scholarly journals Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer

Open Biology ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 180120 ◽  
Author(s):  
Maureen Spit ◽  
Bon-Kyoung Koo ◽  
Madelon M. Maurice
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Signalling Pathways ◽  
Intestinal Homeostasis ◽  
Cell Dynamics ◽  
Cell Proliferation And Differentiation ◽  
Colorectal Cancer Cells ◽  
Recent Developments ◽  
Mutational Activation ◽  
Stem Cell Populations

Rapidly renewing tissues such as the intestinal epithelium critically depend on the activity of small-sized stem cell populations that continuously generate new progeny to replace lost and damaged cells. The complex and tightly regulated process of intestinal homeostasis is governed by a variety of signalling pathways that balance cell proliferation and differentiation. Accumulating evidence suggests that stem cell control and daughter cell fate determination is largely dictated by the microenvironment. Here, we review recent developments in the understanding of intestinal stem cell dynamics, focusing on the roles, mechanisms and interconnectivity of prime signalling pathways that regulate stem cell behaviour in intestinal homeostasis. Furthermore, we discuss how mutational activation of these signalling pathways endows colorectal cancer cells with niche-independent growth advantages during carcinogenesis.

scholarly journals Mathematical modeling of plant cell fate transitions controlled by hormonal signals

2019 ◽  
Author(s):  
Filip Z. Klawe ◽  
Thomas Stiehl ◽  
Peter Bastian ◽  
Christophe Gaillochet ◽  
Jan U. Lohmann ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cell Division ◽  
Cell Fate ◽  
Plant Architecture ◽  
Two Dimensional ◽  
Cell Dynamics ◽  
Non Linear

AbstractCoordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to elucidate the impact of hormonal signaling on the fate transition rates between different zones corresponding to slowly dividing stem cells and fast dividing transit amplifying cells. The model is based on a simplified two-dimensional disc geometry of the SAM and accounts for a continuous displacement towards the periphery of cells produced in the central zone. Coupling growth and hormonal signaling results in a non-linear system of reaction-diffusion equations on a growing domain with the growth velocity depending on the model components. The model is tested by simulating perturbations in the level of key transcription factors that maintain SAM homeostasis. The model provides new insights on how the transcription factor HECATE is integrated in the regulatory network that governs stem cell differentiation.SummaryPlants continuously generate new organs such as leaves, roots and flowers. This process is driven by stem cells which are located in specialized regions, so-called meristems. Dividing stem cells give rise to offspring that, during a process referred to as cell fate transition, become more specialized and give rise to organs. Plant architecture and crop yield crucially depend on the regulation of meristem dynamics. To better understand this regulation, we develop a computational model of the shoot meristem. The model describes the meristem as a two-dimensional disk that can grow and shrink over time, depending on the concentrations of the signalling factors in its interior. This allows studying how the non-linear interaction of multiple transcription factors is linked to cell division and fate-transition. We test the model by simulating perturbations of meristem signals and comparing them to experimental data. The model allows simulating different hypotheses about signal effects. Based on the model we study the specific role of the transcription factor HECATE and provide new insights in its action on cell dynamics and in its interrelation with other known transcription factors in the meristem.

Signaling pathways governing stem-cell fate

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 492-503 ◽  
Author(s):  
Ulrika Blank ◽  
Göran Karlsson ◽  
Stefan Karlsson
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Cell Biology ◽  
Adult Stem Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Recent Developments ◽  
Molecular Machinery

Hematopoietic stem cells (HSCs) are historically the most thoroughly characterized type of adult stem cell, and the hematopoietic system has served as a principal model structure of stem-cell biology for several decades. However, paradoxically, although HSCs can be defined by function and even purified to near-homogeneity, the intricate molecular machinery and the signaling mechanisms regulating fate events, such as self-renewal and differentiation, have remained elusive. Recently, several developmentally conserved signaling pathways have emerged as important control devices of HSC fate, including Notch, Wingless-type (Wnt), Sonic hedgehog (Shh), and Smad pathways. HSCs reside in a complex environment in the bone marrow, providing a niche that optimally balances signals that control self-renewal and differentiation. These signaling circuits provide a valuable structure for our understanding of how HSC regulation occurs, concomitantly with providing information of how the bone marrow microenvironment couples and integrates extrinsic with intrinsic HSC fate determinants. It is the focus of this review to highlight some of the most recent developments concerning signaling pathways governing HSC fate.

scholarly journals Autophagy in the Regulation of Tissue Differentiation and Homeostasis

2020 ◽  
Vol 8 ◽  
Author(s):  
Cristiana Perrotta ◽  
Maria Grazia Cattaneo ◽  
Raffaella Molteni ◽  
Clara De Palma
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Tissue Homeostasis ◽  
Lysosomal Degradation ◽  
Cell Dynamics ◽  
Stem Cell Fate ◽  
Metabolic Plasticity ◽  
Suitable Framework ◽  
The Impact

Autophagy is a constitutive pathway that allows the lysosomal degradation of damaged components. This conserved process is essential for metabolic plasticity and tissue homeostasis and is crucial for mammalian post-mitotic cells. Autophagy also controls stem cell fate and defective autophagy is involved in many pathophysiological processes. In this review, we focus on established and recent breakthroughs aimed at elucidating the impact of autophagy in differentiation and homeostasis maintenance of endothelium, muscle, immune system, and brain providing a suitable framework of the emerging results and highlighting the pivotal role of autophagic response in tissue functions, stem cell dynamics and differentiation rates.

scholarly journals aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation

2013 ◽  
Vol 202 (6) ◽  
pp. 887-900 ◽  
Author(s):  
Michaela T. Niessen ◽  
Jeanie Scott ◽  
Julia G. Zielinski ◽  
Susanne Vorhagen ◽  
Panagiota A. Sotiropoulou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Lineage Tracing ◽  
Premature Aging ◽  
Temporary Increase ◽  
Proliferative Potential ◽  
Cell Dynamics ◽  
Asymmetric Divisions

The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

scholarly journals Intestinal progenitor P-bodies maintain stem cell identity by suppressing pro-differentiation factors

2020 ◽  
Author(s):  
Kasun Buddika ◽  
Yi-Ting Huang ◽  
Alex Butrum-Griffith ◽  
Sam A. Norrell ◽  
Alex M. O’Connor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Transcriptional Control ◽  
Adult Stem Cell ◽  
Loss Of Function ◽  
P Bodies ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Stem Cell Populations

AbstractPost-transcriptional gene regulatory mechanisms allow cells to quickly respond to environmental variation without relying on nascent transcription. However, the role of these mechanisms in cell fate transitions in adult stem cell populations remain poorly understood. We address this question here by investigating the role of Processing bodies (P-bodies), a key site of post-transcriptional control, in adult Drosophila intestinal stem cells. We report that this cell type, but not surrounding differentiated cells, harbor P-bodies that contain Drosophila orthologs of mammalian P-body components DDX6, EDC3, EDC4 and LSM14A/B and are ultrastructurally organized in a “core-shell” structure. A targeted RNAi screen identified 100+ genes that affect normal P-body morphology including patr-1, which is required for mature P-body assembly. Using both verified patr-1 RNAi strains and newly generated patr-1 loss-of-function alleles, we show that P-body assembly defects correlate with loss of intestinal progenitors. RNA-seq analysis found that patr-1 mutant progenitors inappropriately express enterocyte (EC)-specific genes, leading to precocious EC differentiation. We further demonstrate that this process is independent of well-known transcriptional repressor escargot, indicating P-body-dependent post-transcriptional regulation of pro-differentiation genes. Taken together, this work delineates the importance of post-transcriptional mechanisms in adult stem cell maintenance.

scholarly journals Decoding the mechanisms underlying cell-fate decision-making during stem cell differentiation by random circuit perturbation

2020 ◽  
Vol 17 (169) ◽  
pp. 20200500
Author(s):  
Bin Huang ◽  
Mingyang Lu ◽  
Madeline Galbraith ◽  
Herbert Levine ◽  
Jose N. Onuchic ◽  
...  
Keyword(s):  
Decision Making ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Expression Patterns ◽  
Stem Cell Differentiation ◽  
Computational Method ◽  
Embryonic Cells ◽  
Fate Decision ◽  
Stem Cell Populations

Stem cells can precisely and robustly undergo cellular differentiation and lineage commitment, referred to as stemness. However, how the gene network underlying stemness regulation reliably specifies cell fates is not well understood. To address this question, we applied a recently developed computational method, ra ndom ci rcuit pe rturbation (RACIPE), to a nine-component gene regulatory network (GRN) governing stemness, from which we identified robust gene states. Among them, four out of the five most probable gene states exhibit gene expression patterns observed in single mouse embryonic cells at 32-cell and 64-cell stages. These gene states can be robustly predicted by the stemness GRN but not by randomized versions of the stemness GRN. Strikingly, we found a hierarchical structure of the GRN with the Oct4/Cdx2 motif functioning as the first decision-making module followed by Gata6/Nanog. We propose that stem cell populations, instead of being viewed as all having a specific cellular state, can be regarded as a heterogeneous mixture including cells in various states. Upon perturbations by external signals, stem cells lose the capacity to access certain cellular states, thereby becoming differentiated. The new gene states and key parameters regulating transitions among gene states proposed by RACIPE can be used to guide experimental strategies to better understand differentiation and design reprogramming. The findings demonstrate that the functions of the stemness GRN is mainly determined by its well-evolved network topology rather than by detailed kinetic parameters.

scholarly journals Microenvironmental control of stem cell fate in intestinal homeostasis and disease

2015 ◽  
Vol 237 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Sujata Biswas ◽  
Hayley Davis ◽  
Shazia Irshad ◽  
Tessa Sandberg ◽  
Daniel Worthley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Intestinal Homeostasis ◽  
Stem Cell Fate
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