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BBA - General Subjects (v.1830, #2)
Biochemistry and signaling in stem cells, and vice versa
by Iain Farrance; Curt Civin (pp. 2267-2267).
The TGFβ superfamily in stem cell biology and early mammalian embryonic development by Tobias A. Beyer; Masahiro Narimatsu; Alexander Weiss; Laurent David; Jeffrey L. Wrana (pp. 2268-2279).
Members of the Transforming Growth Factor-beta (TGFβ) superfamily of cytokines are essential for early embryonic development and play crucial roles in pluripotency and differentiation of embryonic stem cells in vitro.In this review, we discuss how TGFβ family signals are read by cells and how they are modulated by the cellular context. Furthermore, we review recent advances in our understanding of TGFβ function in embryonic stem cells and point out hot topics at the intersection of TGFβ signaling and stem cell biology fields.TGFβ family signals are essential for early mammalian development and the importance of this pathway is reflected in pluripotent stem cells derived from the mammalian embryo.Understanding signaling pathways underlying pluripotency and cell fate specification holds promises for the advent of personalized regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► The molecular mechanism of TGFβ signaling in stem cell controlling pluripotency. ► Molecular events driven by TGFβ family/SMAD signaling to cell fate determination. ► Integration of the TGFβ pathway with the core pluripotency transcription factors. ► Open questions on the crossroad of stem cell biology and the TGFβ pathway.
Keywords: TGFbeta family; SMAD; Cell fate; Pluripotency; Stem cell
TGF-β family signaling in stem cells by Masayo Sakaki-Yumoto; Yoko Katsuno; Rik Derynck (pp. 2280-2296).
The diversity of cell types and tissue types that originate throughout development derives from the differentiation potential of embryonic stem cells and somatic stem cells. While the former are pluripotent, and thus can give rise to a full differentiation spectrum, the latter have limited differentiation potential but drive tissue remodeling. Additionally cancer tissues also have a small population of self-renewing cells with stem cell properties. These cancer stem cells may arise through dedifferentiation from non-stem cells in cancer tissues, illustrating their plasticity, and may greatly contribute to the resistance of cancers to chemotherapies.The capacity of the different types of stem cells for self-renewal, the establishment and maintenance of their differentiation potential, and the selection of differentiation programs are greatly defined by the interplay of signaling molecules provided by both the stem cells themselves, and their microenvironment, the niche. Here we discuss common and divergent roles of TGF-β family signaling in the regulation of embryonic, reprogrammed pluripotent, somatic, and cancer stem cells.Increasing evidence highlights the similarities between responses of normal and cancer stem cells to signaling molecules, provided or activated by their microenvironment. While TGF-β family signaling regulates stemness of normal and cancer stem cells, its effects are diverse and depend on the cell types and physiological state of the cells.Further mechanistic studies will provide a better understanding of the roles of TGF-β family signaling in the regulation of stem cells. These basic studies may lead to the development of a new therapeutic or prognostic strategies for the treatment of cancers. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Normal and cancer stem cell properties are defined by their microenvironments. ► TGF-β family proteins play key roles in stem cell maintenance and differentiation. ► TGF-β family proteins mediate communication between stem cells and niche. ► TGF-β signaling mediates epithelial–mesenchymal transition in cancer stem cells. ► TGF-β family proteins regulate embryonic stem cell self-renewal and differentiation.
Keywords: Pluripotency; Somatic stem cell; Reprogramming; Cancer stem cell; Epithelial–mesenchymal transition; Niche
On the role of Wnt/β-catenin signaling in stem cells by Kuhl Susanne J. Kühl; Kuhl Michael Kühl (pp. 2297-2306).
Stem cells are mainly characterized by two properties: self-renewal and the potency to differentiate into diverse cell types. These processes are regulated by different growth factors including members of the Wnt protein family. Wnt proteins are secreted glycoproteins that can activate different intracellular signaling pathways.Here we summarize our current knowledge on the role of Wnt/β-catenin signaling with respect to these two main features of stem cells.A particular focus is given on the function of Wnt signaling in embryonic stem cells. Wnt signaling can also improve reprogramming of somatic cells towards iPS cells highlighting the importance of this pathway for self-renewal and pluripotency. As an example for the role of Wnt signaling in adult stem cell behavior, we furthermore focus on intestinal stem cells located in the crypts of the small intestine.A broad knowledge about stem cell properties and the influence of intrinsic and extrinsic factors on these processes is a requirement for the use of these cells in regenerative medicine in the future or to understand cancer development in the adult. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Wnt proteins are secreted glycoproteins that can activate different intracellular signaling pathways. ► Wnt signaling supports self-renewal and pluripotency of embryonic stem cells. ► Wnt signaling can improve reprogramming of somatic cells towards iPS. ► Wnt signaling is important for maintenance of intestinal stem cells.
Keywords: Wnt signaling; Embryonic stem cells; Intestinal stem cells
Sending the right signal: Notch and stem cells by Carolina N. Perdigoto; Allison J. Bardin (pp. 2307-2322).
Notch signaling plays a critical role in multiple developmental programs and not surprisingly, the Notch pathway has also been implicated in the regulation of many adult stem cells, such as those in the intestine, skin, lungs, hematopoietic system, and muscle.In this review, we will first describe molecular mechanisms of Notch component modulation including recent advances in this field and introduce the fundamental principles of Notch signaling controlling cell fate decisions. We will then illustrate its important and varied functions in major stem cell model systems including: Drosophila and mammalian intestinal stem cells and mammalian skin, lung, hematopoietic and muscle stem cells.The Notch receptor and its ligands are controlled by endocytic processes that regulate activation, turnover, and recycling. Glycosylation of the Notch extracellular domain has important modulatory functions on interactions with ligands and on proper receptor activity. Notch can mediate cell fate decisions including proliferation, lineage commitment, and terminal differentiation in many adult stem cell types. Certain cell fate decisions can have precise requirements for levels of Notch signaling controlled through modulatory regulation.We describe the current state of knowledge of how the Notch receptor is controlled through its interaction with ligands and how this is regulated by associated factors. The functional consequences of Notch receptor activation on cell fate decisions are discussed. We illustrate the importance of Notch's role in cell fate decisions in adult stem cells using examples from the intestine, skin, lung, blood, and muscle. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Notch signaling is important during development and in adult stem cells. ► We review receptor and ligand structure and mechanisms of regulation. ► Control of target gene expression and cell fate output are discussed. ► Finally, we give an in-depth description of Notch's function in adult stem cells.
Keywords: Notch signaling; Stem cell; Self-renewal; Differentiation; Proliferation
Stem cell regulation by the Hippo pathway by Samantha E. Hiemer; Xaralabos Varelas (pp. 2323-2334).
The Hippo pathway coordinates cell proliferation, apoptosis, and differentiation, and has emerged as a major regulator of organ development and regeneration. Central to the mammalian Hippo pathway is the action of the transcriptional regulators TAZ (also known as WWTR1) and YAP, which are controlled by a kinase cascade that is sensitive to mechanosensory and cell polarity cues.We review recent studies focused on the Hippo pathway in embryonic and somatic stem cell renewal and differentiation.Accurate control of TAZ and YAP is crucial for the self-renewal of stem cells and in guiding distinct cell fate decisions. In vivo studies have implicated YAP as a key regulator of tissue-specific progenitor cell proliferation and tissue regeneration. Misappropriate activation of nuclear TAZ and YAP transcriptional activity drives tissue overgrowth and is implicated in cancer stem cell-like properties that promote tumor initiation.Understanding the activity and regulation of Hippo pathway effectors will offer insight into human pathologies that evolve from the deregulation of stem cell populations. Given the roles of the Hippo pathway in directing cell fate and tissue regeneration, the discernment of Hippo pathway regulatory cues will be essential for the advancement of regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Recent data linking the Hippo pathway to stem cell renewal and differentiation is discussed. ► The Hippo pathway effectors TAZ and YAP control embryonic and induced pluripotent stem cell renewal. ► TAZ and YAP activity dictates mesenchymal stem cell differentiation. ► TAZ and YAP promote epithelial and neuronal progenitor proliferation. ► TAZ enhances cancer stem cell-like properties.
Keywords: Hippo pathway; TAZ; YAP; Stem cell; Regeneration
Role of key regulators of the cell cycle in maintenance of hematopoietic stem cells by Akinobu Matsumoto; Keiichi I. Nakayama (pp. 2335-2344).
Hematopoietic stem cells (HSCs) are characterized by pluripotentiality and self-renewal ability. To maintain a supply of mature blood cells and to avoid HSC exhaustion during the life span of an organism, most HSCs remain quiescent, with only a limited number entering the cell cycle.The molecular mechanisms by which quiescence is maintained in HSCs are addressed, with recent genetic studies having provided important insight into the relation between the cell cycle activity and stemness of HSCs.The cell cycle is tightly regulated in HSCs by complex factors. Key regulators of the cell cycle in other cell types—including cyclins, cyclin-dependent kinases (CDKs), the retinoblastoma protein family, the transcription factor E2F, and CDK inhibitors—also contribute to such regulation in HSCs. Most, but not all, of these regulators are necessary for maintenance of HSCs, with abnormal activation or suppression of the cell cycle resulting in HSC exhaustion. The cell cycle in HSCs is also regulated by external factors such as cytokines produced by niche cells as well as by the ubiquitin–proteasome pathway.Studies of the cell cycle in HSCs may shed light on the pathogenesis of hematopoietic disorders, serve as a basis for the development of new therapeutic strategies for such disorders, prove useful for the expansion of HSCs in vitro as a possible replacement for blood transfusion, and provide insight into stem cell biology in general. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Most hematopoietic stem cells (HSCs) remain quiescent. ► Quiescence in HSCs is tightly regulated by many cell-cycle regulators. ► In most cases, ablation of such regulators in mouse HSCs results in loss of stemness. ► Future studies are required to translate the mouse knowledge to the clinical setting.
Keywords: Abbreviations; APC/C; anaphase-promoting complex/cyclosome; BM; bone marrow; CDK; cyclin-dependent kinase; CKI; cyclin-dependent kinase inhibitor; CXCL12; chemokine (C-X-C motif) ligand 12; HSC; hematopoietic stem cell; Hsc70; heat shock cognate protein 70; LAP; latency-associated protein; LLC; large latent complex; LTBP-1; latent transforming growth factor‐β binding protein‐1; Rb; retinoblastoma protein; SCF; Skp1–Cul1–F-box protein; TPO; thrombopoietin; TGF-β; transforming growth factor‐βCell cycle; Hematopoietic stem cell; Niche; Ubiquitin–proteasome pathway
DNA double‐strand break response in stem cells: Mechanisms to maintain genomic integrity by Pratik Nagaria; Carine Robert; Feyruz V. Rassool (pp. 2345-2353).
Embryonic stem cells (ESCs) represent the point of origin of all cells in a given organism and must protect their genomes from both endogenous and exogenous genotoxic stress. DNA double-strand breaks (DSBs) are one of the most lethal forms of damage, and failure to adequately repair DSBs would not only compromise the ability of SCs to self-renew and differentiate, but will also lead to genomic instability and disease.Herein, we describe the mechanisms by which ESCs respond to DSB-inducing agents such as reactive oxygen species (ROS) and ionizing radiation, compared to somatic cells. We will also discuss whether the DSB response is fully reprogrammed in induced pluripotent stem cells (iPSCs) and the role of the DNA damage response (DDR) in the reprogramming of these cells.ESCs have distinct mechanisms to protect themselves against DSBs and oxidative stress compared to somatic cells. The response to damage and stress is crucial for the maintenance of self-renewal and differentiation capacity in SCs. iPSCs appear to reprogram some of the responses to genotoxic stress. However, it remains to be determined if iPSCs also retain some DDR characteristics of the somatic cells of origin.The mechanisms regulating the genomic integrity in ESCs and iPSCs are critical for its safe use in regenerative medicine and may shed light on the pathways and factors that maintain genomic stability, preventing diseases such as cancer. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Components of the DNA damage response (DDR) are critical in maintaining genomic integrity of ESCs and iPSCs. ► Failure to adequately repair DSBs can lead to genomic instability and cancer ► ESCs have unique mechanisms for maintaining a highly error-free form of DSB repair. ► DSB response may not be completely reprogrammed in all iPSCs. ► DDR presents a roadblock to high efficacy of iPSC generation during reprogramming.
Keywords: Abbreviations; ATM; ataxia telangiectasia mutated; ATR; ataxia telangiectasia and Rad3-related protein; BRCA1; breast cancer type 1 susceptibility protein; CtBP; C-terminal binding protein; CtIP; CTBP interacting protein; DDR; DNA damage response; DNA-PK; DNA-dependent protein kinase; DSB; double‐strand break; ESC; embryonic stem cell; HR; homologous recombination; iPSC; induced pluripotent stem cell; IR; ionizing radiation; mEF; mouse embryonic fibroblast; MDC1; mediator of DNA damage checkpoint protein 1; MRN; Mre11–Rad50–NBS1; NAC; N-acetyl cysteine; NHEJ; non-homologous end joining; PARP1; poly-ADP-ribose polymerase; RPA; replication protein A; ROS; reactive oxygen species; SC; stem cell; SCE; sister chromatid exchange; SSB; single‐strand break; XRCC; X-ray repair cross-complementing protein; 53BP1; p53-binding protein 1Embryonic stem cell; Induced pluripotent stem cell; DNA damage; Double‐strand break repair
Like a rolling histone: Epigenetic regulation of neural stem cells and brain development by factors controlling histone acetylation and methylation by Tobias Lilja; Nina Heldring; Ola Hermanson (pp. 2354-2360).
The development of the nervous system is a highly organized process involving the precise and coordinated timing of many complex events. These events require proper expression of genes promoting survival, differentiation, and maturation, but also repression of alternative cell fates and restriction of cell-type-specific gene expression.As the enzymes mediating post-translational histone acetylation and methylation are regulating higher order chromatin structure and controlling gene transcription, knowledge of the roles for these enzymes becomes crucial for understanding neural development and disease. The widespread expression and general biological roles for chromatin-modifying factors have hampered the studies of such enzymes in neural development, but in recent years, in vivo and in vitro studies have started to shed light on the various processes these enzymes regulate. In this review we summarize the implications of chromatin-modifying enzymes in neural development, with particular emphasis on enzymes regulating histone acetylation and methylation.Enzymes controlling histone acetylation and methylation are involved in the whole process of neural development, from controlling proliferation and undifferentiated, “poised”, state of stem cells to promoting and inhibiting neurogenic and gliogenic pathways and neuronal survival as well as neurite outgrowth.Aberrant enzymatic activities of histone acetyl transferases, deacetylases, and demethylases have been chemically and genetically associated with neural developmental disorders and cancer. Future studies may aim at linking the genetic and developmental studies to more in-depth biochemical characterization to provide a clearer picture of how to improve the diagnosis, prognosis, and treatment of such disorders. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Comprehensive summary of epigenetic regulation of stem cells of the nervous system. ► Histone acetylation and methylation control neural stem cell state and fate. ► Aberrant activities of histone-modifying enzymes directly linked to human disease.
Keywords: Deacetylase; Demethylase; Neuron; Astrocyte; Oligodendrocyte; Progenitor
Exploring metabolic pathways that contribute to the stem cell phenotype by Nathaniel M. Vacanti; Christian M. Metallo (pp. 2361-2369).
Stem cells must negotiate their surrounding nutritional and signaling environment and respond accordingly to perform various functions. Metabolic pathways enable these responses, providing energy and biosynthetic precursors for cell proliferation, motility, and other functions. As a result, metabolic enzymes and the molecules which control them are emerging as attractive targets for the manipulation of stem cells. To exploit these targets a detailed characterization of metabolic flux regulation is required.Here we outline recent advances in our understanding of metabolism in pluripotent stem cells and adult progenitors. We describe the regulation of glycolysis, mitochondrial metabolism, and the redox state of stem cells, highlighting key enzymes and transcription factors involved in the control of these pathways.A general description of stem cell metabolism has emerged, involving increased glycolysis, limited oxidative metabolism, and resistance to oxidative damage. Moving forward, the application of systems-based approaches to stem cells will help shed light on metabolic pathway utilization in proliferating and quiescent stem cells.Metabolic flux contributes to the unique properties of stem cells and progenitors. This review provides a detailed overview of how stem cells metabolize their surrounding nutrients to proliferate and maintain lineage homeostasis. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Pluripotent stem cells exhibit elevated glycolytic flux and limited O2 consumption. ► Normal stem cells and cancer stem cells control ROS levels to resist oxidative damage. ► Manipulation of metabolic pathways can influence differentiation and reprogramming. ► Hypoxia inducible factors and c-Myc regulate the metabolic phenotype of stem cells.
Keywords: Abbreviations; 2HG; (R)2-hydroxyglutarate; 2PG; 2-phosphoglycerate; 3PG; 3-phosphoglycerate; 6PG; 6-phosphogluconate; 6PGL; 6-phosphgluconolactone; 8-OHdG; 8-hydroxy-2'-deoxyguanosine; AcCoA; acetyl coenzyme A; ACLY; ATP citrate lyase; ACO1; aconitase 1; ACO2; aconitase 2; ALDH; aldehyde dehydrogenase; ALDO; aldolase; ATP; adenosine triphosphate; BPG; 1,3-bisphosphoglycerate; CIT; citrate; CYS; cysteine; DHAP; dihydroxyacetone phosphate; ENO; enolase; ESCs; embryonic stem cells; F6P; fructose-6-phosphate; FAs; fatty acids; FBP; fructose-1,6-bisphosphate; FH; fumarate hydratase; FUM; fumarate; G6P; glucose-6-phosphate; G6PD; glucose-6-phosphate dehydrogenase; GAP; glyceraldehyde-3-phosphate; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; GCLC; glutamate-cysteine ligase; GCLM; glutamate-cysteine ligase modifier subunit; GlcNAc; N-acetylglucosamine; GLN; glutamine; GLS; glutaminase; GLU; glutamate; Gluc; glucose; GLY; glycine; GSR; glutathione reductase; GSH; glutathione (reduced); GSS; glutathione synthetase; GSSG; glutathione (oxidized); HBP; hexosamine biosynthesis pathway; hESCs; human embryonic stem cells; HIFs; hypoxia inducible factors; HK; hexokinase; ICT; isocitrate; IDH; isocitrate dehydrogenase; iPSCs; induced pluripotent stem cells; LAC; lactate; LDH; lactate dehydrogenase; MAL; malate; MalCoA; malonyl coenzyme A; MEETHF; methylenetetrahydrofolate; MEFs; mouse embryonic fibroblasts; mESCs; mouse embryonic stem cells; MSCs; mesenchymal stem cells; mTOR; mammalian target of rapamycin; NAC; N-acetyl-; l; -cysteine; NAD; +; nicotinamide adenine dinucleotide (oxidized); NADH; nicotinamide adenine dinucleotide (reduced); NADP; +; nicotinamide adenine dinucleotide phosphate (oxidized); NADPH; nicotinamide adenine dinucleotide phosphate (reduced); OAC; oxaloacetate; OXPHOS; oxidative phosphorylation; PDH; pyruvate dehydrogenase; PDK; pyruvate dehydrogenase kinase; PEP; phosphoenolpyruvate; PFK; phosphofructokinase; PGAM; phosphoglycerate mutase; PGD; phosphogluconate dehydrogenase; PGK; phosphoglycerate kinase; PHI; phosphohexose isomerase; PKM1; pyruvate kinase M1; PKM2; pyruvate kinase M2; PPP; pentose phosphate pathway; PSCs; pluripotent stem cells; PYR; pyruvate; R5P; ribulose-5-phosphate; ROS; reactive oxygen species; SDH; succinate dehydrogenase; SER; serine; SHMTs; serine hydroxymethyltransferases; SUC; succinate; TALDO; transaldolase; TCA; tricarboxylic acid; THF; tetrahydrofolate; TKT; transketolase; UCP2; uncoupling protein 2; WT; wild type; αKG; α-ketoglutarate; γ-GLU-CYS; γ-glutamylcysteine; Δ; m; mitochondrial membrane potentialMetabolic flux; Stem cell; Pluripotent cell; Glycolysis; Cellular redox
Hematopoietic stem cell development and regulatory signaling in zebrafish by Chunxia Zhang; Roger Patient; Feng Liu (pp. 2370-2374).
Hematopoietic stem cells (HSCs) are a population of multipotent cells that can self-renew and differentiate into all blood lineages. HSC development must be tightly controlled from cell fate determination to self-maintenance during adulthood. This involves a panel of important developmental signaling pathways and other factors which act synergistically within the HSC population and/or in the HSC niche. Genetically conserved processes of HSC development plus many other developmental advantages make the zebrafish an ideal model organism to elucidate the regulatory mechanisms underlying HSC programming.This review summarizes recent progress on zebrafish HSCs with particular focus on how developmental signaling controls hemogenic endothelium-derived HSC development. We also describe the interaction of different signaling pathways during these processes.The hematopoietic stem cell system is a paradigm for stem cell studies. Use of the zebrafish model to study signaling regulation of HSCs in vivo has resulted in a great deal of information concerning HSC biology in vertebrates.These new findings facilitate a better understanding of molecular mechanisms of HSC programming, and will provide possible new strategies for the treatment of HSC-related hematological diseases, such as leukemia. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Hematopoietic stem cell development is highly conserved in zebrafish. ► Regulatory signaling in HSC development is conserved in zebrafish. ► The interaction between different signaling pathways tightly controls HSC development.
Keywords: Signaling; Hematopoietic stem cell; Hemogenic endothelium; Dorsal aorta; Zebrafish
Signal transduction pathways, intrinsic regulators, and the control of cell fate choice by Nancy Fossett (pp. 2375-2384).
Information regarding changes in organismal status is transmitted to the stem cell regulatory machinery by a limited number of signal transduction pathways. Consequently, these pathways derive their functional specificity through interactions with stem cell intrinsic master regulators, notably transcription factors. Identifying the molecular underpinnings of these interactions is critical to understanding stem cell function.This review focuses on studies in Drosophila that identify the gene regulatory basis for interactions between three different signal transduction pathways and an intrinsic master transcriptional regulator in the context of hematopoietic stem-like cell fate choice. Specifically, the interface between the GATA:FOG regulatory complex and the JAK/STAT, BMP, and Hedgehog pathways is examined.The GATA:FOG complex coordinates information transmitted by at least three different signal transduction pathways as a means to control stem-like cell fate choice. This illustrates emerging principles concerning regulation of stem cell function and describes a gene regulatory link between changes in organismal status and stem cell response.The Drosophila model system offers a powerful approach to identify the molecular basis of how stem cells receive, interpret, and then respond to changes in organismal status. This article is part of a Special Issue entitled: Biochemistry of Stem Cells.► GATA:FOG interactions with JAK/STAT, BMP and Hedgehog pathways are discussed. ► These interactions control cell fate choice during Drosophila hematopoiesis. ► Emerging principles regarding regulation of stem cell function are discussed. ► Regulatory links between organism status and stem-like cell response are described.
Keywords: GATA; Friend of GATA; JAK/STAT; Bone morphogenic protein; Hedgehog; Hematopoiesis
Pivots of pluripotency: The roles of non-coding RNA in regulating embryonic and induced pluripotent stem cells by Jeffrey S. Huo; Elias T. Zambidis (pp. 2385-2394).
Induced pluripotent stem cells (iPSC) derived from reprogrammed patient somatic cells possess enormous therapeutic potential. However, unlocking the full capabilities of iPSC will require an improved understanding of the molecular mechanisms which govern the induction and maintenance of pluripotency, as well as directed differentiation to clinically relevant lineages. Induced pluripotency of a differentiated cell is mediated by sequential cascades of genetic and epigenetic reprogramming of somatic histone and DNA CpG methylation marks. These genome-wide changes are mediated by a coordinated activity of transcription factors and epigenetic modifying enzymes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are now recognized as an important third class of regulators of the pluripotent state.This review surveys the currently known roles and mechanisms of ncRNAs in regulating the embryonic and induced pluripotent states.Through a variety of mechanisms, ncRNAs regulate constellations of key pluripotency genes and epigenetic regulators, and thus critically determine induction and maintenance of the pluripotent state.A further understanding of the roles of ncRNAs in regulating pluripotency may help assess the quality of human iPSC reprogramming. Additionally, ncRNA biology may help decipher potential transcriptional and epigenetic commonalities between the self renewal processes that govern both ESC and tumor initiating cancer stem cells (CSC). This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Regulatory non-coding RNAs play important roles in embryonic stem cell processes ► Opposing pro- and anti-differentiation miRNAs regulate pluripotency ► miRNAs can catalyze or enhance the generation of induced pluripotent stem cells ► Long noncoding RNAs are increasingly recognized as regulators of pluripotency ► ncRNAs may define stem cell quality and may also regulate cancer stem cells
Keywords: Human embryonic stem cells; Human induced pluripotent stem cells; hESC; microRNAs; Long noncoding RNA; lncRNA
The biochemistry of hematopoietic stem cell development by P. Kaimakis; M. Crisan; E. Dzierzak (pp. 2395-2403).
The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from ‘hemogenic’ endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation.The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed.The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult.HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC generation in the developing embryo provides important new knowledge on how these complex stem cells are made, sustained and expanded in the embryo to give rise to the complete adult hematopoietic system, thus stimulating novel strategies for producing increased numbers of clinically useful HSCs. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Current knowledge about hematopoietic stem cell ontogeny in vertebrate embryos ► Intrinsic/transcription factors – SCL, Runx, and Gata2 – that direct HSC generation ► Developmental morphogens/factors that are extrinsic cues for HSC generation
Keywords: Hematopoietic stem cell; Aorta–gonad–mesonephros (AGM); Development; Transcription factor; Signaling pathway
Hematopoietic stem cell niche: An interplay among a repertoire of multiple functional niches by Ayako Nakamura-Ishizu; Toshio Suda (pp. 2404-2409).
Hematopoietic stem cell (HSC) niche of the BM provides a specialized microenvironment for the regulation of HSCs. The strict control of HSCs by the niche coordinates the balance between the proliferation and the differentiation of HSCs for the homeostasis of the blood system in steady states and during stress hematopoiesis. The osteoblastic and vascular niches are the classically identified constituents of the BM niche.Recent research broadens our understanding of the BM niche as an assembly of multiple niche cells within the BM. We provide an overview of the HSC niche aiming to delineate the defined and possible niche cell interactions which collectively modulate the HSC integrity.Multiple cells in the BM, including osteoblasts, vascular endothelia, perivascular mesenchymal cells and HSC progeny cells, function conjunctively as niche cells to regulate HSCs.The study of HSC niche cells and their functions provides insights into stem cell biology and also may be extrapolated into the study of cancer stem cells. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Recent advances in the study of HSC niche in the bone marrow are discussed. ► The cellular components of the HSC niche and crucial cellular signaling are discussed. ► The niche components form a complex interplay among each other.
Keywords: Hematopoietic stem cell; Niche; Osteoblast; Vascular; Progeny
Major signaling pathways in intestinal stem cells by Tim Vanuytsel; Stefania Senger; Alessio Fasano; Terez Shea-Donohue (pp. 2410-2426).
The discovery of markers to identify the intestinal stem cell population and the generation of powerful transgenic mouse models to study stem cell physiology have led to seminal discoveries in stem cell biology.In this review we give an overview of the current knowledge in the field of intestinal stem cells (ISCs) highlighting the most recent progress on markers defining the ISC population and pathways governing intestinal stem cell maintenance and differentiation. Furthermore we review their interaction with other stem cell related pathways. Finally we give an overview of alteration of these pathways in human inflammatory gastrointestinal diseases.We highlight the complex network of interactions occurring among different pathways and put in perspective the many layers of regulation that occur in maintaining the intestinal homeostasis.Understanding the involvement of ISCs in inflammatory diseases can potentially lead to new therapeutic approaches to treat inflammatory GI pathologies such as IBD and celiac disease and could reveal the molecular mechanisms leading to the pathogenesis of dysplasia and cancer in inflammatory chronic conditions. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► The two stem cell populations in the small intestine have distinct markers. ► Critical pathways in the intestine are Wnt, Notch, Hedgehog, BMP, and Hippo/Yap. ► Alterations of stem cell signaling pathways occur in gut inflammatory pathologies.
Keywords: Abbreviations; GI; gastrointestinal; BrdU; bromodeoxyuridine; LRC; label-retaining cells; CBC; crypt base columnar cells; ISC; intestinal stem cell; DSS; dextran sodium sulfate; KO; knockout; FAP; familial adenomatous polyposis; bHLH; basic helix-loop-helix; IBD; inflammatory bowel disease; CD; Crohn's disease; UC; ulcerative colitis; SNP; single nucleotide polymorphism; GSI; γ-secretase inhibitor; SMC; smooth muscle cells; ISEMF; intestinal subepithelial myofibroblastsIntestinal stem cell; Wnt; Notch; Hedgehog; Bmp; Hippo
Biochemistry of epidermal stem cells by Richard L. Eckert; Gautam Adhikary; Sivaprakasam Balasubramanian; Ellen A. Rorke; Mohan C. Vemuri; Shayne E. Boucher; Jackie R. Bickenbach; Candace Kerr (pp. 2427-2434).
The epidermis is an important protective barrier that is essential for maintenance of life. Maintaining this barrier requires continuous cell proliferation and differentiation. Moreover, these processes must be balanced to produce a normal epidermis. The stem cells of the epidermis reside in specific locations in the basal epidermis, hair follicle and sebaceous glands and these cells are responsible for replenishment of this tissue.A great deal of effort has gone into identifying protein epitopes that mark stem cells, in identifying stem cell niche locations, and in understanding how stem cell populations are related. We discuss these studies as they apply to understanding normal epidermal homeostasis and skin cancer.An assortment of stem cell markers have been identified that permit assignment of stem cells to specific regions of the epidermis, and progress has been made in understanding the role of these cells in normal epidermal homeostasis and in conditions of tissue stress. A key finding is the multiple stem cell populations exist in epidermis that give rise to different structures, and that multiple stem cell types may contribute to repair in damaged epidermis.Understanding epidermal stem cell biology is likely to lead to important therapies for treating skin diseases and cancer, and will also contribute to our understanding of stem cells in other systems. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Epidermal stem cells are an important model for study of tissue maintenance. ► Molecular markers identify specific epidermal stem cell populations. ► Specific signaling cascades are involved in regulating stem cell survival. ► Specific stem cells have been identified in epidermal cancers.
Keywords: Abbreviations; HF; hair follicle; IF; interfollicular; SG; sebaceous gland; miRNA; microRNA; SCC; squamous cell carcinoma; KSC; keratinocyte stem cellStem cell; Hair follicle; Interfollicular stem cell; Epidermis; Keratinocyte
Signaling mechanisms regulating adult neural stem cells and neurogenesis by Roland Faigle; Hongjun Song (pp. 2435-2448).
Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain.Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity.Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies.A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Adult neurogenesis is regulated via both extrinsic environmental influences and intrinsic genetic factors. ► We review individual signaling mechanisms and their cross-talk in regulating adult neurogenesis. ► We highlight emerging principles in the growing field of adult neural stem cell biology.
Keywords: Adult neurogenesis; Neural stem cell; Niche; Signaling
Cardiac stem cell therapy to modulate inflammation upon myocardial infarction by F. van den Akker; J.C. Deddens; P.A. Doevendans; J.P.G. Sluijter (pp. 2449-2458).
After myocardial infarction (MI) a local inflammatory reaction clears the damaged myocardium from dead cells and matrix debris at the onset of scar formation. The intensity and duration of this inflammatory reaction are intimately linked to post-infarct remodeling and cardiac dysfunction. Strikingly, treatment with standard anti-inflammatory drugs worsens clinical outcome, suggesting a dual role of inflammation in the cardiac response to injury. Cardiac stem cell therapy with different stem or progenitor cells, e.g. mesenchymal stem cells (MSC), was recently found to have beneficial effects, mostly related to paracrine actions. One of the suggested paracrine effects of cell therapy is modulation of the immune system.MSC are reported to interact with several cells of the immune system and could therefore be an excellent means to reduce detrimental inflammatory reactions and promote the switch to the healing phase upon cardiac injury. This review focuses on the potential use of MSC therapy for post-MI inflammation. To understand the effects MSC might have on the post-MI heart the cellular and molecular changes in the myocardium after MI need to be understood.By studying the general pathways involved in immunomodulation, and examining the interactions with cell types important for post-MI inflammation, it becomes clear that MSC treatment might provide a new therapeutic opportunity to improve cardiac outcome after acute injury.Using stem cells to target the post-MI inflammation is a novel therapy which could have considerable clinical implications. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► The immune response after MI is intimately linked to long term cardiac outcome. ► Neutrophils and macrophages play important roles in post-MI inflammation. ► Stem cells can modulate the immune response both in vitro and in vivo. ► MSC could be used as therapy for inflammation after acute cardiac injury.
Keywords: Mesenchymal stem cell; Myocardial infarction; Inflammation; Mononuclear cell; Neutrophil; T-cell
Biochemistry and biology: Heart-to-heart to investigate cardiac progenitor cells by Isotta Chimenti; Elvira Forte; Francesco Angelini; Elisa Messina; Alessandro Giacomello (pp. 2459-2469).
Cardiac regenerative medicine is a rapidly evolving field, with promising future developments for effective personalized treatments. Several stem/progenitor cells are candidates for cardiac cell therapy, and emerging evidence suggests how multiple metabolic and biochemical pathways strictly regulate their fate and renewal.In this review, we will explore a selection of areas of common interest for biology and biochemistry concerning stem/progenitor cells, and in particular cardiac progenitor cells. Numerous regulatory mechanisms have been identified that link stem cell signaling and functions to the modulation of metabolic pathways, and vice versa. Pharmacological treatments and culture requirements may be exploited to modulate stem cell pluripotency and self-renewal, possibly boosting their regenerative potential for cell therapy.Mitochondria and their many related metabolites and messengers, such as oxygen, ROS, calcium and glucose, have a crucial role in regulating stem cell fate and the balance of their functions, together with many metabolic enzymes. Furthermore, protein biochemistry and proteomics can provide precious clues on the definition of different progenitor cell populations, their physiology and their autocrine/paracrine regulatory/signaling networks.Interdisciplinary approaches between biology and biochemistry can provide productive insights on stem/progenitor cells, allowing the development of novel strategies and protocols for effective cardiac cell therapy clinical translation. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Metabolism tightly controls cardiac stem cell biology and fate. ► Oxygen, calcium and glucose levels regulate stem cell differentiation. ► Signaling networks can be modulated to control stem cell fate. ► Proteomics offers powerful discovery tools to study stem cell biology.
Keywords: Cardiac progenitor cells; Hypoxia; Calcium signaling; Paracrine effects; Cardiogenic pharmacological treatments; Cardiogenic small molecules
Bioreactors to influence stem cell fate: Augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems by Andrew B. Yeatts; Daniel T. Choquette; John P. Fisher (pp. 2470-2480).
Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro.This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems.The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased.Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Perfusion bioreactors can regulate MSC exposure to shear stress and oxygen tension ► Shear stress and oxygen tension can enhance MSC differentiation pathways ► Bioreactors can be used to regulate oxygen and shear to direct MSC differentiation
Keywords: Bioreactor; Mesenchymal stem cell; Cell signaling; Shear; Oxygen tension
Developmental signaling pathways in cancer stem cells of solid tumors by Christina Karamboulas; Laurie Ailles (pp. 2481-2495).
The intricate regulation of several signaling pathways is essential for embryonic development and adult tissue homeostasis. Cancers commonly display aberrant activity within these pathways. A population of cells identified in several cancers, termed cancer stem cells (CSCs) show similar properties to normal stem cells and evidence suggests that altered developmental signaling pathways play an important role in maintaining CSCs and thereby the tumor itself.This review will focus on the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon cancers. We describe the roles these pathways play in normal tissue homeostasis through the regulation of stem cell fate in these three tissues, and the experimental evidence indicating that the role of these pathways in cancers of these is directly linked to CSCs.A large body of evidence is accumulating to indicate that the deregulation of Notch, Wnt and Hedgehog pathways play important roles in both normal and cancer stem cells. We are only beginning to understand how these pathways interact, how they are coordinated during normal development and adult tissue homeostasis, and how they are deregulated during cancer. However, it is becoming increasingly clear that if we are to target CSCs therapeutically, it will likely be necessary to develop combination therapies.If CSCs are the driving force behind tumor maintenance and growth then understanding the molecular mechanisms regulating CSCs is essential. Such knowledge will contribute to better targeted therapies that could significantly enhance cancer treatments and patient survival. This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Cancer may be viewed as a disease in which normal cellular homeostasis is disrupted. ► Developmental signaling pathways are often deregulated in cancer. ► Cancer stem cells have been identified and characterized in many solid tumors. ► Breast, brain and colon cancer stem cells are the most well-characterized. ► Hh, Notch and Wnt pathways play important roles in normal and cancer stem cells.
Keywords: Cancer stem cells; Notch; Hedgehog; Wnt
The cancer stem cell niche(s): The crosstalk between glioma stem cells and their microenvironment by Alina Filatova; Till Acker; Boyan K. Garvalov (pp. 2496-2508).
The initiation and progression of various types of tumors, including glioma, are driven by a population of cells with stem cell properties. Glioma stem cells (GSCs) are located in specialized microenvironments (niches) within tumors. These niches represent the hallmarks of malignant gliomas (vascular proliferations, hypoxia/necrosis) and bear analogy to the microenvironments in which physiological stem cells in the brain are found.Here we review the progress that has been made towards uncovering the function of the perivascular and the hypoxic niche and the molecular pathways that control the properties of GSCs within them. We propose models of how the different niches and GSC pools in them interact with each other.GSCs are not merely passive residents of their niches, but actively contribute to the shaping of the niches through a complex crosstalk with different components of the microenvironment. For example, GSCs play a dominant role in promoting new blood vessel formation through a variety of mechanisms, including the hypoxia dependent stimulation of angiogenesis, recruitment of endothelial progenitor cells and direct transdifferentiation into endothelial cells. Recent work has also revealed that GSCs can recruit and modulate the function of various immune cells to suppress anti-tumor immune responses and to foster tumor-promoting inflammation, which in turn could support the maintenance of GSCs.These findings underscore the central role of the GSC microenvironment in driving glioma progression making the GSC niche a prime therapeutic target for the design of therapies aimed at eradicating GSCs.This article is part of a Special Issue entitled Biochemistry of Stem Cells.► Glioma stem cells (GSCs) are located in perivascular and hypoxic niches. ► GSCs and their niches intricately crosstalk, regulating each other's function. ► HIF-1α and HIF-2α are the key regulators of GSCs within the hypoxic niche. ► Notch signaling plays a key role within the perivascular niche. ► Niches are prime targets in tumor therapy as they maintain cancer stem cells.
Keywords: Hypoxia inducible factor; Glioma; Perivascular niche; Hypoxic niche; Tumor associated macrophage; Cancer stem cell