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138-398: A specialized type of differentiation, known as terminal differentiation , is of importance in some tissues, including vertebrate nervous system , striated muscle , epidermis and gut. During terminal differentiation, a precursor cell formerly capable of cell division permanently leaves the cell cycle, dismantles the cell cycle machinery and often expresses a range of genes characteristic of

276-442: A mesendodermal fate, with Oct4 actively suppressing genes associated with a neural ectodermal fate. Similarly, increased levels of Sox2 and decreased levels of Oct4 promote differentiation towards a neural ectodermal fate, with Sox2 inhibiting differentiation towards a mesendodermal fate. Regardless of the lineage cells differentiate down, suppression of NANOG has been identified as a necessary prerequisite for differentiation. In

414-441: A mesendodermal fate, with Oct4 actively suppressing genes associated with a neural ectodermal fate. Similarly, increased levels of Sox2 and decreased levels of Oct4 promote differentiation towards a neural ectodermal fate, with Sox2 inhibiting differentiation towards a mesendodermal fate. Regardless of the lineage cells differentiate down, suppression of NANOG has been identified as a necessary prerequisite for differentiation. In

552-455: A purine analog, has proven to induce dedifferentiation in myotubes . These manifestly dedifferentiated cells—now performing essentially as stem cells—could then redifferentiate into osteoblasts and adipocytes . Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species . Each cell type is defined by its particular pattern of regulated gene expression . Cell differentiation

690-454: A purine analog, has proven to induce dedifferentiation in myotubes . These manifestly dedifferentiated cells—now performing essentially as stem cells—could then redifferentiate into osteoblasts and adipocytes . Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species . Each cell type is defined by its particular pattern of regulated gene expression . Cell differentiation

828-655: A cell's size, shape, membrane potential , metabolic activity , and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics . With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Metabolic composition, however, gets dramatically altered where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having

966-406: A conformational change in the receptor. The shape of the cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic activity. The receptor then catalyzes reactions that phosphorylate other proteins, activating them. A cascade of phosphorylation reactions eventually activates a dormant transcription factor or cytoskeletal protein, thus contributing to the differentiation process in

1104-406: A conformational change in the receptor. The shape of the cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic activity. The receptor then catalyzes reactions that phosphorylate other proteins, activating them. A cascade of phosphorylation reactions eventually activates a dormant transcription factor or cytoskeletal protein, thus contributing to the differentiation process in

1242-455: A cup-like shape called the "egg cylinder" as well as chromosomal alteration in which one of the X-chromosomes under random inactivation in the early stage of the egg cylinder, known as X-inactivation . During this development, the egg cylinder epiblast cells are systematically targeted by Fibroblast growth factors , Wnt signaling, and other inductive factors via the surrounding yolk sac and

1380-430: A few closely related cell types. Finally, unipotent cells can differentiate into only one cell type, but are capable of self-renewal . In cytopathology , the level of cellular differentiation is used as a measure of cancer progression. " Grade " is a marker of how differentiated a cell in a tumor is. Three basic categories of cells make up the mammalian body: germ cells , somatic cells , and stem cells . Each of

1518-427: A few closely related cell types. Finally, unipotent cells can differentiate into only one cell type, but are capable of self-renewal . In cytopathology , the level of cellular differentiation is used as a measure of cancer progression. " Grade " is a marker of how differentiated a cell in a tumor is. Three basic categories of cells make up the mammalian body: germ cells , somatic cells , and stem cells . Each of

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1656-439: A fully totipotent cell, but instead into a "complex cellular variation" of totipotency. The human development model can be used to describe how totipotent cells arise. Human development begins when a sperm fertilizes an egg and the resulting fertilized egg creates a single totipotent cell, a zygote . In the first hours after fertilization, this zygote divides into identical totipotent cells, which can later develop into any of

1794-659: A hollow sphere of cells, called a blastocyst . The blastocyst has an outer layer of cells, and inside this hollow sphere, there is a cluster of cells called the inner cell mass . The cells of the inner cell mass go on to form virtually all of the tissues of the human body. Although the cells of the inner cell mass can form virtually every type of cell found in the human body, they cannot form an organism. These cells are referred to as pluripotent . Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include: A pathway that

1932-656: A hollow sphere of cells, called a blastocyst . The blastocyst has an outer layer of cells, and inside this hollow sphere, there is a cluster of cells called the inner cell mass . The cells of the inner cell mass go on to form virtually all of the tissues of the human body. Although the cells of the inner cell mass can form virtually every type of cell found in the human body, they cannot form an organism. These cells are referred to as pluripotent . Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include: A pathway that

2070-854: A large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through histone modification and/or pioneer factors . In particular, it is important to know whether a nucleosome is covering a given genomic binding site or not. This can be determined using a chromatin immunoprecipitation assay. DNA-nucleosome interactions are characterized by two states: either tightly bound by nucleosomes and transcriptionally inactive, called heterochromatin , or loosely bound and usually, but not always, transcriptionally active, called euchromatin . The epigenetic processes of histone methylation and acetylation, and their inverses demethylation and deacetylation primarily account for these changes. The effects of acetylation and deacetylation are more predictable. An acetyl group

2208-853: A large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through histone modification and/or pioneer factors . In particular, it is important to know whether a nucleosome is covering a given genomic binding site or not. This can be determined using a chromatin immunoprecipitation assay. DNA-nucleosome interactions are characterized by two states: either tightly bound by nucleosomes and transcriptionally inactive, called heterochromatin , or loosely bound and usually, but not always, transcriptionally active, called euchromatin . The epigenetic processes of histone methylation and acetylation, and their inverses demethylation and deacetylation primarily account for these changes. The effects of acetylation and deacetylation are more predictable. An acetyl group

2346-400: A non-pluripotent cell, typically an adult somatic cell , by inducing a "forced" expression of certain genes and transcription factors . These transcription factors play a key role in determining the state of these cells and also highlights the fact that these somatic cells do preserve the same genetic information as early embryonic cells. The ability to induce cells into a pluripotent state

2484-404: A pre-implantation epiblast; such epiblast is able to generate the entire fetus, and one epiblast cell is able to contribute to all cell lineages if injected into another blastocyst. On the other hand, several marked differences can be observed between the pre- and post-implantation epiblasts, such as their difference in morphology, in which the epiblast after implantation changes its morphology into

2622-432: A small number of genes, including OCT4 and NANOG, are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation. While the DNA sequence of most cells of an organism is the same, the binding patterns of transcription factors and the corresponding gene expression patterns are different. To

2760-430: A small number of genes, including OCT4 and NANOG, are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation. While the DNA sequence of most cells of an organism is the same, the binding patterns of transcription factors and the corresponding gene expression patterns are different. To

2898-451: A soft matrix without the use of diffusing factors. The stem-cell properties appear to be linked to tension in the cells' actin network. One identified mechanism for matrix-induced differentiation is tension-induced proteins, which remodel chromatin in response to mechanical stretch. The RhoA pathway is also implicated in this process. A billion-years-old, likely holozoan , protist , Bicellum brasieri with two types of cells, shows that

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3036-448: A soft matrix without the use of diffusing factors. The stem-cell properties appear to be linked to tension in the cells' actin network. One identified mechanism for matrix-induced differentiation is tension-induced proteins, which remodel chromatin in response to mechanical stretch. The RhoA pathway is also implicated in this process. A billion-years-old, likely holozoan , protist , Bicellum brasieri with two types of cells, shows that

3174-449: A stem cell that has the potential to differentiate into any of the three germ layers : endoderm (gut, lungs and liver), mesoderm (muscle, skeleton, blood vascular, urogenital, dermis), or ectoderm (nervous, sensory, epidermis), but not into extra-embryonic tissues like the placenta or yolk sac. Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs, are a type of pluripotent stem cell artificially derived from

3312-844: Is Wnt signaling pathway . The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells. On the other hand, disruption of β-catenin , a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors. Growth factors comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include bone morphogenetic proteins , transforming growth factors (TGFs), and fibroblast growth factors (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to Smad proteins. Depletion of growth factors promotes

3450-796: Is Wnt signaling pathway . The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells. On the other hand, disruption of β-catenin , a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors. Growth factors comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include bone morphogenetic proteins , transforming growth factors (TGFs), and fibroblast growth factors (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to Smad proteins. Depletion of growth factors promotes

3588-475: Is also consistent with the state of euchromatin found in ESCs. Due to their great similarity to ESCs, the medical and research communities are interested iPSCs. iPSCs could potentially have the same therapeutic implications and applications as ESCs but without the controversial use of embryos in the process, a topic of great bioethical debate. The induced pluripotency of somatic cells into undifferentiated iPS cells

3726-542: Is also research on converting multipotent cells into pluripotent cells. Multipotent cells are found in many, but not all human cell types. Multipotent cells have been found in cord blood , adipose tissue, cardiac cells, bone marrow , and mesenchymal stem cells (MSCs) which are found in the third molar . MSCs may prove to be a valuable source for stem cells from molars at 8–10 years of age, before adult dental calcification. MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes. In biology, oligopotency

3864-401: Is associated with gene activation, whereas trimethylation of lysine 27 on histone 3 represses genes During differentiation, stem cells change their gene expression profiles. Recent studies have implicated a role for nucleosome positioning and histone modifications during this process. There are two components of this process: turning off the expression of embryonic stem cell (ESC) genes, and

4002-472: Is associated with gene activation, whereas trimethylation of lysine 27 on histone 3 represses genes During differentiation, stem cells change their gene expression profiles. Recent studies have implicated a role for nucleosome positioning and histone modifications during this process. There are two components of this process: turning off the expression of embryonic stem cell (ESC) genes, and the activation of cell fate genes. Lysine specific demethylase 1 ( KDM1A )

4140-424: Is based on mechanical signalling by the cytoskeleton using Embryonic differentiation waves . The mechanical signal is then epigenetically transduced via signal transduction systems (of which specific molecules such as Wnt are part) to result in differential gene expression. In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate

4278-424: Is based on mechanical signalling by the cytoskeleton using Embryonic differentiation waves . The mechanical signal is then epigenetically transduced via signal transduction systems (of which specific molecules such as Wnt are part) to result in differential gene expression. In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate

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4416-446: Is controlled by reduction of Sox2/Oct4 dimerization on SoxOct DNA elements controlling naive pluripotency. Primed pluripotent stem cells from different species could be reset to naive state using a cocktail containing Klf4 and Sox2 or "super-Sox" − a chimeric transcription factor with enhanced capacity to dimerize with Oct4. The baseline stem cells commonly used in science that are referred as embryonic stem cells (ESCs) are derived from

4554-555: Is either added to or removed from the positively charged Lysine residues in histones by enzymes called histone acetyltransferases or histone deactylases , respectively. The acetyl group prevents Lysine's association with the negatively charged DNA backbone. Methylation is not as straightforward, as neither methylation nor demethylation consistently correlate with either gene activation or repression. However, certain methylations have been repeatedly shown to either activate or repress genes. The trimethylation of lysine 4 on histone 3 (H3K4Me3)

4692-555: Is either added to or removed from the positively charged Lysine residues in histones by enzymes called histone acetyltransferases or histone deactylases , respectively. The acetyl group prevents Lysine's association with the negatively charged DNA backbone. Methylation is not as straightforward, as neither methylation nor demethylation consistently correlate with either gene activation or repression. However, certain methylations have been repeatedly shown to either activate or repress genes. The trimethylation of lysine 4 on histone 3 (H3K4Me3)

4830-524: Is facilitated by active DNA demethylation involving the DNA base excision repair enzymatic pathway. This pathway entails erasure of CpG methylation (5mC) in primordial germ cells via the initial conversion of 5mC to 5-hydroxymethylcytosine (5hmC), a reaction driven by high levels of the ten-eleven dioxygenase enzymes TET-1 and TET-2 . In cell biology, pluripotency (Latin: pluripotentia , lit.   'ability for many [things]') refers to

4968-408: Is guided by the cell adhesion molecules consisting of four amino acids, arginine , glycine , asparagine , and serine , is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm , mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming

5106-408: Is guided by the cell adhesion molecules consisting of four amino acids, arginine , glycine , asparagine , and serine , is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm , mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming

5244-420: Is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog , in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells. The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation

5382-419: Is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog , in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells. The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation

5520-532: Is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them. Expression of Shh (Sonic hedgehog) upregulates

5658-532: Is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them. Expression of Shh (Sonic hedgehog) upregulates

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5796-417: Is often controlled by cell signaling . Many of the signal molecules that convey information from cell to cell during the control of cellular differentiation are called growth factors . Although the details of specific signal transduction pathways vary, these pathways often share the following general steps. A ligand produced by one cell binds to a receptor in the extracellular region of another cell, inducing

5934-417: Is often controlled by cell signaling . Many of the signal molecules that convey information from cell to cell during the control of cellular differentiation are called growth factors . Although the details of specific signal transduction pathways vary, these pathways often share the following general steps. A ligand produced by one cell binds to a receptor in the extracellular region of another cell, inducing

6072-426: Is regulated by various regulators, including PLETHORA 1 and PLETHORA 2 ; and PLETHORA 3 , PLETHORA 5 , and PLETHORA 7 , whose expression were found by Kareem to be auxin -provoked. (These are also known as PLT1, PLT2, PLT3, PLT5, PLT7, and expressed by genes of the same names.) As of 2019 , this is expected to open up future research into pluripotency in root tissues. Multipotency is when progenitor cells have

6210-449: Is still intact in the post-implantation epiblast, as demonstrated by the conserved expression of Nanog , Fut4 , and Oct-4 in EpiSCs, until somitogenesis and can be reversed midway through induced expression of Oct-4 . Un-induced pluripotency has been observed in root meristem tissue culture, especially by Kareem et al 2015, Kim et al 2018, and Rosspopoff et al 2017. This pluripotency

6348-542: Is termed a "bivalent domain" and rendering these genes sensitive to rapid induction or repression. Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase -mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility. The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes. Upon differentiation,

6486-493: Is termed a "bivalent domain" and rendering these genes sensitive to rapid induction or repression. Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase -mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility. The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes. Upon differentiation,

6624-404: Is the ability of progenitor cells to differentiate into a few cell types . It is a degree of potency . Examples of oligopotent stem cells are the lymphoid or myeloid stem cells. A lymphoid cell specifically, can give rise to various blood cells such as B and T cells, however, not to a different blood cell type like a red blood cell. Examples of progenitor cells are vascular stem cells that have

6762-463: Is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, et al. on aberrant epigenomic programming in human induced pluripotent stem cells . As induced pluripotent stem cells (iPSCs) are thought to mimic embryonic stem cells in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction,

6900-462: Is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, et al. on aberrant epigenomic programming in human induced pluripotent stem cells . As induced pluripotent stem cells (iPSCs) are thought to mimic embryonic stem cells in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction,

7038-408: Is thought to prevent the use of enhancer regions of pluripotency genes, thereby inhibiting their transcription. It interacts with Mi-2/NuRD complex (nucleosome remodelling and histone deacetylase) complex, giving an instance where methylation and acetylation are not discrete and mutually exclusive, but intertwined processes. A final question to ask concerns the role of cell signaling in influencing

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7176-461: Is thus a transition of a cell from one cell type to another and it involves a switch from one pattern of gene expression to another. Cellular differentiation during development can be understood as the result of a gene regulatory network . A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive input and create output elsewhere in the network. The systems biology approach to developmental biology emphasizes

7314-460: Is thus a transition of a cell from one cell type to another and it involves a switch from one pattern of gene expression to another. Cellular differentiation during development can be understood as the result of a gene regulatory network . A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive input and create output elsewhere in the network. The systems biology approach to developmental biology emphasizes

7452-484: The epigenome , and the majority of current knowledge about the subject consists of speculations on plausible candidate regulators of epigenetic remodeling. We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change. The first major candidate

7590-443: The activation of cell fate genes. Lysine specific demethylase 1 ( KDM1A ) is thought to prevent the use of enhancer regions of pluripotency genes, thereby inhibiting their transcription. It interacts with Mi-2/NuRD complex (nucleosome remodelling and histone deacetylase) complex, giving an instance where methylation and acetylation are not discrete and mutually exclusive, but intertwined processes. A final question to ask concerns

7728-473: The actual reprogramming of somatic cells in order to induce pluripotency. It has been theorized that certain epigenetic factors might actually work to clear the original somatic epigenetic marks in order to acquire the new epigenetic marks that are part of achieving a pluripotent state. Chromatin is also reorganized in iPSCs and becomes like that found in ESCs in that it is less condensed and therefore more accessible. Euchromatin modifications are also common which

7866-560: The approximately 37.2 trillion (3.72x10 ) cells in an adult human has its own copy or copies of the genome except certain cell types , such as red blood cells , that lack nuclei in their fully differentiated state. Most cells are diploid ; they have two copies of each chromosome . Such cells, called somatic cells, make up most of the human body, such as skin and muscle cells. Cells differentiate to specialize for different functions. Germ line cells are any line of cells that give rise to gametes —eggs and sperm—and thus are continuous through

8004-558: The approximately 37.2 trillion (3.72x10) cells in an adult human has its own copy or copies of the genome except certain cell types , such as red blood cells , that lack nuclei in their fully differentiated state. Most cells are diploid ; they have two copies of each chromosome . Such cells, called somatic cells, make up most of the human body, such as skin and muscle cells. Cells differentiate to specialize for different functions. Germ line cells are any line of cells that give rise to gametes —eggs and sperm—and thus are continuous through

8142-633: The authors conducted whole-genome profiling of DNA methylation patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines. Female adipose cells, lung fibroblasts , and foreskin fibroblasts were reprogrammed into induced pluripotent state with the OCT4 , SOX2 , KLF4 , and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, et al. observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of CG dinucleotides in ESCs and iPSCs were methylated,

8280-587: The authors conducted whole-genome profiling of DNA methylation patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines. Female adipose cells, lung fibroblasts , and foreskin fibroblasts were reprogrammed into induced pluripotent state with the OCT4 , SOX2 , KLF4 , and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, et al. observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of CG dinucleotides in ESCs and iPSCs were methylated,

8418-417: The authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both

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8556-417: The authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both

8694-457: The capacity to become both endothelial or smooth muscle cells. In cell biology , a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type. It is currently unclear if true unipotent stem cells exist. Hepatoblasts, which differentiate into hepatocytes (which constitute most of the liver ) or cholangiocytes (epithelial cells of the bile duct), are bipotent. A close synonym for unipotent cell

8832-484: The cell to pull against the matrix at focal adhesions, which triggers a cellular mechano-transducer to generate a signal to be informed what force is needed to deform the matrix. To determine the key players in matrix-elasticity-driven lineage specification in MSCs, different matrix microenvironments were mimicked. From these experiments, it was concluded that focal adhesions of the MSCs were the cellular mechano-transducer sensing

8970-437: The cell to pull against the matrix at focal adhesions, which triggers a cellular mechano-transducer to generate a signal to be informed what force is needed to deform the matrix. To determine the key players in matrix-elasticity-driven lineage specification in MSCs, different matrix microenvironments were mimicked. From these experiments, it was concluded that focal adhesions of the MSCs were the cellular mechano-transducer sensing

9108-485: The cell's final function (e.g. myosin and actin for a muscle cell). Differentiation may continue to occur after terminal differentiation if the capacity and functions of the cell undergo further changes. Among dividing cells, there are multiple levels of cell potency , which is the cell's ability to differentiate into other cell types. A greater potency indicates a larger number of cell types that can be derived. A cell that can differentiate into all cell types, including

9246-485: The cell's final function (e.g. myosin and actin for a muscle cell). Differentiation may continue to occur after terminal differentiation if the capacity and functions of the cell undergo further changes. Among dividing cells, there are multiple levels of cell potency , which is the cell's ability to differentiate into other cell types. A greater potency indicates a larger number of cell types that can be derived. A cell that can differentiate into all cell types, including

9384-411: The cellular mechanisms underlying these switches, in animal species these are very different from the well-characterized gene regulatory mechanisms of bacteria , and even from those of the animals' closest unicellular relatives . Specifically, cell differentiation in animals is highly dependent on biomolecular condensates of regulatory proteins and enhancer DNA sequences. Cellular differentiation

9522-410: The cellular mechanisms underlying these switches, in animal species these are very different from the well-characterized gene regulatory mechanisms of bacteria , and even from those of the animals' closest unicellular relatives . Specifically, cell differentiation in animals is highly dependent on biomolecular condensates of regulatory proteins and enhancer DNA sequences. Cellular differentiation

9660-434: The decision to adopt a stem, progenitor, or mature cell fate This section will focus primarily on mammalian stem cells . In systems biology and mathematical modeling of gene regulatory networks, cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor ) or oscillatory. The first question that can be asked

9798-433: The decision to adopt a stem, progenitor, or mature cell fate This section will focus primarily on mammalian stem cells . In systems biology and mathematical modeling of gene regulatory networks, cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor ) or oscillatory. The first question that can be asked

9936-402: The development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes

10074-745: The differences of the matrix elasticity. The non-muscle myosin IIa-c isoforms generates the forces in the cell that lead to signaling of early commitment markers. Nonmuscle myosin IIa generates the least force increasing to non-muscle myosin IIc. There are also factors in the cell that inhibit non-muscle myosin II, such as blebbistatin . This makes the cell effectively blind to the surrounding matrix. Researchers have achieved some success in inducing stem cell-like properties in HEK 239 cells by providing

10212-513: The differences of the matrix elasticity. The non-muscle myosin IIa-c isoforms generates the forces in the cell that lead to signaling of early commitment markers. Nonmuscle myosin IIa generates the least force increasing to non-muscle myosin IIc. There are also factors in the cell that inhibit non-muscle myosin II, such as blebbistatin . This makes the cell effectively blind to the surrounding matrix. Researchers have achieved some success in inducing stem cell-like properties in HEK 239 cells by providing

10350-554: The differentiated phenotype. Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression. TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 ( H3K4me3 ) and promote gene activation through histone acetylation. PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what

10488-550: The differentiated phenotype. Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression. TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 ( H3K4me3 ) and promote gene activation through histone acetylation. PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what

10626-643: The differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription. Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency. Retinoic acid can induce differentiation of human and mouse ESCs, and Notch signaling

10764-588: The differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription. Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency. Retinoic acid can induce differentiation of human and mouse ESCs, and Notch signaling

10902-435: The epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Little direct data is available concerning the specific signals that influence the epigenome , and the majority of current knowledge about

11040-418: The evolution of differentiated multicellularity , possibly but not necessarily of animal lineages, occurred at least 1 billion years ago and possibly mainly in freshwater lakes rather than the ocean. Multipotent Cell potency is a cell 's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as

11178-456: The evolution of differentiated multicellularity , possibly but not necessarily of animal lineages, occurred at least 1 billion years ago and possibly mainly in freshwater lakes rather than the ocean. Terminal differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during

11316-401: The first two of which are used in induced pluripotent stem cell (iPSC) reprogramming, along with Klf4 and c-Myc – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency . It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit

11454-400: The first two of which are used in induced pluripotent stem cell (iPSC) reprogramming, along with Klf4 and c-Myc – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency . It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit

11592-635: The former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila . RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of

11730-582: The former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila . RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of

11868-611: The gene activation potential to differentiate into discrete cell types. For example, a hematopoietic stem cell – and this cell type can differentiate itself into several types of blood cell like lymphocytes , monocytes , neutrophils , etc., but it is still ambiguous whether HSC possess the ability to differentiate into brain cells , bone cells or other non-blood cell types. Research related to multipotent cells suggests that multipotent cells may be capable of conversion into unrelated cell types. In another case, human umbilical cord blood stem cells were converted into human neurons. There

12006-493: The gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency , multipotency , oligopotency , and finally unipotency . Totipotency (Latin: totipotentia , lit.   'ability for all [things]') is the ability of a single cell to divide and produce all of the differentiated cells in an organism . Spores and zygotes are examples of totipotent cells. In

12144-557: The generations. Stem cells, on the other hand, have the ability to divide for indefinite periods and to give rise to specialized cells. They are best described in the context of normal human development. Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming

12282-556: The generations. Stem cells, on the other hand, have the ability to divide for indefinite periods and to give rise to specialized cells. They are best described in the context of normal human development. Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming

12420-453: The genus Volvox , a model system for studying how unicellular organisms can evolve into multicellular organisms. In Volvox carteri , the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell. Since each cell, regardless of cell type, possesses

12558-450: The genus Volvox , a model system for studying how unicellular organisms can evolve into multicellular organisms. In Volvox carteri , the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell. Since each cell, regardless of cell type, possesses

12696-484: The importance of investigating how developmental mechanisms interact to produce predictable patterns ( morphogenesis ). However, an alternative view has been proposed recently . Based on stochastic gene expression, cellular differentiation is the result of a Darwinian selective process occurring among cells. In this frame, protein and gene networks are the result of cellular processes and not their cause. While evolutionarily conserved molecular processes are involved in

12834-481: The importance of investigating how developmental mechanisms interact to produce predictable patterns ( morphogenesis ). However, an alternative view has been proposed recently. Based on stochastic gene expression, cellular differentiation is the result of a Darwinian selective process occurring among cells. In this frame, protein and gene networks are the result of cellular processes and not their cause. While evolutionarily conserved molecular processes are involved in

12972-410: The induction of mouse cells. These induced cells exhibit similar traits to those of embryonic stem cells (ESCs) but do not require the use of embryos. Some of the similarities between ESCs and iPSCs include pluripotency, morphology , self-renewal ability, a trait that implies that they can divide and replicate indefinitely, and gene expression . Epigenetic factors are also thought to be involved in

13110-408: The laboratory, cells can change shape or may lose specific properties such as protein expression—which processes are also termed dedifferentiation. Some hypothesize that dedifferentiation is an aberration that likely results in cancers , but others explain it as a natural part of the immune response that was lost to humans at some point of evolution. A newly discovered molecule dubbed reversine ,

13248-406: The laboratory, cells can change shape or may lose specific properties such as protein expression—which processes are also termed dedifferentiation. Some hypothesize that dedifferentiation is an aberration that likely results in cancers , but others explain it as a natural part of the immune response that was lost to humans at some point of evolution. A newly discovered molecule dubbed reversine ,

13386-471: The lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot. Other important mechanisms fall under the category of asymmetric cell divisions , divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling. In

13524-469: The lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot. Other important mechanisms fall under the category of asymmetric cell divisions , divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling. In

13662-410: The likely existence of further such mechanisms. In order to fulfill the purpose of regenerating a variety of tissues, adult stems are known to migrate from their niches, adhere to new extracellular matrices (ECM) and differentiate. The ductility of these microenvironments are unique to different tissue types. The ECM surrounding brain, muscle and bone tissues range from soft to stiff. The transduction of

13800-410: The likely existence of further such mechanisms. In order to fulfill the purpose of regenerating a variety of tissues, adult stems are known to migrate from their niches, adhere to new extracellular matrices (ECM) and differentiate. The ductility of these microenvironments are unique to different tissue types. The ECM surrounding brain, muscle and bone tissues range from soft to stiff. The transduction of

13938-429: The mechanisms of reprogramming (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation. Three transcription factors, OCT4, SOX2, and NANOG –

14076-429: The mechanisms of reprogramming (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation. Three transcription factors, OCT4, SOX2, and NANOG –

14214-448: The placental tissue, is known as totipotent . In mammals, only the zygote and subsequent blastomeres are totipotent, while in plants, many differentiated cells can become totipotent with simple laboratory techniques. A cell that can differentiate into all cell types of the adult organism is known as pluripotent . Such cells are called meristematic cells in higher plants and embryonic stem cells in animals, though some groups report

14352-448: The placental tissue, is known as totipotent . In mammals, only the zygote and subsequent blastomeres are totipotent, while in plants, many differentiated cells can become totipotent with simple laboratory techniques. A cell that can differentiate into all cell types of the adult organism is known as pluripotent . Such cells are called meristematic cells in higher plants and embryonic stem cells in animals, though some groups report

14490-431: The presence of adult pluripotent cells. Virally induced expression of four transcription factors Oct4 , Sox2 , c-Myc , and Klf4 ( Yamanaka factors ) is sufficient to create pluripotent (iPS) cells from adult fibroblasts . A multipotent cell is one that can differentiate into multiple different, but closely related cell types. Oligopotent cells are more restricted than multipotent, but can still differentiate into

14628-429: The presence of adult pluripotent cells. Virally induced expression of four transcription factors Oct4 , Sox2 , c-Myc , and Klf4 ( Yamanaka factors ) is sufficient to create pluripotent (iPS) cells from adult fibroblasts . A multipotent cell is one that can differentiate into multiple different, but closely related cell types. Oligopotent cells are more restricted than multipotent, but can still differentiate into

14766-604: The production of BMI1 , a component of the PcG complex that recognizes H3K27me3 . This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway . In culture, Bmi1 mediates the Hedgehog pathway's ability to promote human mammary stem cell self-renewal. In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1

14904-456: The production of BMI1 , a component of the PcG complex that recognizes H3K27me3 . This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway . In culture, Bmi1 mediates the Hedgehog pathway's ability to promote human mammary stem cell self-renewal. In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1

15042-514: The progenitor and embryonic cell lines. In vitro -induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively. Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in cell fate determination , as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of transcription . Second,

15180-514: The progenitor and embryonic cell lines. In vitro -induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively. Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in cell fate determination , as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of transcription . Second,

15318-640: The realm of gene silencing , Polycomb repressive complex 2 , one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3). By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression. PcG knockout ES cells do not differentiate efficiently into

15456-526: The realm of gene silencing , Polycomb repressive complex 2 , one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3). By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression. PcG knockout ES cells do not differentiate efficiently into

15594-416: The role of cell signaling in influencing the epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Little direct data is available concerning the specific signals that influence

15732-419: The same genome . A specialized type of differentiation, known as terminal differentiation , is of importance in some tissues, including vertebrate nervous system , striated muscle , epidermis and gut. During terminal differentiation, a precursor cell formerly capable of cell division permanently leaves the cell cycle, dismantles the cell cycle machinery and often expresses a range of genes characteristic of

15870-419: The same genome, determination of cell type must occur at the level of gene expression. While the regulation of gene expression can occur through cis- and trans-regulatory elements including a gene's promoter and enhancers , the problem arises as to how this expression pattern is maintained over numerous generations of cell division . As it turns out, epigenetic processes play a crucial role in regulating

16008-418: The same genome, determination of cell type must occur at the level of gene expression. While the regulation of gene expression can occur through cis- and trans-regulatory elements including a gene's promoter and enhancers , the problem arises as to how this expression pattern is maintained over numerous generations of cell division . As it turns out, epigenetic processes play a crucial role in regulating

16146-511: The same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of cytosine methylation in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities, DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs. However, upon examining methylation patterns more closely,

16284-510: The same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of cytosine methylation in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities, DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs. However, upon examining methylation patterns more closely,

16422-465: The skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues. Dedifferentiation , or integration, is a cellular process seen in the more basal life forms in animals, such as worms and amphibians where a differentiated cell reverts to an earlier developmental stage—usually as part of a regenerative process. Dedifferentiation also occurs in plant cells. And, in cell culture in

16560-462: The skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues. Dedifferentiation , or integration, is a cellular process seen in the more basal life forms in animals, such as worms and amphibians where a differentiated cell reverts to an earlier developmental stage—usually as part of a regenerative process. Dedifferentiation also occurs in plant cells. And, in cell culture in

16698-553: The source of embryonic stem cells , becomes pluripotent. Research on Caenorhabditis elegans suggests that multiple mechanisms including RNA regulation may play a role in maintaining totipotency at different stages of development in some species. Work with zebrafish and mammals suggest a further interplay between miRNA and RNA-binding proteins (RBPs) in determining development differences. In mouse primordial germ cells , genome -wide reprogramming leading to totipotency involves erasure of epigenetic imprints. Reprogramming

16836-487: The spectrum of cell potency, totipotency represents the cell with the greatest differentiation potential, being able to differentiate into any embryonic cell, as well as any extraembryonic tissue cell. In contrast, pluripotent cells can only differentiate into embryonic cells. A fully differentiated cell can return to a state of totipotency. The conversion to totipotency is complex and not fully understood. In 2011, research revealed that cells may differentiate not into

16974-419: The stem cells into these cells types is not directed solely by chemokine cues and cell to cell signaling. The elasticity of the microenvironment can also affect the differentiation of mesenchymal stem cells (MSCs which originate in bone marrow.) When MSCs are placed on substrates of the same stiffness as brain, muscle and bone ECM, the MSCs take on properties of those respective cell types. Matrix sensing requires

17112-418: The stem cells into these cells types is not directed solely by chemokine cues and cell to cell signaling. The elasticity of the microenvironment can also affect the differentiation of mesenchymal stem cells (MSCs which originate in bone marrow.) When MSCs are placed on substrates of the same stiffness as brain, muscle and bone ECM, the MSCs take on properties of those respective cell types. Matrix sensing requires

17250-422: The subject consists of speculations on plausible candidate regulators of epigenetic remodeling. We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change. The first major candidate

17388-478: The target cell. Cells and tissues can vary in competence, their ability to respond to external signals. Signal induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate. Yamamoto and Jeffery investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction. Through reciprocal transplants, Yamamoto and Jeffery found that

17526-472: The target cell. Cells and tissues can vary in competence, their ability to respond to external signals. Signal induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate. Yamamoto and Jeffery investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction. Through reciprocal transplants, Yamamoto and Jeffery found that

17664-748: The terminal nature of cellular differentiation and the integrity of lineage commitment; and implies that with the proper tools, all cells are totipotent and may form all kinds of tissue. Some of the possible medical and therapeutic uses for iPSCs derived from patients include their use in cell and tissue transplants without the risk of rejection that is commonly encountered. iPSCs can potentially replace animal models unsuitable as well as in vitro models used for disease research. Findings with respect to epiblasts before and after implantation have produced proposals for classifying pluripotency into two states: "naive" and "primed", representing pre- and post-implantation epiblast, respectively. Naive-to-primed continuum

17802-496: The three germ layers of a human ( endoderm , mesoderm , or ectoderm ), or into cells of the placenta ( cytotrophoblast or syncytiotrophoblast ). After reaching a 16-cell stage, the totipotent cells of the morula differentiate into cells that will eventually become either the blastocyst 's Inner cell mass or the outer trophoblasts . Approximately four days after fertilization and after several cycles of cell division, these totipotent cells begin to specialize. The inner cell mass,

17940-528: The three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation. Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes. Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but cannot maintain

18078-480: The three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation. Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes. Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but cannot maintain

18216-419: The transcription of target genes. While highly expressed, their levels require a precise balance to maintain pluripotency, perturbation of which will promote differentiation towards different lineages based on how the gene expression levels change. Differential regulation of Oct-4 and SOX2 levels have been shown to precede germ layer fate selection. Increased levels of Oct4 and decreased levels of Sox2 promote

18354-418: The transcription of target genes. While highly expressed, their levels require a precise balance to maintain pluripotency, perturbation of which will promote differentiation towards different lineages based on how the gene expression levels change. Differential regulation of Oct-4 and SOX2 levels have been shown to precede germ layer fate selection. Increased levels of Oct4 and decreased levels of Sox2 promote

18492-557: The trophoblast tissue, such that they become instructively specific according to the spatial organization. Another major difference is that post-implantation epiblast stem cells are unable to contribute to blastocyst chimeras , which distinguishes them from other known pluripotent stem cells. Cell lines derived from such post-implantation epiblasts are referred to as epiblast-derived stem cells , which were first derived in laboratory in 2007. Both ESCs and EpiSCs are derived from epiblasts but at difference phases of development. Pluripotency

18630-518: Was initially pioneered in 2006 using mouse fibroblasts and four transcription factors, Oct4 , Sox2 , Klf4 and c- Myc ; this technique, called reprogramming , later earned Shinya Yamanaka and John Gurdon the Nobel Prize in Physiology or Medicine. This was then followed in 2007 by the successful induction of human iPSCs derived from human dermal fibroblasts using methods similar to those used for

18768-475: Was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior. A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice. An alternative model of cellular differentiation during embryogenesis is that positional information

18906-427: Was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior. A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice. An alternative model of cellular differentiation during embryogenesis is that positional information

19044-918: Was originally hailed as the end of the controversial use of embryonic stem cells . However, iPSCs were found to be potentially tumorigenic , and, despite advances, were never approved for clinical stage research in the United States until recently. Currently, autologous iPSC-derived dopaminergic progenitor cells are used in trials for treating Parkinson's disease. Setbacks such as low replication rates and early senescence have also been encountered when making iPSCs, hindering their use as ESCs replacements. Somatic expression of combined transcription factors can directly induce other defined somatic cell fates ( transdifferentiation ); researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (connective tissue cells) into fully functional neurons . This result challenges

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