scholarly journals Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells

2021 ◽  
Vol 22 (18) ◽  
pp. 9667
Author(s):  
Geoffrey Brown
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Lineage ◽  
Cell Types ◽  
Mature Cell ◽  
Cellular Gene ◽  
Hematopoietic Stem ◽  
Homeostatic Process ◽  
Epigenetic Events

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2407
Author(s):  
Ruicen He ◽  
Arthur Dantas ◽  
Karl Riabowol
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Histone Acetyltransferases ◽  
Specific Cell ◽  
Cell Fates ◽  
Cell Identity ◽  
Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

scholarly journals The Winding Road of Cardiac Regeneration—Stem Cell Omics in the Spotlight

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 255 ◽  
Author(s):  
Miruna Mihaela Micheu ◽  
Alina Ioana Scarlatescu ◽  
Alexandru Scafa-Udriste ◽  
Maria Dorobantu
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Great Promise ◽  
Omics Data

Despite significant progress in treating ischemic cardiac disease and succeeding heart failure, there is still an unmet need to develop effective therapeutic strategies given the persistent high-mortality rate. Advances in stem cell biology hold great promise for regenerative medicine, particularly for cardiac regeneration. Various cell types have been used both in preclinical and clinical studies to repair the injured heart, either directly or indirectly. Transplanted cells may act in an autocrine and/or paracrine manner to improve the myocyte survival and migration of remote and/or resident stem cells to the site of injury. Still, the molecular mechanisms regulating cardiac protection and repair are poorly understood. Stem cell fate is directed by multifaceted interactions between genetic, epigenetic, transcriptional, and post-transcriptional mechanisms. Decoding stem cells’ “panomic” data would provide a comprehensive picture of the underlying mechanisms, resulting in patient-tailored therapy. This review offers a critical analysis of omics data in relation to stem cell survival and differentiation. Additionally, the emerging role of stem cell-derived exosomes as “cell-free” therapy is debated. Last but not least, we discuss the challenges to retrieve and analyze the huge amount of publicly available omics data.

scholarly journals daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009881
Author(s):  
Matthew J. Wirick ◽  
Allison R. Cale ◽  
Isaac T. Smith ◽  
Amelia F. Alessi ◽  
Margaret R. Starostik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Rna Binding ◽  
Cell Model ◽  
Cell Types ◽  
Adult Cell ◽  
Heterochronic Gene ◽  
Foxo Transcription Factors ◽  
Dauer Larvae

Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71

2021 ◽  
Author(s):  
Matthew J Wirick ◽  
Allison R Cale ◽  
Isaac T Smith ◽  
Amelia F Alessi ◽  
Margaret R Starostik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Rna Binding ◽  
Cell Model ◽  
Cell Types ◽  
Adult Cell ◽  
Heterochronic Gene ◽  
Foxo Transcription Factors ◽  
Dauer Larvae

Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽  
2021 ◽  
Author(s):  
Dirk Loeffler ◽  
Florin Schneiter ◽  
Weijia Wang ◽  
Arne Wehling ◽  
Tobias Kull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Human Blood ◽  
Asymmetric Cell Division ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

scholarly journals Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2420-2429 ◽  
Author(s):  
Christoph Schaniel ◽  
Dario Sirabella ◽  
Jiajing Qiu ◽  
Xiaohong Niu ◽  
Ihor R. Lemischka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Fate ◽  
Sonic Hedgehog ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cell Niche ◽  
Wnt Inhibitory Factor 1 ◽  
Stem Cell Pool

Abstract The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions.

scholarly journals Stem cell culture on polyvinyl alcohol hydrogels having different elasticity and immobilized with ECM-derived oligopeptides

2017 ◽  
Vol 37 (7) ◽  
pp. 647-660 ◽  
Author(s):  
Saradaprasan Muduli ◽  
Li-Hua Chen ◽  
Meng-Pei Li ◽  
Zhao-wen Heish ◽  
Cheng-Hui Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
Poly Vinyl Alcohol ◽  
Hematopoietic Stem ◽  
Stem Cell Culture

Abstract The physical characteristics of cell culture materials, such as their elasticity, affect stem cell fate with respect to cell proliferation and differentiation. We systematically investigated the morphologies and characteristics of several stem cell types, including human amniotic-derived stem cells, human hematopoietic stem cells, human induced pluripotent stem (iPS) cells, and embryonic stem (ES) cells on poly(vinyl alcohol) (PVA) hydrogels immobilized with and without extracellular matrix-derived oligopeptide. Human ES cells did not adhere well to soft PVA hydrogels immobilized with oligovitronectin, whereas they did adhere well to PVA hydrogel dishes with elasticities greater than 15 kPa. These results indicate that biomaterials such as PVA hydrogels should be designed to possess minimum elasticity to facilitate human ES cell attachment. PVA hydrogels immobilized with and without extracellular matrix-derived oligopeptides are excellent candidates of cell culture biomaterials for investigations into how cell culture biomaterial elasticity affects stem cell culture and differentiation.

Bcr-Abl Impairs T Cell Development From Murine Induced Pluripotent Stem Cells and Hematopoietic Stem Cells; A Partial Explanation for the Concept That Ph+ Clone Never Involves T Cell Lineage in CML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3748-3748
Author(s):  
Bidisha Chanda ◽  
Kiyoko Izawa ◽  
Ratanakanit Harnprasopwat ◽  
Keisuke Takahashi ◽  
Seiichiro Kobayashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Pluripotent Stem Cells ◽  
Conflicts Of Interest ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Hematopoietic Stem

Abstract Abstract 3748 Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder generally believed to originate from a hematopoietic stem cell carrying the BCR-ABL fusion gene, which generally encodes 210kD and 190kD constitutively active tyrosine kinases termed as p210 and p190, respectively. In spite of the putative stem cell origin and the competence for differentiation toward mature B cells, there is a longstanding consensus that CML never involves the T cell lineage at least in chronic phase. To gain insight into this apparent conflict, we used in vitro T cell differentiation model from murine pluripotent stem cells (PSCs) as well as hematopoietic stem cells (HSCs). C57BL/6 MEFs were reprogrammed using a polycistronic lentiviral Tet-On vector encoding human Oct4, Sox2 and Klf4, which were tandemly linked via porcine teschovirus-1 2A peptides, together with another lentiviral vector expressing rtTA driven by the EF-1a promoter. Almost all the vector sequences including the transgenes were deleted by adenovirus-mediated transduction of Crerecombinase after derivation of iPSCs, and only remnant 291-bp LTRs containing a single loxP site remained in the genome. A clone of MEF-iPSCs were retrovirally transduced with p190DccER, a ligand-controllable p190-estrogen receptor fusion protein, whose tyrosine kinase activity absolutely depends on 4-hydroxytamoxyfen (4-HT).For T cell lineage differentiation, p190DccER-MEF-iPSCs were recovered from a feeder-free culture supplemented with LIF and plated onto a subconfluent OP9-DL1 monolayer in the presence of Flt3 ligand and IL7 with or without 0.5 mM 4-HT.After 3 weeks of culture, iPSC-derived blood cells were collected and subjected to FACS analysis for their lineage confirmation. About 70% of lymphocyte-like cells from the 4-HT(-) culture expressed CD3, but only 20% of counterparts from the 4-HT(+)culture expressed CD3, suggesting impaired T cell development by Bcr-Abl. Next, c-Kit+Sca1+Lin− (KSL) bone marrow cells were prepared by FACS from 8-weeks old C57BL/6 mice treated with 5-FU. KSL cells were similarly transduced with p190DccER and were subjected to the OP9-DL1co-culture system with or without 0.5 mM 4-HT.After 2 weeks of culture, 90% of lymphocytes from the 4-HT(-)culture revealed CD3+TCRβ+ phenotype, but only 30% of those were double positive in the presence of 4-HT(+). In addition, 96% of lymphocytes from the 4-HT(-) culture progressed to the DN2 stage with c-Kit−CD44+CD25+phenotype, whereas 40% of those from the 4-HT(+) culture arrested at the DN1 stage showing c-Kit+CD44+CD25−.Since IL7 plays a central role at the stage from DN1 to DN2 of progenitor T cells, Bcr-Abl is suggested to impair T cell development possibly through interfering with the IL7 signal. The precise mechanism underlying impaired T lymphopoiesis by Bcr-Abl is under investigation. Disclosures: No relevant conflicts of interest to declare.

Clonal Compensation Between Hematopoietic Stem Cells upon Differentiation Deficiency

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 422-422
Author(s):  
Rong Lu ◽  
Lisa Nguyen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Blood Cell ◽  
Cell Tracking ◽  
Conflicts Of Interest ◽  
Genetically Modified ◽  
Cell Types ◽  
Clonal Expansion ◽  
Hematopoietic Stem ◽  
Organ Systems

Abstract In most organ systems, regeneration is a coordinated effort that involves many stem cells, but little is known about how individual stem cells compensate for the functional deficiencies of other stem cells. Functional coordination between stem cells is critically important during disease progression and treatment when a subset of HSCs fail or become malignant. We hypothesize that individual HSCs heterogeneously compensate for specific deficiencies, as recent work from our group and others suggest that HSCs heterogeneously supply blood. To test this hypothesis, we tracked mouse HSCs in vivo using a single-cell tracking technology that we had previously developed. We found that individual HSCs heterogeneously compensate for the lymphopoiesis deficiencies of other HSCs by increasing individual clonal expansion and altering lineage bias. Clonal expansion refers to the increase in clonal progenies. Lineage bias refers to the preferential production of specific blood cell types. This compensation rescues the overall blood supply and influences blood cell types outside of the deficient lineages in distinct patterns. We identified the molecular regulators and signaling pathways associated with this form of HSC coordination using RNA sequencing. Specifically, the STAT3 pathway and NF-B signalingwere activated, and PTEN signaling was inhibited in HSCs during the compensation process. To investigate the dynamics of HSC coordination, we employed a genetically modified mouse model that expresses simian diphtheria toxin (DT) receptor under the control of the CD11b promoter. Monocytes derived from this mouse line can be ablated upon DT administration. We co-transplanted HSCs derived from normal and the genetically modified mice, then conditionally ablated the monocyte population repeatedly, and tracked the temporal responses of individual normal HSCs. Our time-course analysis revealed that a distinct subset of HSC clones produced rapid and persistent responses to the blood perturbations. These clones had not been highly active in the affected lineages prior to the perturbation. We identified several significant temporal profiles that indicate a remarkable heterogeneity in the responses of HSCs to blood system changes. Together, these data suggest that HSC differentiation is coordinated in a deterministic manner during compensation and is independent of the normal differentiation program. Our findings suggest that stem cells interact with each other and form a coordinated cellular network that is robust enough to withstand minor functional disruptions. Individual HSCs distinctly adapt their differentiation program to compensate for deficient HSCs and specifically overproduce undersupplied cell types. The heterogeneity in the compensation activities of individual HSC clones may be essential for maintaining robustness in blood regeneration and suggests that stem cell coordination is a complex process. A better understanding of the clonal level differences in individual HSCs is critically important for identifying the pathogenesis of blood diseases. Exploiting the innate compensation capacity of stem cell networks may improve the diagnosis and treatment of many diseases. For example, the identification of the molecular regulators and pathways involved in HSC compensation can help develop new therapeutic treatments that enhance the innate compensation capacity of stem cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Stem Cell Fate Analysis Revisited: Interpretation of Individual Clone Dynamics in the Light of a New Paradigm of Stem Cell Organization

2007 ◽  
Vol 2007 ◽  
pp. 1-9 ◽  
Author(s):  
Ingo Roeder ◽  
Katrin Braesel ◽  
Ronny Lorenz ◽  
Markus Loeffler
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Cell System ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Cell Organization ◽  
Experimental Findings ◽  
Self Organizing

Many experimental findings on heterogeneity, flexibility, and plasticity of tissue stem cells are currently challenging stem cell concepts that assume a cell intrinsically predefined, unidirectional differentiation program. In contrast to these classical concepts, nonhierarchical self-organizing systems provide an elegant and comprehensive alternative to explain the experimental data. Here we present the application of such a self-organizing concept to quantitatively describe the hematopoietic stem cell system. Focusing on the analysis of individual-stem-cell fates and clonal dynamics, we particularly discuss implications of the theoretical results on the interpretation of experimental findings. We demonstrate that it is possible to understand hematopoietic stem cell organization without assumptions on unidirectional developmental hierarchies, preprogrammed asymmetric division events or other assumptions implying the existence of a predetermined stem cell entity. The proposed perspective, therefore, changes the general paradigm of thinking about stem cells.

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