Editing Cellular differentiation

{{Short description|Transformation of a stem cell to a more specialized cell}}
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{{Distinguish|Cell division}}
[[File:Final stem cell differentiation (1).svg|thumb|upright=1.5|[[Stem cell]] differentiation into various animal tissue types]]
[[File:Stimuli.pdf|thumb|Cell-count distribution featuring cellular differentiation for three types of cells (progenitor <math>z</math>, osteoblast <math>y</math>, and chondrocyte <math>x</math>) exposed to pro-osteoblast stimulus.<ref name=CME>{{cite journal | vauthors = Kryven I, Röblitz S, Schütte C | title = Solution of the chemical master equation by radial basis functions approximation with interface tracking | journal = BMC Systems Biology | volume = 9 | issue = 1 | pages = 67 | date = October 2015 | pmid = 26449665 | pmc = 4599742 | doi = 10.1186/s12918-015-0210-y | doi-access = free }} {{open access}}</ref>]]

'''Cellular differentiation''' is the process in which a [[stem cell]] changes from one type to a differentiated one.<ref>{{cite book | vauthors = Slack JM | date = 2013 | title = Essential Developmental Biology | publisher = Wiley-Blackwell | location = Oxford | isbn = 9780470923511 }}</ref><ref>{{cite journal | vauthors = Slack JM | title = Metaplasia and transdifferentiation: from pure biology to the clinic | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 5 | pages = 369–378 | date = May 2007 | pmid = 17377526 | doi = 10.1038/nrm2146 | s2cid = 3353748 }}</ref> Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a [[multicellular organism]] as it changes from a simple [[zygote]] to a complex system of [[Tissue (biology)|tissues]] and cell types. Differentiation continues in adulthood as [[adult stem cell]]s divide and create fully differentiated [[Cell division|daughter cells]] during tissue repair and during normal cell turnover. Some differentiation occurs in response to [[antigen]] exposure. Differentiation dramatically changes a cell's size, shape, [[membrane potential]], [[metabolism|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<ref>{{cite journal | vauthors = Yanes O, Clark J, Wong DM, Patti GJ, Sánchez-Ruiz A, Benton HP, Trauger SA, Desponts C, Ding S, Siuzdak G | title = Metabolic oxidation regulates embryonic stem cell differentiation | journal = Nature Chemical Biology | volume = 6 | issue = 6 | pages = 411–417 | date = June 2010 | pmid = 20436487 | pmc = 2873061 | doi = 10.1038/nchembio.364 }}</ref> 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 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 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 the placental tissue, is known as ''[[totipotent]]''. In mammals, only the zygote and subsequent [[blastomere]]s 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 [[Meristem|meristematic cells]] in higher plants and [[embryonic stem cell]]s in animals, though some groups report the presence of adult pluripotent cells. Virally induced expression of four transcription factors [[Oct4]], [[Sox2]], {{Nowrap|[[c-Myc]]}}, and [[Klf4]] ([[Yamanaka factors]]) is sufficient to create pluripotent (iPS) cells from adult [[fibroblast]]s.<ref>{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–676 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 | hdl-access = free | s2cid = 1565219 | hdl = 2433/159777 }}</ref> A [[multipotent]] cell is one that can differentiate into multiple different, but closely related cell types.<ref name="Schoeler">{{cite book| vauthors = Schöler HR | veditors = Knoepffler N, Schipanski D, Sorgner SL |title=Humanbiotechnology as Social Challenge|publisher=Ashgate Publishing|year=2007|isbn=978-0-7546-5755-2|page=28|chapter=The Potential of Stem Cells: An Inventory}}</ref> [[Cell potency#Oligopotent|Oligopotent cells]] are more restricted than multipotent, but can still differentiate into a few closely related cell types.<ref name="Schoeler" /> Finally, [[unipotent]] cells can differentiate into only one cell type, but are capable of [[stem cell self-renewal|self-renewal]].<ref name="Schoeler" /> In [[cytopathology]], the level of cellular differentiation is used as a measure of [[cancer]] progression. "[[Grading (tumors)|Grade]]" is a marker of how differentiated a cell in a tumor is.<ref>{{cite web|title=NCI Dictionary of Cancer Terms|url=http://www.cancer.gov/dictionary?CdrID=46445|access-date=1 November 2013|publisher=National Cancer Institute}}</ref>

==Mammalian cell types==
{{See also|List of distinct cell types in the adult human body}}

Three basic categories of cells make up the mammalian body: [[germ cell]]s, [[somatic cell]]s, and [[stem cell]]s. Each of the approximately 37.2 trillion (3.72x10<sup>13</sup>) cells in an adult human has its own copy or copies of the [[genome]] except certain [[cell types]], such as [[red blood cell]]s, 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.<ref>{{Cite book|title = Molecular Cell Biology| vauthors = Lodish H |publisher = New York: W. H. Freeman|year = 2000|isbn = 978-0-7167-3136-8|url = https://archive.org/details/molecularcellbio00lodi|edition = 4th|at = Section 14.2|url-access = registration}}</ref>

Germ line cells are any line of cells that give rise to [[gametes]]—eggs and sperm—and thus are continuous through 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.<ref>{{cite journal | vauthors = Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z | title = Stem cells: past, present, and future | journal = Stem Cell Research & Therapy | volume = 10 | issue = 1 | pages = 68 | date = February 2019 | pmid = 30808416 | doi = 10.1186/s13287-019-1165-5 | doi-access = free | pmc = 6390367 }}</ref>
          
Development begins when a [[sperm]] fertilizes an [[egg (biology)|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 a hollow sphere of cells, called a [[blastocyst]].<ref>{{cite book | vauthors = Kumar R | title = Textbook of Human Embryology | publisher = I.K. International Publishing House | isbn = 9788190675710 | year = 2008 | page = 22 | url = https://books.google.com/books?id=MhmT-avx3DUC&pg=PA22 }}</ref> 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]].<ref>{{Cite book|title = Encyclopedia of Neuroscience| vauthors = Binder MD, Hirokawa N, Windhorst U |publisher = Springer|year = 2009|isbn = 978-3540237358 }}</ref>

Pluripotent stem cells undergo further specialization into [[multipotent]] [[progenitor cell]]s that then give rise to functional cells. Examples of stem and progenitor cells include:<ref>{{cite journal | vauthors = Tesche LJ, Gerber DA | title = Tissue-derived stem and progenitor cells | journal = Stem Cells International | volume = 2010 | pages = 824876 | date = October 2009 | doi = 10.4061/2010/824876 | doi-access = free | pmid = 21048854 | pmc = 2963308 }}</ref><ref>{{cite journal | vauthors = Kriegstein A, Alvarez-Buylla A | title = The glial nature of embryonic and adult neural stem cells | journal = Annual Review of Neuroscience | volume = 32 | issue =  | pages = 149–184 | date = 21 July 2009 | pmid = 19555289 | pmc = 3086722 | doi = 10.1146/annurev.neuro.051508.135600 }}</ref><ref>{{cite journal | vauthors = Morgan JE, Partridge TA | title = Muscle satellite cells | journal = The International Journal of Biochemistry & Cell Biology | volume = 35 | issue = 8 | pages = 1151–1156 | date = August 2003 | pmid = 12757751 | doi = 10.1016/s1357-2725(03)00042-6 }}</ref>
* ''[[Radial glial cell]]s'' (embryonic neural stem cells) that give rise to excitatory neurons in the fetal brain through the process of [[neurogenesis]].<ref>{{cite journal | vauthors = Rakic P | title = Evolution of the neocortex: a perspective from developmental biology | journal = Nature Reviews. Neuroscience | volume = 10 | issue = 10 | pages = 724–735 | date = October 2009 | pmid = 19763105 | pmc = 2913577 | doi = 10.1038/nrn2719 }}</ref><ref>{{cite journal | vauthors = Lui JH, Hansen DV, Kriegstein AR | title = Development and evolution of the human neocortex | journal = Cell | volume = 146 | issue = 1 | pages = 18–36 | date = July 2011 | pmid = 21729779 | pmc = 3610574 | doi = 10.1016/j.cell.2011.06.030 }}</ref><ref>{{cite journal | vauthors = Rash BG, Ackman JB, Rakic P | title = Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation | journal = Science Advances | volume = 2 | issue = 2 | pages = e1501733 | date = February 2016 | pmid = 26933693 | pmc = 4771444 | doi = 10.1126/sciadv.1501733 | bibcode = 2016SciA....2E1733R }}</ref>
* ''[[Hematopoietic stem cells]]'' (adult stem cells) from the [[bone marrow]] that give rise to red blood cells, [[white blood cell]]s, and [[platelet]]s.
* ''[[Mesenchymal stem cells]]'' (adult stem cells) from the bone marrow that give rise to stromal cells, fat cells, and types of bone cells
* ''[[Epithelia]]l stem cells'' (progenitor cells) that give rise to the various types of skin cells
* ''Muscle [[satellite cell]]s'' (progenitor cells) that contribute to differentiated [[muscle tissue]].
A pathway that is guided by the cell adhesion molecules consisting of four amino acids, [[arginine]], [[glycine]], [[asparagine]], and [[serine]], is created as the cellular blastomere [[gastrulation|differentiates]] from the single-layered [[blastula]] to the three primary [[germ layer|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 the skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues.
==Dedifferentiation==
[[Image:Dedifferentiated liposarcoma - intermed mag.jpg|thumb|right|[[Micrograph]] showing ''some dedifferentiation'', (at left edge of image). + A ''differentiated'' component, showing [[lipoblast]]s and increased [[blood vessels|vascularity]], (right edge of image). + ''Fully differentiated'' [[adipose tissue]], showing a few blood vessels, (center of image). ([[Micrograph]] of [[liposarcoma]] prepared with [[H&E stain]]).]]

[[Dedifferentiation]], or integration, is a cellular process seen in the more [[Basal (phylogenetics)|basal]] life forms in animals, such as [[worm]]s and [[amphibian]]s where a differentiated cell reverts to an earlier developmental stage{{mdash}}usually as part of a [[Regeneration (biology)|regenerative]] process.<ref name="dediff1">{{cite book | vauthors = Stocum DL | chapter = Amphibian Regeneration and Stem Cells | series = Current Topics in Microbiology and Immunology | title = Regeneration: Stem Cells and Beyond | volume = 280 | pages = 1–70 | year = 2004 | pmid = 14594207 | doi = 10.1007/978-3-642-18846-6_1 | isbn = 978-3-540-02238-1 }}</ref><ref name="dediff2">{{cite journal | vauthors = Casimir CM, Gates PB, Patient RK, Brockes JP | title = Evidence for dedifferentiation and metaplasia in amphibian limb regeneration from inheritance of DNA methylation | journal = Development | volume = 104 | issue = 4 | pages = 657–668 | date = December 1988 | pmid = 3268408 | doi = 10.1242/dev.104.4.657 }}</ref> Dedifferentiation also occurs in plant cells.<ref>{{cite journal | vauthors = Giles KL |title=Dedifferentiation and Regeneration in Bryophytes: A Selective Review |journal=New Zealand Journal of Botany |volume=9 |issue=4 |pages=689–94 |url=http://www.rsnz.org/publish/nzjb/1971/47.php |doi=10.1080/0028825x.1971.10430231 |year=1971 |bibcode=1971NZJB....9..689G |access-date=2008-01-01 |archive-url=https://web.archive.org/web/20081204174703/http://www.rsnz.org/publish/nzjb/1971/47.php |archive-date=2008-12-04 |url-status=dead |url-access=subscription }}</ref> And, in [[cell culture]] in the laboratory, cells can change shape or may lose specific properties such as protein expression{{mdash}}which processes are also termed dedifferentiation.<ref>{{cite journal | vauthors = Schnabel M, Marlovits S, Eckhoff G, Fichtel I, Gotzen L, Vécsei V, Schlegel J | title = Dedifferentiation-associated changes in morphology and gene expression in primary human articular chondrocytes in cell culture | journal = Osteoarthritis and Cartilage | volume = 10 | issue = 1 | pages = 62–70 | date = January 2002 | pmid = 11795984 | doi = 10.1053/joca.2001.0482 | doi-access = free }}</ref>

Some hypothesize that dedifferentiation is an aberration that likely results in [[cancer]]s,<ref>{{cite journal | vauthors = Sell S | title = Cellular origin of cancer: dedifferentiation or stem cell maturation arrest? | journal = Environmental Health Perspectives | volume = 101 | issue = Suppl 5 | pages = 15–26 | date = December 1993 | pmid = 7516873 | pmc = 1519468 | doi = 10.2307/3431838 | jstor = 3431838 }}</ref> 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]], a [[purine]] analog, has proven to induce dedifferentiation in [[myotube]]s. These manifestly dedifferentiated cells{{mdash}}now performing essentially as stem cells{{mdash}}could then redifferentiate into [[osteoblast]]s and [[adipocyte]]s.<ref>{{cite journal | vauthors = Tsonis PA | title = Stem cells from differentiated cells | journal = Molecular Interventions | volume = 4 | issue = 2 | pages = 81–83 | date = April 2004 | pmid = 15087480 | doi = 10.1124/mi.4.2.4 | url = http://molinterv.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15087480 | url-status = dead | access-date = 2010-12-26 | archive-url = http://arquivo.pt/wayback/20160523205221/http://molinterv.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15087480 | archive-date = 2016-05-23 | url-access = subscription }}</ref>
[[File:Bischoff SR - Nuclear Reprogramming.pdf|thumb|401x401px|Diagram exposing several methods used to revert adult somatic cells to [[totipotency]] or [[pluripotency]].]]

==Mechanisms==
{{See also|Embryonic differentiation waves}}

=== Gene regulatory networks ===
[[Image:Cell Differentiation.jpg|upright=1.5|thumb|Mechanisms of cellular differentiation]]

Each specialized cell type in an organism [[Gene expression|expresses]] a [[subset]] of all the [[gene]]s that constitute the genome of that [[species]]. Each cell type is defined by its particular pattern of [[regulation of gene expression|regulated gene expression]]. Cell differentiation 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.<ref name=DeLeon>{{cite journal | vauthors = Ben-Tabou de-Leon S, Davidson EH | title = Gene regulation: gene control network in development | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 36 | issue = 191 | pages = 191–212 | year = 2007 | pmid = 17291181 | doi = 10.1146/annurev.biophys.35.040405.102002 | url = https://resolver.caltech.edu/CaltechAUTHORS:LEOarbbs07 }}</ref> The [[systems biology]] approach to developmental biology emphasizes the importance of investigating how developmental mechanisms interact to produce predictable patterns ([[morphogenesis]]). However, recent research suggests there may be an alternative view. 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.<ref>{{cite journal | vauthors = Capp JP, Laforge B | title = A Darwinian and Physical Look at Stem Cell Biology Helps Understanding the Role of Stochasticity in Development | language = English | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 659 | date = 23 July 2020 | pmid = 32793600 | pmc = 7391792 | doi = 10.3389/fcell.2020.00659 | doi-access = free }}</ref>

[[File:Signal transduction pathways.svg|thumb|left|240px|An overview of major signal transduction pathways.]]

=== Signaling pathways ===
Cellular differentiation 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 factor]]s. 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 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 the target cell.<ref name=Gilbert>{{cite book | vauthors = Knisely K, Gilbert SF |title=Developmental Biology |publisher=Sinauer Associates |location=Sunderland, Mass |year=2009 |page=147 |isbn=978-0-87893-371-6 |edition=8th }}</ref> Cells and tissues can vary in competence, their ability to respond to external signals.<ref name=Rudel>Rudel and Sommer; The evolution of developmental mechanisms. ''Developmental Biology'' 264, 15-37, 2003 {{cite journal | vauthors = Rudel D, Sommer RJ | title = The evolution of developmental mechanisms | journal = Developmental Biology | volume = 264 | issue = 1 | pages = 15–37 | date = December 2003 | pmid = 14623229 | doi = 10.1016/S0012-1606(03)00353-1 | doi-access = free }}</ref>

=== Inductive signaling ===
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.<ref name=Rudel/> Yamamoto and Jeffery<ref name=Yamamoto>Yamamoto Y and WR Jeffery; Central role for the lens in cave fish eye degeneration. '' Science '' 289 (5479), 631-633, 2000 {{cite journal | vauthors = Yamamoto Y, Jeffery WR | title = Central role for the lens in cave fish eye degeneration | journal = Science | volume = 289 | issue = 5479 | pages = 631–633 | date = July 2000 | pmid = 10915628 | doi = 10.1126/science.289.5479.631 | bibcode = 2000Sci...289..631Y }}</ref> investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction.<ref name=Rudel/> Through reciprocal transplants, Yamamoto and Jeffery<ref name=Yamamoto/> found that 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.<ref name=Rudel/>

=== Asymmetric cell division ===
Other important mechanisms fall under the category of [[asymmetric cell division]]s, 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.<ref name="Rudel" /> In 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 [[Drosophila embryogenesis#Anterior-posterior axis patterning in Drosophila|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 the genus ''[[Volvox]]'', a model system for studying how unicellular organisms can evolve into multicellular organisms.<ref name="Rudel" /> 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.<ref name="Rudel" /><ref name="Kirk">Kirk MM, A Ransick, SE Mcrae, DL Kirk; The relationship between cell size and cell fate in ''Volvox carteri''. ''Journal of Cell Biology'' 123, 191-208, 1993 {{cite journal | vauthors = Kirk MM, Ransick A, McRae SE, Kirk DL | title = The relationship between cell size and cell fate in Volvox carteri | journal = The Journal of Cell Biology | volume = 123 | issue = 1 | pages = 191–208 | date = October 1993 | pmid = 8408198 | pmc = 2119814 | doi = 10.1083/jcb.123.1.191 }}</ref>

=== Evolutionary perspectives on mechanisms ===
While [[evolution]]arily conserved molecular processes are involved in the cellular mechanisms underlying these switches, in animal species these are very different from the well-characterized [[operon|gene regulatory mechanisms]] of [[bacteria]], and even from those of the animals' closest [[holozoa|unicellular relatives]].<ref name="Newman">{{cite journal | vauthors = Newman SA | title = Cell differentiation: What have we learned in 50 years? | journal = Journal of Theoretical Biology | volume = 485 | pages = 110031 | date = January 2020 | pmid = 31568790 | doi = 10.1016/j.jtbi.2019.110031 | bibcode = 2020JThBi.48510031N | arxiv = 1907.09551 | doi-access = free }}</ref> Specifically, cell differentiation in animals is highly dependent on [[biomolecular condensate]]s of regulatory proteins and [[Enhancer (genetics)|enhancer]] DNA sequences.

==Epigenetic control==
{{Main|Epigenetics in stem cell differentiation}}

Since each cell, regardless of cell type, possesses 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-regulatory element|cis-]] and [[trans-regulatory element]]s including a gene's [[Promoter (biology)|promoter]] and [[Enhancer (genetics)|enhancers]], the problem arises as to how this expression pattern is maintained over numerous generations of [[cell division]].<ref>{{cite journal | vauthors = Madrigal P, Deng S, Feng Y, Militi S, Goh KJ, Nibhani R, Grandy R, Osnato A, Ortmann D, Brown S, Pauklin S | title = Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation | journal = Nature Communications | volume = 14 | issue = 1 | pages = 405 | date = January 2023 | pmid = 36697417 | pmc = 9876972 | doi = 10.1038/s41467-023-36116-9 | bibcode = 2023NatCo..14..405M }}</ref> As it turns out, [[epigenetic]] processes play a crucial role in regulating 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.<ref>{{cite journal | vauthors = Rabajante JF, Babierra AL | title = Branching and oscillations in the epigenetic landscape of cell-fate determination | journal = Progress in Biophysics and Molecular Biology | volume = 117 | issue = 2–3 | pages = 240–249 | date = March 2015 | pmid = 25641423 | doi = 10.1016/j.pbiomolbio.2015.01.006 | s2cid = 2579314 }}</ref>

===Importance of epigenetic control===

The first question that can be asked 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.'' <ref name = "Lister">{{cite journal | vauthors = Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR | title = Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells | journal = Nature | volume = 471 | issue = 7336 | pages = 68–73 | date = March 2011 | pmid = 21289626 | pmc = 3100360 | doi = 10.1038/nature09798 | bibcode = 2011Natur.471...68L }}</ref> 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, 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 [[CpG site|CG dinucleotides]] in ESCs and iPSCs were methylated, 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,<ref name= "Lister"/> DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs.

However, upon examining methylation patterns more closely, 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 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 (genetics)|transcription]]. Second, 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.

===Mechanisms of epigenetic regulation===

====Pioneer factors (Oct4, Sox2, Nanog)====
Three transcription factors, OCT4, SOX2, and [[Homeobox protein NANOG|NANOG]] – 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]].<ref name = "Christophersen">{{cite journal | vauthors = Christophersen NS, Helin K | title = Epigenetic control of embryonic stem cell fate | journal = The Journal of Experimental Medicine | volume = 207 | issue = 11 | pages = 2287–2295 | date = October 2010 | pmid = 20975044 | pmc = 2964577 | doi = 10.1084/jem.20101438 }}</ref> It is thought that they achieve this through alterations in [[chromatin]] structure, such as [[histone modification]] and DNA methylation, to restrict or permit 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.<ref name="ReferenceA">{{cite journal | vauthors = Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S | title = Pluripotency factors in embryonic stem cells regulate differentiation into germ layers | journal = Cell | volume = 145 | issue = 6 | pages = 875–889 | date = June 2011 | pmid = 21663792 | pmc = 5603300 | doi = 10.1016/j.cell.2011.05.017 }}</ref> Increased levels of Oct4 and decreased levels of Sox2 promote a [[Gastrulation|mesendodermal]] fate, with Oct4 actively suppressing genes associated with a neural [[neurulation|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.<ref name="ReferenceA"/>

====Polycomb repressive complex (PRC2)====
In the realm of [[gene silencing]], [[PRC2|Polycomb repressive complex 2]], one of two classes of the [[Polycomb-group proteins|Polycomb group]] (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3).<ref name= "Christophersen"/><ref name="Jiang">{{cite journal | vauthors = Zhu J, Adli M, Zou JY, Verstappen G, Coyne M, Zhang X, Durham T, Miri M, Deshpande V, De Jager PL, Bennett DA, Houmard JA, Muoio DM, Onder TT, Camahort R, Cowan CA, Meissner A, Epstein CB, Shoresh N, Bernstein BE | title = Genome-wide chromatin state transitions associated with developmental and environmental cues | journal = Cell | volume = 152 | issue = 3 | pages = 642–654 | date = January 2013 | pmid = 23333102 | pmc = 3563935 | doi = 10.1016/j.cell.2012.12.033 }}</ref><ref name = "Guenther">{{cite journal | vauthors = Guenther MG, Young RA | title = Transcription. Repressive transcription | journal = Science | volume = 329 | issue = 5988 | pages = 150–151 | date = July 2010 | pmid = 20616255 | pmc = 3006433 | doi = 10.1126/science.1193995 | bibcode = 2010Sci...329..150G }}</ref> 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.<ref name= "Christophersen"/> PcG knockout ES cells do not differentiate efficiently into the three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation.<ref name= "Christophersen"/> Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes.

====Trithorax group proteins (TrxG)====
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 the differentiated phenotype.<ref name= "Christophersen"/> Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression.<ref name= "Christophersen"/><ref name = "Guenther"/> 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.<ref name = "Guenther"/> PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what is termed a "bivalent domain" and rendering these genes sensitive to rapid induction or repression.<ref name = "Meissner">{{cite journal | vauthors = Meissner A | title = Epigenetic modifications in pluripotent and differentiated cells | journal = Nature Biotechnology | volume = 28 | issue = 10 | pages = 1079–1088 | date = October 2010 | pmid = 20944600 | doi = 10.1038/nbt.1684 | s2cid = 205274850 }}</ref>

====DNA methylation====
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.<ref name = "Meissner"/> The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes.<ref name= "Christophersen"/> Upon differentiation, a small number of genes, including OCT4 and NANOG,<ref name = "Meissner"/> 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.<ref name= "Christophersen"/>

====Nucleosome positioning====
While the [[nucleic acid sequence|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 a large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through [[histone modification]] and/or [[pioneer factor]]s. 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.<ref>{{Cite web|url=http://www.bio.brandeis.edu/haberlab/jehsite/chIP.html|title=Chromatin Immuprecipitation|website=www.bio.brandeis.edu|access-date=2016-12-26|archive-date=2017-11-25|archive-url=https://web.archive.org/web/20171125204418/http://www.bio.brandeis.edu/haberlab/jehsite/chIP.html|url-status=dead}}</ref>

=====Histone acetylation and methylation=====
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 is either added to or removed from the positively charged Lysine residues in histones by enzymes called [[histone acetyltransferase]]s or [[histone deactylase]]s, 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) is associated with gene activation, whereas trimethylation of lysine 27 on histone 3 represses genes.<ref name="pmid12667454">{{cite journal | vauthors = Krogan NJ, Dover J, Wood A, Schneider J, Heidt J, Boateng MA, Dean K, Ryan OW, Golshani A, Johnston M, Greenblatt JF, Shilatifard A | title = The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation | journal = Molecular Cell | volume = 11 | issue = 3 | pages = 721–729 | date = March 2003 | pmid = 12667454 | doi = 10.1016/S1097-2765(03)00091-1 | doi-access = free }}</ref><ref name="pmid12667453">{{cite journal | vauthors = Ng HH, Robert F, Young RA, Struhl K | title = Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity | journal = Molecular Cell | volume = 11 | issue = 3 | pages = 709–719 | date = March 2003 | pmid = 12667453 | doi = 10.1016/S1097-2765(03)00092-3 | doi-access = free }}</ref><ref name="pmid15680324">{{cite journal | vauthors = Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ, Gingeras TR, Schreiber SL, Lander ES | title = Genomic maps and comparative analysis of histone modifications in human and mouse | journal = Cell | volume = 120 | issue = 2 | pages = 169–181 | date = January 2005 | pmid = 15680324 | doi = 10.1016/j.cell.2005.01.001 | s2cid = 7193829 | doi-access = free }}</ref>

=====In stem cells=====
{{further|Stem cell}}

During differentiation, stem cells change their gene expression profiles. Recent studies have implicated a role for nucleosome positioning and histone modifications during this process.<ref name = "Teif_et_al">{{cite journal | vauthors = Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K | title = Genome-wide nucleosome positioning during embryonic stem cell development | journal = Nature Structural & Molecular Biology | volume = 19 | issue = 11 | pages = 1185–1192 | date = November 2012 | pmid = 23085715 | doi = 10.1038/nsmb.2419 | s2cid = 34509771 }}</ref> 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 ([[LSD1|KDM1A]]) is thought to prevent the use of [[enhancer (genetics)|enhancer]] regions of pluripotency genes, thereby inhibiting their transcription.<ref name="ReferenceB">{{cite journal | vauthors = Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM, Foster CT, Cowley SM, Young RA | title = Enhancer decommissioning by LSD1 during embryonic stem cell differentiation | journal = Nature | volume = 482 | issue = 7384 | pages = 221–225 | date = February 2012 | pmid = 22297846 | pmc = 4144424 | doi = 10.1038/nature10805 | bibcode = 2012Natur.482..221W }}</ref> It interacts with [[NuRD|Mi-2/NuRD complex]] (nucleosome remodelling and histone deacetylase) complex,<ref name="ReferenceB"/> giving an instance where methylation and acetylation are not discrete and mutually exclusive, but intertwined processes.

===Role of signaling in epigenetic control===

A final question to ask concerns 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 the [[epigenome]], and the majority of current knowledge about the subject consists of speculations on plausible candidate regulators of epigenetic remodeling.<ref name = "Mohammad">{{cite journal | vauthors = Mohammad HP, Baylin SB | title = Linking cell signaling and the epigenetic machinery | journal = Nature Biotechnology | volume = 28 | issue = 10 | pages = 1033–1038 | date = October 2010 | pmid = 20944593 | doi = 10.1038/nbt1010-1033 | s2cid = 6911946 }}</ref> 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 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.<ref name = "Mohammad"/> On the other hand, disruption of [[Beta-catenin|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 (protein)|Smad]] proteins.<ref name = "Mohammad"/> Depletion of growth factors promotes the differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription.<ref name = "Mohammad"/>

Several other signaling pathways are also considered to be primary candidates. Cytokine [[leukemia inhibitory factor]]s 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.<ref name = "Niwa">{{cite journal | vauthors = Niwa H, Burdon T, Chambers I, Smith A | title = Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3 | journal = Genes & Development | volume = 12 | issue = 13 | pages = 2048–2060 | date = July 1998 | pmid = 9649508 | pmc = 316954 | doi = 10.1101/gad.12.13.2048 }}</ref> [[Retinoic acid]] can induce differentiation of human and mouse ESCs,<ref name = "Mohammad"/> and [[Notch signaling]] 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.<ref name = "Mohammad"/>

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 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 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.<ref name = "Liu">{{cite journal | vauthors = Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS | title = Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells | journal = Cancer Research | volume = 66 | issue = 12 | pages = 6063–6071 | date = June 2006 | pmid = 16778178 | pmc = 4386278 | doi = 10.1158/0008-5472.CAN-06-0054 }}</ref> In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1 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.<ref name = "Leung">{{cite journal | vauthors = Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M, Marino S | title = Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas | journal = Nature | volume = 428 | issue = 6980 | pages = 337–341 | date = March 2004 | pmid = 15029199 | doi = 10.1038/nature02385 | s2cid = 29965488 | bibcode = 2004Natur.428..337L }}</ref> A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice.<ref name = "Zencak">{{cite journal | vauthors = Zencak D, Lingbeek M, Kostic C, Tekaya M, Tanger E, Hornfeld D, Jaquet M, Munier FL, Schorderet DF, van Lohuizen M, Arsenijevic Y | title = Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation | journal = The Journal of Neuroscience | volume = 25 | issue = 24 | pages = 5774–5783 | date = June 2005 | pmid = 15958744 | pmc = 6724881 | doi = 10.1523/JNEUROSCI.3452-04.2005 }}</ref>

An alternative model of cellular differentiation during embryogenesis is that positional information 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 the likely existence of further such mechanisms.

=== Effect of matrix elasticity ===
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 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.<ref name=":0">{{cite journal | vauthors = Engler AJ, Sen S, Sweeney HL, Discher DE | title = Matrix elasticity directs stem cell lineage specification | journal = Cell | volume = 126 | issue = 4 | pages = 677–689 | date = August 2006 | pmid = 16923388 | doi = 10.1016/j.cell.2006.06.044 | s2cid = 16109483 | doi-access = free }}</ref>
Matrix sensing requires 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 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.<ref name=":0" /> Researchers have achieved some success in inducing stem cell-like properties in HEK 239 cells by providing a soft matrix without the use of diffusing factors.<ref>{{cite journal | vauthors = Guo J, Wang Y, Sachs F, Meng F | title = Actin stress in cell reprogramming | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 49 | pages = E5252–E5261 | date = December 2014 | pmid = 25422450 | pmc = 4267376 | doi = 10.1073/pnas.1411683111 | bibcode = 2014PNAS..111E5252G | doi-access = free | author-link3 = Frederick Sachs }}</ref> 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.<ref>{{cite journal | vauthors = Guilak F, Cohen DM, Estes BT, Gimble JM, Liedtke W, Chen CS | title = Control of stem cell fate by physical interactions with the extracellular matrix | journal = Cell Stem Cell | volume = 5 | issue = 1 | pages = 17–26 | date = July 2009 | pmid = 19570510 | pmc = 2768283 | doi = 10.1016/j.stem.2009.06.016 }}</ref> The RhoA pathway is also implicated in this process.<ref>{{cite journal | vauthors = Vining KH, Mooney DJ | title = Mechanical forces direct stem cell behaviour in development and regeneration | journal = Nature Reviews. Molecular Cell Biology | volume = 18 | issue = 12 | pages = 728–742 | date = December 2017 | pmid = 29115301 | pmc = 5803560 | doi = 10.1038/nrm.2017.108 }}</ref>

== Evolutionary history ==
{{See also|Bangiomorpha}}

A billion-years-old, likely [[holozoa]]n, [[protist]], ''[[Bicellum brasieri]]'' with two types of cells, shows that the evolution of differentiated [[multicellularity]], possibly but not necessarily of animal lineages, [[History of life|occurred at least 1 billion years ago]] and possibly mainly in [[Freshwater ecosystem|freshwater lakes]] rather than <!--at and in-->the ocean.<ref>{{cite news |title=Billion-year-old fossil reveals missing link in the evolution of animals |url=https://phys.org/news/2021-04-billion-year-old-fossil-reveals-link-evolution.html |access-date=9 May 2021 |work=phys.org |language=en}}</ref><ref>{{cite news |title=Billion-year-old fossil found preserved in Torridon rocks |url=https://www.bbc.com/news/uk-scotland-highlands-islands-56917272 |access-date=22 May 2021 |work=BBC News |date=2021-04-29}}</ref><!--https://gizmodo.com/scientists-find-billion-year-old-fossil-life-something-1846792843--><!--https://www.forbes.com/sites/davidbressan/2021/04/30/one-billion-year-old-fossil-could-be-the-oldest-multicellular-animal/--><ref>{{cite journal | vauthors = Strother PK, Brasier MD, Wacey D, Timpe L, Saunders M, Wellman CH | title = A possible billion-year-old holozoan with differentiated multicellularity | language = English | journal = Current Biology | volume = 31 | issue = 12 | pages = 2658–2665.e2 | date = June 2021 | pmid = 33852871 | doi = 10.1016/j.cub.2021.03.051 | doi-access = free | bibcode = 2021CBio...31E2658S }} [[File:CC-BY icon.svg|50px]] Available under [https://creativecommons.org/licenses/by/4.0/ CC BY 4.0].</ref>{{clarify|date=May 2021 |reason=How does this compare to other findings – like of ''[[Bangiomorpha]]'' – and exactly in which way is it a first / oldest specimen (if it is)?}}

== See also ==
* [[Interbilayer Forces in Membrane Fusion]]
* [[Fusion mechanism]]
* [[Lipid bilayer fusion]]
* [[Cell-cell fusogens]]
* [[CAF-1]]
* [[List of human cell types derived from the germ layers]]

== References ==
{{Reflist|30em}}

{{Stem cells}}
{{Authority control}}

{{DEFAULTSORT:Cellular Differentiation}}
[[Category:Cellular processes]]
[[Category:Developmental biology]]
[[Category:Induced stem cells]]