scholarly journals Homo- and heterodimerization of bHLH transcription factors balance stemness and bipotential differentiation

2019 ◽  
Author(s):  
Aleix Puig-Barbé ◽  
Joaquín de Navascués
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Adult Stem Cells ◽  
Cell Types ◽  
E Proteins ◽  
Self Renewal ◽  
Helix Loop Helix ◽  
Mechanism Of Interaction ◽  
Bhlh Transcription Factors

ABSTRACTMultipotent adult stem cells must balance self-renewal with differentiation into various mature cell types. How this activity is molecularly regulated is poorly understood. By using genetic and molecular analyses in vivo, we show that a small network of basic Helix-Loop-Helix (bHLH) transcription factors controls both stemness and bi-potential differentiation in the Drosophila adult intestine. We find that homodimers of Daughterless (Da, homolog to mammalian E proteins) maintain the self-renewal of intestinal stem cells and antagonise the activity of heterodimers of Da and Scute (Sc, homolog to ASCL and known to promote intestinal secretory differentiation). We find a novel role for the HLH factor Extramacrochaetae (Emc, homolog to Id proteins), titrating Da and Sc to promote absorptive differentiation. We further show that Emc prevents committed absorptive progenitors from de-differentiating, revealing the plasticity of these cells. This mechanism of interaction partner-switching enables the active maintenance of stemness, but primes stem cells for differentiation along two alternative fates. Such regulatory logic could be recapitulated in other bipotent stem cell systems.

scholarly journals The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 667
Author(s):  
Meera Krishnan ◽  
Sahil Kumar ◽  
Luis Johnson Kangale ◽  
Eric Ghigo ◽  
Prasad Abnave
Keyword(s):  
Stem Cells ◽  
Animal Models ◽  
Adult Stem Cells ◽  
The Body ◽  
In Vivo Studies ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Organ Systems

Adult stem cells (ASCs) are the undifferentiated cells that possess self-renewal and differentiation abilities. They are present in all major organ systems of the body and are uniquely reserved there during development for tissue maintenance during homeostasis, injury, and infection. They do so by promptly modulating the dynamics of proliferation, differentiation, survival, and migration. Any imbalance in these processes may result in regeneration failure or developing cancer. Hence, the dynamics of these various behaviors of ASCs need to always be precisely controlled. Several genetic and epigenetic factors have been demonstrated to be involved in tightly regulating the proliferation, differentiation, and self-renewal of ASCs. Understanding these mechanisms is of great importance, given the role of stem cells in regenerative medicine. Investigations on various animal models have played a significant part in enriching our knowledge and giving In Vivo in-sight into such ASCs regulatory mechanisms. In this review, we have discussed the recent In Vivo studies demonstrating the role of various genetic factors in regulating dynamics of different ASCs viz. intestinal stem cells (ISCs), neural stem cells (NSCs), hematopoietic stem cells (HSCs), and epidermal stem cells (Ep-SCs).

scholarly journals Hair follicle stem cells regulate retinoid metabolism to maintain the self-renewal niche for melanocyte stem cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Zhiwei Lu ◽  
Yuhua Xie ◽  
Huanwei Huang ◽  
Kaiju Jiang ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Notch Pathway ◽  
Cell Types ◽  
Receptor Protein ◽  
Self Renewal ◽  
Functional Studies ◽  
Kit Ligand ◽  
Melanocyte Stem Cells ◽  
Hair Follicle Stem Cells

Metabolites are major biological parameters sensed by many cell types in vivo, whether they function as signaling mediators of SC and niche cross talk to regulate tissue regeneration is largely unknown. We show here that deletion of the Notch pathway co-factor RBP-J specifically in mouse HFSCs triggers adjacent McSCs to precociously differentiate in their shared niche. Transcriptome screen and in vivo functional studies revealed that the elevated level of retinoic acid (RA) caused by de-repression of RA metabolic process genes as a result of RBP-J deletion in HFSCs triggers ectopic McSCs differentiation in the niche. Mechanistically the increased level of RA sensitizes McSCs to differentiation signal KIT-ligand by increasing its c-Kit receptor protein level in vivo. Using genetic approach, we further pinpointed HFSCs as the source of KIT-ligand in the niche. We discover that HFSCs regulate the metabolite RA level in vivo to allow self-renewal of neighboring McSCs.

scholarly journals Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Bruno Sainz ◽  
Emily Carron ◽  
Mireia Vallespinós ◽  
Heather L. Machado
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cross Talk ◽  
Tumor Biology ◽  
Cell Types ◽  
Tumor Formation ◽  
Self Renewal ◽  
Numerous Cell ◽  
Key Drivers

Cancer stem cells (CSCs) are a unique subset of cells within tumors with stemlike properties that have been proposed to be key drivers of tumor initiation and progression. CSCs are functionally defined by their unlimited self-renewal capacity and their ability to initiate tumor formationin vivo. Like normal stem cells, CSCs exist in a cellular niche comprised of numerous cell types including tumor-associated macrophages (TAMs) which provides a unique microenvironment to protect and promote CSC functions. TAMs provide pivotal signals to promote CSC survival, self-renewal, maintenance, and migratory ability, and in turn, CSCs deliver tumor-promoting cues to TAMs that further enhance tumorigenesis. Studies in the last decade have aimed to understand the molecular mediators of CSCs and TAMs, and recent advances have begun to elucidate the complex cross talk that occurs between these two cell types. In this review, we discuss the molecular interactions that define CSC-TAM cross talk at each stage of tumor progression and examine the clinical implications of targeting these interactions.

Identification of Key Cellular Regulators That Interact with Id1 To Control Hematopoietic Stem Cell Behavior.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1319-1319
Author(s):  
Vladimir Jankovic ◽  
Alessia Ciarrocchi ◽  
Tony DeBlasio ◽  
Robert Benezra ◽  
Stephen D. Nimer
Keyword(s):  
Transcription Factors ◽  
Transcriptional Repression ◽  
Genetic Interaction ◽  
Dominant Negative ◽  
Double Knockout ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Helix Loop Helix

Abstract The ability of hematopoietic stem cells to tightly regulate the transition from relative quiescence and self-renewal to the transiently amplifying, differentiating progenitor fate is critical for HSC homeostasis as well as their regenerative capacity. We have recently described the diminished frequency and rapid exhaustion of HSC self-renewal capacity in the absence of the dominant negative helix-loop-helix molecule Id1. Furthermore, Id1 null HSCs have an increased rate of cycling, coupled with accelerated myeloid commitment both in vivo and in vitro. This is reflected in the elevated expression of myelo-erythroid transcription factors (c/EBPalpha and GATA1) within the Lin−c-kit+Sca-1+ population - “myeloid priming”. The major targets of Id1 mediated transcriptional repression are the ubiquitous E protein E2A as well as Ets transcription factors (Ets1 and Ets2). We hypothesized that the unrestrained activity of these and/or other targets of Id1 transcriptional repression leads to premature HSC commitment in Id1 null animals. Indeed, we show that HSC differentiation in culture can be delayed by transduction of E2A directed shRNA specifically in Id1 null, but not in wild-type Id1 expressing cells. This indicates an abnormal E2A activity in Id1 null HSCs that could be responsible for their increased differentiation status. To further define the transcriptional deregulation in Id1 null HSCs, we have used the Affymetrix microarray technology. We observed ~3 fold increased expression of the CDK inhibitor p21 in freshly isolated Id1 null HSCs and have confirmed this result by multiple independent qPCR measurements. The transcriptional induction of p21 by E2A as well as its repression by Id1 have been well established. Therefore, the observed p21 induction could be explained by the elevated level of E2A activity in HSCs in the absence of Id1 expression. To explore the functional significance of Id1 mediated p21 regulation in HSCs, we have generated p21/Id1 double knockout animals. Surprisingly, despite its reported function in restricting the cell cycle entry of normal HSCs, we show that in the context of Id1 loss, p21 expression is required for the accelerated HSC cycling, and unlike Id1 single null HSCs, p21/Id1 double knockout HSCs do not show accelerated myeloid differentiation in culture. Therefore, we propose that Id1 actively represses E2A activity in HSCs, as well as the induction of p21, which could be an important component of the HSC commitment program. Further studies will be presented defining the in vivo relevance of the Id1/p21 genetic interaction for HSC growth and differentiation.

scholarly journals Stem cells in the adult pancreas and liver

2007 ◽  
Vol 404 (2) ◽  
pp. 169-178 ◽  
Author(s):  
Zoë D. Burke ◽  
Shifaan Thowfeequ ◽  
Macarena Peran ◽  
David Tosh
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Liver Failure ◽  
Adult Stem Cells ◽  
Cellular Therapy ◽  
Cell Types ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
Undifferentiated Cells

Stem cells are undifferentiated cells that can self-renew and generate specialized (functional) cell types. The remarkable ability of stem cells to differentiate towards functional cells makes them suitable modalities in cellular therapy (which means treating diseases with the body's own cells). Potential targets for cellular therapy include diabetes and liver failure. However, in order for stem cells to be clinically useful, we must learn to identify them and to regulate their differentiation. We will use the intestine as a classical example of a stem cell compartment, and then examine the evidence for the existence of adult stem cells in two endodermally derived organs: pancreas and liver. We will review the characteristics of the putative stem cells in these tissues and the transcription factors controlling their differentiation towards functional cell types.

scholarly journals T helper cells modulate intestinal stem cell renewal and differentiation

2017 ◽  
Author(s):  
Moshe Biton ◽  
Adam L. Haber ◽  
Semir Beyaz ◽  
Noga Rogel ◽  
Christopher Smillie ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Epithelial Cells ◽  
Immune Cell ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
T Helper ◽  
Self Renewal

AbstractIn the small intestine, a cellular niche of diverse accessory cell types supports the rapid generation of mature epithelial cell types through self-renewal, proliferation, and differentiation of intestinal stem cells (ISCs). However, not much is known about interactions between immune cells and ISCs, and it is unclear if and how immune cell dynamics affect eventual ISC fate or the balance between self-renewal and differentiation. Here, we used single-cell RNA-seq (scRNA-Seq) of intestinal epithelial cells (IECs) to identify new mechanisms for ISC–immune cell interactions. Surprisingly, MHC class II (MHCII) is enriched in two distinct subsets of Lgr5+ crypt base columnar ISCs, which are also distinguished by higher proliferation rates. Using co-culture of T cells with intestinal organoids, cytokine stimulations, and in vivo mouse models, we confirm that CD4+ T helper (Th) cells communicate with ISCs and affect their differentiation, in a manner specific to the Th subtypes and their signature cytokines and dependent on MHCII expression by ISCs. Specific inducible knockout of MHCII in intestinal epithelial cells in mice in vivo results in expansion of the ISC pool. Mice lacking T cells have expanded ISC pools, whereas specific depletion of Treg cells in vivo results in substantial reduction of ISC numbers. Our findings show that interactions between Th cells and ISCs mediated via MHCII expressed in intestinal epithelial stem cells help orchestrate tissue-wide responses to external signals.

Stem Cells in T-ALL Have a Primitive CD133+/CD34+/CD7- Phenotype.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1885-1885
Author(s):  
Charlotte V. Cox ◽  
Roger S. Evely ◽  
Nicholas J. Goulden ◽  
Allison Blair
Keyword(s):  
Stem Cells ◽  
Cell Types ◽  
Scid Mice ◽  
Cell Of Origin ◽  
Proliferating Cells ◽  
Self Renewal ◽  
Proliferative Ability

Abstract The cell of origin of childhood acute lymphoblastic leukaemia (ALL) has been the subject of conflicting reports in recent years. One model suggests that many haemopoietic cell types are susceptible to transformation and the level of commitment of the target cell influences the characteristics of the resulting blast cell population. A second model suggests that primitive haemopoietic cells are the targets for transformation, with some differentiation occurring subsequent to the transformation event. This model suggests a hierarchy of progenitors may exist in ALL. In support of this latter model, we have demonstrated that leukaemic stem cells in B-ALL have a primitive CD34+/CD10−/CD19− phenotype and T-ALL cells with NOD/SCID engrafting capacity are CD34+/CD4−. In this investigation we have attempted to further purify and characterise leukaemic stem cells from children with T-ALL. Cells from 7 patients were sorted for expression of CD34 and CD7 and the sorted subfractions evaluated for long-term proliferative ability in vitro using a serum free suspension culture assay and in the NOD/SCID mouse model. In this group of patients, the CD34+/CD7+ fraction represented 7±6% of cells at sorting, 6±4% were CD34+/CD7− and the majority were CD34−/CD7+ (60±12%). After 3 weeks in culture, the majority of proliferating cells were derived from the CD34+/CD7− subfraction (53±16%). By week 6, >70% of proliferating cells were derived from the CD34+/CD7− subfraction. Unsorted ALL cells and the sorted subfractions from 4 of these patients, were evaluated for their ability to engraft sublethally irradiated NOD/SCID mice. In each case, engraftment was achieved using 105–106 unsorted cells (25–80% CD45+) and with the CD34+/CD7− subfraction only (4–84% CD45+ with 3x103–8x104 cells). There was no engraftment with the other subfractions despite injecting up to 100 fold more cells. The engrafted cells had the same karyotype as the patient at diagnosis and expressed high levels of CD2, CD4 and CD7 implying they had differentiated in vivo. The self-renewal capacity of the CD34+/CD7− cells was evaluated by secondary transplantation. CD45+ cells from NOD/SCIDs engrafted with CD34+/CD7− cells successfully engrafted secondary recipients with equivalent levels of human cell engraftment, demonstrating these cells were capable of self-renewal. These findings suggest that cells with a more primitive phenotype may be the targets for transformation in T-ALL, rather than committed lymphocytes. To further investigate this hypothesis, we sorted cells from 4 of these patients for expression of CD133 and CD7 and evaluated their proliferative ability as described above. Results to date indicate that the CD133+/CD7− fraction represents only 0.35% of nucleated cells at sorting. However, after 3 weeks in culture, 48±9% of proliferating cells were derived from this subfraction and by week 6, 58±20% of cells were derived from the CD133+/CD7− subfraction. In vivo analyses completed in 2 patients to date have shown that only the CD133+/CD7− subfraction was capable of engrafting NOD/SCID mice (0.5–54% CD45+ using 3x103–105 cells). These results demonstrate that T-ALL cells with long-term proliferative and NOD/SCID repopulating capacity express the primitive haemopoietic cell antigens CD133 and CD34 and lack expression of T-lineage markers. These findings add further support to the concept of a common cell of origin for acute leukaemias.

scholarly journals Basic Helix-Loop-Helix Transcription Factor Heterocomplex of Yas1p and Yas2p Regulates Cytochrome P450 Expression in Response to Alkanes in the Yeast Yarrowia lipolytica

2007 ◽  
Vol 6 (4) ◽  
pp. 734-743 ◽  
Author(s):  
Setsu Endoh-Yamagami ◽  
Kiyoshi Hirakawa ◽  
Daisuke Morioka ◽  
Ryouichi Fukuda ◽  
Akinori Ohta
Keyword(s):  
Cytochrome P450 ◽  
Transcription Factors ◽  
Yarrowia Lipolytica ◽  
Bhlh Protein ◽  
Genome Database ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Bhlh Transcription Factors

ABSTRACT The expression of the ALK1 gene, which encodes cytochrome P450, catalyzing the first step of alkane oxidation in the alkane-assimilating yeast Yarrowia lipolytica, is highly regulated and can be induced by alkanes. Previously, we identified a cis-acting element (alkane-responsive element 1 [ARE1]) in the ALK1 promoter. We showed that a basic helix-loop-helix (bHLH) protein, Yas1p, binds to ARE1 in vivo and mediates alkane-dependent transcription induction. Yas1p, however, does not bind to ARE1 by itself in vitro, suggesting that Yas1p requires another bHLH protein partner for its DNA binding, as many bHLH transcription factors function by forming heterodimers. To identify such a binding partner of Yas1p, here we screened open reading frames encoding proteins with the bHLH motif from the Y. lipolytica genome database and identified the YAS2 gene. The deletion of the YAS2 gene abolished the alkane-responsive induction of ALK1 transcription and the growth of the yeast on alkanes. We revealed that Yas2p has transactivation activity. Furthermore, Yas1p and Yas2p formed a protein complex that was required for the binding of these proteins to ARE1. These findings allow us to postulate a model in which bHLH transcription factors Yas1p and Yas2p form a heterocomplex and mediate the transcription induction in response to alkanes.

scholarly journals Reciprocal interaction between mesenchymal stem cells and transit amplifying cells regulates tissue homeostasis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Junjun Jing ◽  
Jifan Feng ◽  
Jingyuan Li ◽  
Hu Zhao ◽  
Thach-Vu Ho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Wnt Signaling ◽  
Adult Stem Cells ◽  
Cell Types ◽  
Tissue Homeostasis ◽  
Canonical Wnt Signaling ◽  
Multiple Organs ◽  
Canonical Wnt

Interaction between adult stem cells and their progeny is critical for tissue homeostasis and regeneration. In multiple organs, mesenchymal stem cells (MSCs) give rise to transit amplifying cells (TACs), which then differentiate into different cell types. However, whether and how MSCs interact with TACs remains unknown. Using the adult mouse incisor as a model, we present in vivo evidence that TACs and MSCs have distinct genetic programs and engage in reciprocal signaling cross talk to maintain tissue homeostasis. Specifically, an IGF-WNT signaling cascade is involved in the feedforward from MSCs to TACs. TACs are regulated by tissue-autonomous canonical WNT signaling and can feedback to MSCs and regulate MSC maintenance via Wnt5a/Ror2-mediated non-canonical WNT signaling. Collectively, these findings highlight the importance of coordinated bidirectional signaling interaction between MSCs and TACs in instructing mesenchymal tissue homeostasis, and the mechanisms identified here have important implications for MSC–TAC interaction in other organs.

scholarly journals Identification of dividing, determined sensory neuron precursors in the mammalian neural crest

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3545-3559
Author(s):  
A.L. Greenwood ◽  
E.E. Turner ◽  
D.J. Anderson
Keyword(s):  
Transcription Factors ◽  
Neural Crest ◽  
Sensory Neurons ◽  
Large Diameter ◽  
Defined Medium ◽  
Culture Conditions ◽  
Helix Loop Helix ◽  
Pou Domain ◽  
Bhlh Transcription Factors

Sensory and autonomic neurons of the vertebrate peripheral nervous system are derived from the neural crest. Here we use the expression of lineage-specific transcription factors as a means to identify neuronal subtypes that develop in rat neural crest cultures grown in a defined medium. Sensory neurons, identified by expression of the POU-domain transcription factor Brn-3.0, develop from dividing precursors that differentiate within 2 days following emigration from the neural tube. Most of these precursors generate sensory neurons even when challenged with BMP2, a factor that induces autonomic neurogenesis in many other cells in the explants. Moreover, BMP2 fails to prevent expression of the sensory-specific basic helix-loop-helix (bHLH) transcription factors neurogenin1, neurogenin2 and neuroD, although it induces expression of the autonomic-specific bHLH factor MASH1 and the paired homeodomain factor Phox2a in other cells. These data suggest that there are mitotically active precursors in the mammalian neural crest that can generate sensory neurons even in the presence of a strong autonomic-inducing cue. Further characterization of the neurons generated from such precursors indicates that, under these culture conditions, they exhibit a proprioceptive and/or mechanosensory, but not nociceptive, phenotype. Such precursors may therefore correspond to a lineally (Frank, E. and Sanes, J. (1991) Development 111, 895–908) and genetically (Ma, Q., Fode, C., Guillemot, F. and Anderson, D. J. (1999) Genes Dev. 13, in press) distinct subset of early-differentiating precursors of large-diameter sensory neurons identified in vivo.

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