrant” samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A “checkerboard” model was introduced to explain the observed heterogeneity in PT.ResultsWithin PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFβ pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway.ConclusionWith a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFβ and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

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Section: Within Tumor Heterogeneity Of Signaling Pathway Activitysupporting

confidence: 76%

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Inda

Swinderen

Brussel

et al. 2020

Preprint

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“…This must entail fundamental considerations for SC well-being such as localizing the SCs at the most well-protected zone (outer limbus) and accrediting SCs with infrequent division. The quiescence state of SCs is believed to be accompanied by reduction in DNA replication, metabolism, gene transcription and protein translation 16 . Notably, these processes were associated with molecular damage due to the production of toxic agents or errors in biosynthesis of macromolecules 79 80 .…”

Section: Discussionmentioning

confidence: 99%

“…noggin) were associated with the exit from quiescence state and the transition into active SC state 18 16 . The bioinformatic analysis of limbal clusters suggests that qLSC engage Pi3K pathway, the BMP-regulated transcription factors Id1/3 63 64 65 , the tumor suppressor gene Trp53 16 , Cyclin D2 68 69 and the Wnt inhibitor Srf1 86 , all of which were linked with growth arrest. Of interest, aLSCs were enriched for TNF, WNT and Ap-1 pathways (Fig.…”

Section: Discussionmentioning

confidence: 99%

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Altshuler

Amitai-Lange

Tarazi

et al. 2020

Preprint

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AbstractStem cells (SCs) are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. It was several decades ago, when limbal epithelial SCs (LSCs) that regenerate the corneal epithelium were one of the first sporadic, quiescent SCs ever discovered. However, LSC dynamics, heterogeneity and genetic signature are largely unknown. Moreover, recent accumulating evidence strongly suggested that epithelial SCs are actually abundant, frequently dividing cells that display stochastic behavior.In this work, we performed an in-depth analysis of the murine limbal epithelium by single-cell RNA sequencing and quantitative lineage tracing. The generated data provided an atlas of cell states of the corneal epithelial lineage, and particularly, revealed the co-existence of two novel LSC populations that reside in separate and well-defined sub-compartments. In the “outer” limbus, we identified a primitive widespread population of quiescent LSCs (qLSCs) that uniformly express Krt15/Gpha2/Ifitm3/Cd63 proteins, while the “inner” limbus host prevalent active LSCs (aLSCs) co-expressing Krt15-GFP/Atf3/Mt1-2/Socs3. Analysis of LSC population dynamics suggests that while qLSCs and aLSCs possess different proliferation rates, they both follow similar stochastic rules that dictate their self-renewal and differentiation. Finally, T cells were distributed in close proximity to qLSCs. Indeed, their absence or inhibition resulted in the loss of quiescence and delayed wound healing. Taken together, we propose that divergent regenerative strategies are tailored to properly support tissue-specific physiological constraints. The present study suggests that in the case of the cornea, quiescent epithelial SCs are abundant, follow stochastic rules and neutral drift dynamics.

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“…For the signaling pathways we enriched TP53 regulates metabolic genes, aging, regulation of epidermis development, transcriptional regulation by TP53, interleukin-10 signaling, NABA secreted factors, cytokine-mediated signaling pathway, and negative regulation of cell proliferation; in particular, the upstream gene of the P53 signaling pathway, Tp53, predicts apoptosis of hair follicles [38,39]. In addition, we inferred that inner bulge cells had earlier expression patterns of the marker genes Krt6a [40] and Krt10 [41], and developed earlier than outer bulge cells, about which there have been few reports [42]. On the whole, our study revealed the function of intermediate cells 10 in promoting the growth of cashmere and maintaining its attachment to the skin.…”

Section: Dp Cell Ultimate Fate: Hair Follicle Development and New Casmentioning

confidence: 79%

Single-cell sequencing reveals the intermediate cell state and function of dermal papilla cells in the hair follicle cycle of cashmere goats

Yang¹,

Liu²,

Che³

et al. 2020

Preprint

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Background: Human hair loss and regeneration has stimulated interest in the natural hair cycle worldwide; however, such research is difficult because the periodicity of human or mouse hair is not visually obvious. Dermal papilla cells (DP cells) play an important role in the development of hair follicles, but knowledge of the differentiation and mechanisms of DP stem cells during transition through the hair follicle cycle are still limited, although some studies have reported that DP cells may have an intermediate cell state during differentiation, the classification and function of specific cell states are not clear. Results: Here, we used cashmere goats, that have obvious periodicity of hair follicles, as model animals and, based on unbiased single cell RNA sequencing, we identified and isolated DP cell data. Pseudotime ordering analysis was used to successfully construct a DP cell lineage differentiation trajectory and revealed the sequential activation of key genes, signaling pathways, and functions involved in cell fate decisions. At the same time, we analyzed the mechanisms of different cell fates and revealed the function of four different intermediate cells: Intermediate cells 10 showed important functions in the growth of cashmere and maintenance of cashmere attachment to the skin; intermediate cells 1 revealed important functions in the process of apoptosis and cashmere shedding of secondary hair follicles; intermediate cells 0 initiated new follicular cycles and completed the migration of hair follicles and the occurrence of cashmere; and intermediate cells 15 are suggested to be DP progenitor cells. Conclusions: In development and apoptosis, inner bulge cells not only earlier than outer bulge cells, but occurred faster and was more thorough,this helps a deeper understanding of the role of bulge cells. Pseudogenes play another important role in function which promoted the competitive endogenous RNA (ceRNA) hybridization of pseudogenes.In different hair follicle cycles, DP cells will differentiate into different intermediate state cells and perform different functions, and the marker genes of the cells also changed. Intermediate cells 10 showed important functions in the growth of cashmere and maintenance of cashmere attachment to the skin; intermediate cells 1 revealed important functions in the process of apoptosis and cashmere shedding of secondary hair follicles; intermediate cells 0 initiated new follicular cycles and completed the migration of hair follicles and the occurrence of cashmere; and intermediate cells 15 are DP progenitor cells, this conclusion provides an unprecedented deeper understanding of the function of DP cells.

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Mechanisms, Hallmarks, and Implications of Stem Cell Quiescence

Cited by 115 publications

References 105 publications

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Capturing limbal epithelial stem cell population dynamics, signature, and their niche

Single-cell sequencing reveals the intermediate cell state and function of dermal papilla cells in the hair follicle cycle of cashmere goats

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