scholarly journals Division-independent differentiation mandates proliferative competition among stem cells

2017 ◽  
Author(s):  
Amy Reilein ◽  
David Melamed ◽  
Simon Tavaré ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Experimental Evidence ◽  
Adult Stem Cells ◽  
Proliferation Rate ◽  
Quantitative Modeling ◽  
Stem Cell Division ◽  
Follicle Stem Cells ◽  
The Impact

SUMMARYCancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem lineage (1, 2). It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate stem cell proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetric division outcomes or by population asymmetry strategies, in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: a variant, faster-proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cell it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, Drosophila Follicle Stem Cells (FSCs) provided a favorable model system to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that FSC division and FSC differentiation are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.SIGNIFICANCEAdult stem cells support tissue maintenance throughout life but they also can be cells of origin for cancer, allowing clonal expansion and long-term maintenance of the first oncogenic mutations. We considered how a mutation that increases the proliferation rate of a stem cell would affect the probability of its competitive survival and amplification for different potential organizations of stem cells. Quantitative modeling showed that the key characteristic predicting the impact of relative proliferation rate on competition is whether differentiation of a stem cell is coupled to its division. We then used Drosophila Follicle Stem Cells to provide definitive experimental evidence for the general prediction that relative proliferation rates dictate stem cell competition specifically for stem cells that exhibit division-independent differentiation.

scholarly journals Division-independent differentiation mandates proliferative competition among stem cells

2018 ◽  
Vol 115 (14) ◽  
pp. E3182-E3191 ◽  
Author(s):  
Amy Reilein ◽  
David Melamed ◽  
Simon Tavaré ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Lineage ◽  
Proliferation Rate ◽  
Genetic Changes ◽  
Stem Cell Lineage ◽  
Stem Cell Division ◽  
Follicle Stem Cells ◽  
The Impact

Cancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem cell lineage. It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetrical division outcomes or by population asymmetry strategies in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: A variant, faster proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cells, it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, Drosophila follicle stem cells (FSCs) provided a favorable system with which to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that division and differentiation of an individual FSC are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.

scholarly journals Opposing JAK-STAT and Wnt signaling gradients define a stem cell domain by regulating differentiation at two borders

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
David Melamed ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Wnt Pathway ◽  
Adult Stem Cell ◽  
Follicle Cells ◽  
Pathway Activity ◽  
Stem Cell Division ◽  
Follicle Stem Cells ◽  
Stat Pathway

Many adult stem cell communities are maintained by population asymmetry, where stochastic behaviors of multiple individual cells collectively result in a balance between stem cell division and differentiation. We investigated how this is achieved for Drosophila Follicle Stem Cells (FSCs) by spatially-restricted niche signals. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. We show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC domain, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. Wnt pathway activity declines from the anterior, promotes anterior FSC locations and EC production, and opposes FC production. The pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs and FCs at either end of opposing signaling gradients, and impose a pattern of proliferation that matches derivative production.

scholarly journals Emerging mechanisms of asymmetric stem cell division

2018 ◽  
Vol 217 (11) ◽  
pp. 3785-3795 ◽  
Author(s):  
Zsolt G. Venkei ◽  
Yukiko M. Yamashita
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Asymmetric Cell Division ◽  
Binary Outcomes ◽  
Cellular Mechanisms ◽  
Asymmetric Cell Divisions ◽  
Cell Divisions ◽  
Dividing Cells ◽  
Stem Cell Division

The asymmetric cell division of stem cells, which produces one stem cell and one differentiating cell, has emerged as a mechanism to balance stem cell self-renewal and differentiation. Elaborate cellular mechanisms that orchestrate the processes required for asymmetric cell divisions are often shared between stem cells and other asymmetrically dividing cells. During asymmetric cell division, cells must establish asymmetry/polarity, which is guided by varying degrees of intrinsic versus extrinsic cues, and use intracellular machineries to divide in a desired orientation in the context of the asymmetry/polarity. Recent studies have expanded our knowledge on the mechanisms of asymmetric cell divisions, revealing the previously unappreciated complexity in setting up the cellular and/or environmental asymmetry, ensuring binary outcomes of the fate determination. In this review, we summarize recent progress in understanding the mechanisms and regulations of asymmetric stem cell division.

scholarly journals Integrins control the positioning and proliferation of follicle stem cells in the Drosophila ovary

2008 ◽  
Vol 182 (4) ◽  
pp. 801-815 ◽  
Author(s):  
Alana M. O'Reilly ◽  
Hsiu-Hsiang Lee ◽  
Michael A. Simon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Cell Communication ◽  
Self Renewal ◽  
Ovarian Stem Cells ◽  
Stem Cell Populations ◽  
Integrin Ligand ◽  
Follicle Stem Cells ◽  
Drosophila Ovary

Adult stem cells are maintained in specialized microenvironments called niches, which promote self-renewal and prevent differentiation. In this study, we show that follicle stem cells (FSCs) in the Drosophila melanogaster ovary rely on cues that are distinct from those of other ovarian stem cells to establish and maintain their unique niche. We demonstrate that integrins anchor FSCs to the basal lamina, enabling FSCs to maintain their characteristic morphology and position. Integrin-mediated FSC anchoring is also essential for proper development of differentiating prefollicle cells that arise from asymmetrical FSC divisions. Our results support a model in which FSCs contribute to the formation and maintenance of their own niche by producing the integrin ligand, laminin A (LanA). Together, LanA and integrins control FSC proliferation rates, a role that is separable from their function in FSC anchoring. Importantly, LanA-integrin function is not required to maintain other ovarian stem cell populations, demonstrating that distinct pathways regulate niche–stem cell communication within the same organ.

scholarly journals Cytoplasmic labile iron accumulates in aging stem cells perturbing a key rheostat for identity control

2021 ◽  
Author(s):  
Yun-Ruei Kao ◽  
Jiahao Chen ◽  
Rajni Kumari ◽  
Madhuri Tatiparthy ◽  
Yuhong Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Adult Stem Cells ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Labile Iron Pool ◽  
Wide Range ◽  
Labile Iron ◽  
Iron Pool

Bone marrow resident and rarely dividing haematopoietic stem cells (HSC) harbour an extensive self-renewal capacity to sustain life-long blood formation; albeit their function declines during ageing. Various molecular mechanisms confer stem cell identity, ensure long-term maintenance and are known to be deregulated in aged stem cells. How these programs are coordinated, particularly during cell division, and what triggers their ageing-associated dysfunction has been unknown. Here, we demonstrate that HSC, containing the lowest amount of cytoplasmic chelatable iron (labile iron pool) among hematopoietic cells, activate a limited iron response during mitosis. Engagement of this iron homeostasis pathway elicits mobilization and β-oxidation of arachidonic acid and enhances stem cell-defining transcriptional programs governed by histone acetyl transferase Tip60/KAT5. We further find an age-associated expansion of the labile iron pool, along with loss of Tip60/KAT5-dependent gene regulation to contribute to the functional decline of ageing HSC, which can be mitigated by iron chelation. Together, our work reveals cytoplasmic redox active iron as a novel rheostat in adult stem cells; it demonstrates a role for the intracellular labile iron pool in coordinating a cascade of molecular events which reinforces HSC identity during cell division and to drive stem cell ageing when perturbed. As loss of iron homeostasis is commonly observed in the elderly, we anticipate these findings to trigger further studies into understanding and therapeutic mitigation of labile iron pool-dependent stem cell dysfunction in a wide range of degenerative and malignant pathologies.

scholarly journals Opposing Wnt and JAK-STAT signaling gradients define a stem cell domain by regulating spatially patterned cell division and differentiation at two borders

2020 ◽  
Author(s):  
David Melamed ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Adult Stem Cells ◽  
Wnt Pathway ◽  
Opposite Polarity ◽  
Follicle Cells ◽  
Pathway Activity ◽  
Stat Signaling ◽  
Stat Pathway

AbstractMany adult stem cells are maintained as a community by population asymmetry, wherein stochastic actions of individual cells collectively result in a balance between stem cell division and differentiation. We have used Drosophila Follicle Stem Cells (FSCs) as a paradigm to explore the extracellular niche signals that define a stem cell domain and organize stem cell behavior. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. Here we show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC and EC domains, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. A Wnt pathway gradient of opposite polarity promotes more anterior FSC locations and EC production and opposes FC production. Promotion of both FSC division and conversion to FCs by JAK-STAT signaling buffers the effects of genetically altered pathway activity on FSC numbers and balances the four-fold higher rate of differentiation at the posterior face of the FSC domain with a higher rate of FSC division in the most posterior layer. However, genetic elimination of Wnt pathway activity exacerbated elevated FC production resulting from increased JAK-STAT pathway activity, leading to rapid FSC depletion despite high rates of division. The two pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs (high Wnt, low JAK-STAT) and FCs (low Wnt, high JAK-STAT) at each end of opposing signaling gradients, further enforced by quiescence at the anterior border due to declining JAK-STAT pathway activity.

scholarly journals Planarian stem cells sense the identity of the missing pharynx to launch its targeted regeneration

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tisha E Bohr ◽  
Divya A Shiroor ◽  
Carolyn E Adler
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Types ◽  
Erk Signaling ◽  
Stem Cell Population ◽  
Cell Responses ◽  
Stem Cell Division ◽  
Tissue Production ◽  
Single Organ

In order to regenerate tissues successfully, stem cells must detect injuries and restore missing cell types through largely unknown mechanisms. Planarian flatworms have an extensive stem cell population responsible for regenerating any organ after amputation. Here, we compare planarian stem cell responses to different injuries by either amputation of a single organ, the pharynx, or removal of tissues from other organs by decapitation. We find that planarian stem cells adopt distinct behaviors depending on what tissue is missing to target progenitor and tissue production towards missing tissues. Loss of non-pharyngeal tissues only increases non-pharyngeal progenitors, while pharynx removal selectively triggers division and expansion of pharynx progenitors. By pharmacologically inhibiting either mitosis or activation of the MAP kinase ERK, we identify a narrow window of time during which stem cell division and ERK signaling produces pharynx progenitors necessary for regeneration. These results indicate that planarian stem cells can tailor their output to match the regenerative needs of the animal.

scholarly journals Embryonic attenuated Wnt/β-catenin signaling defines niche location and long-term stem cell fate in hair follicle

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Zijian Xu ◽  
Wenjie Wang ◽  
Kaiju Jiang ◽  
Zhou Yu ◽  
Huanwei Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hair Follicle ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Adult Stem Cells ◽  
Stem Cell Markers ◽  
Hair Follicle Stem Cells ◽  
Follicle Stem Cells

Long-term adult stem cells sustain tissue regeneration throughout the lifetime of an organism. They were hypothesized to originate from embryonic progenitor cells that acquire long-term self-renewal ability and multipotency at the end of organogenesis. The process through which this is achieved often remains unclear. Here, we discovered that long-term hair follicle stem cells arise from embryonic progenitor cells occupying a niche location that is defined by attenuated Wnt/β-catenin signaling. Hair follicle initiation is marked by placode formation, which depends on the activation of Wnt/β-catenin signaling. Soon afterwards, a region with attenuated Wnt/β-catenin signaling emerges in the upper follicle. Embryonic progenitor cells residing in this region gain expression of adult stem cell markers and become definitive long-term hair follicle stem cells at the end of organogenesis. Attenuation of Wnt/β-catenin signaling is a prerequisite for hair follicle stem cell specification because it suppresses Sox9, which is required for stem cell formation.

scholarly journals Roles of Melatonin in Goat Hair Follicle Stem Cell Proliferation and Pluripotency Through Regulating the Wnt Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Weidong Zhang ◽  
Niu Wang ◽  
Tongtong Zhang ◽  
Meng Wang ◽  
Wei Ge ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Hair Follicle ◽  
Wnt Signaling Pathway ◽  
Hematopoietic Progenitor Cell ◽  
Hair Follicle Stem Cells ◽  
Follicle Stem Cells ◽  
The Impact

Emerging studies show that melatonin promotes cashmere development through hypodermic implantation. However, the impact and underlying mechanisms are currently unknown. In vitro study has previously demonstrated that melatonin induces cashmere growth by regulating the proliferation of goat secondary hair follicle stem cells (gsHFSCs), but there is limited information concerning the effects of melatonin on cell pluripotency. It is also known that Wnt signaling may actively participate in regulating cell proliferation and stem cell pluripotency. Therefore, in the current investigation, goat hair follicle stem cells were exposed to multiple concentrations of melatonin and different culture times to reveal the relationship between melatonin and the activation of Wnt signaling. A proportionally high Catenin beta-1 (CTNNB1) response was induced by 500 ng/L of melatonin, but it was then suppressed with the dosages over 1,000 ng/L. Greater amounts of CTNNB1 entered the cell nuclei by extending the exposure time to 72 h, which activated transcription factor 4/lymphoid enhancer-binding factor 1 and promoted the expression of the proliferation-related genes C-MYC, C-JUN, and CYCLIND1. Moreover, nuclear receptor ROR-alpha (RORα) and bone morphogenetic protein 4 (BMP4) were employed to analyze the underlying mechanism. RORα presented a sluggish concentration/time-dependent rise, but BMP4 was increased dramatically by melatonin exposure, which revealed that melatonin might participate in regulating the pluripotency of hair follicle stem cells. Interestingly, NOGGIN, which is a BMP antagonist and highly relevant to cell stemness, was also stimulated by melatonin. These findings demonstrated that melatonin exposure and/or NOGGIN overexpression in hair follicle stem cells might promote the expression of pluripotency markers Homeobox protein NANOG, Organic cation/carnitine transporter 4, and Hematopoietic progenitor cell antigen CD34. Our findings here provided a comprehensive view of Wnt signaling in melatonin stimulated cells and melatonin mediated stemness of gsHFSCs by regulating NOGGIN, which demonstrates a regulatory mechanism of melatonin enhancement on the growth of cashmere.

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