A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration
Chemoattractant gradients frequently guide migrating cells. To achieve the most directional signal, such gradients should be maintained with concentrations around the dissociation constant ( K d ) 1 – 6 of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whe...
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| Veröffentlicht in: | Nature cell biology 2020-03, Vol.22 (3), p.266-273 |
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| creator | Lau, Stephanie Feitzinger, Anna Venkiteswaran, Gayatri Wang, John Lewellis, Stephen W. Koplinski, Chad A. Peterson, Francis C. Volkman, Brian F. Meier-Schellersheim, Martin Knaut, Holger |
| description | Chemoattractant gradients frequently guide migrating cells. To achieve the most directional signal, such gradients should be maintained with concentrations around the dissociation constant (
K
d
)
1
–
6
of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range to achieve robust migration. We find that the Cxcl12 (also known as Sdf1) attractant gradient ranges from 0 to 12 nM, values similar to the 3.4 nM
K
d
of its receptor Cxcr4. When we increase the
K
d
of Cxcl12 for Cxcr4, primordium migration is less directional. Furthermore, a negative-feedback loop between Cxcl12 and its clearance receptor Ackr3 (also known as Cxcr7) regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of the cytoplasmic tail of Ackr3 also results in less directional primordium migration. Thus, directed migration of the primordium is dependent on a close match between the Cxcl12 concentration and the
K
d
of Cxcl12 for Cxcr4, which is maintained by buffering of the chemokine levels. Quantitative modelling confirms the plausibility of this mechanism. We anticipate that buffering of attractant concentration is a general mechanism for ensuring robust cell migration.
Lau et al. quantify endogenous concentrations of the chemokine Cxcl12 and its binding affinity for its cognate receptor Cxcr4 in zebrafish embryos, uncovering a negative-feedback loop governing directional cell migration in vivo. |
| doi_str_mv | 10.1038/s41556-020-0465-4 |
| format | Article |
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K
d
)
1
–
6
of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range to achieve robust migration. We find that the Cxcl12 (also known as Sdf1) attractant gradient ranges from 0 to 12 nM, values similar to the 3.4 nM
K
d
of its receptor Cxcr4. When we increase the
K
d
of Cxcl12 for Cxcr4, primordium migration is less directional. Furthermore, a negative-feedback loop between Cxcl12 and its clearance receptor Ackr3 (also known as Cxcr7) regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of the cytoplasmic tail of Ackr3 also results in less directional primordium migration. Thus, directed migration of the primordium is dependent on a close match between the Cxcl12 concentration and the
K
d
of Cxcl12 for Cxcr4, which is maintained by buffering of the chemokine levels. Quantitative modelling confirms the plausibility of this mechanism. We anticipate that buffering of attractant concentration is a general mechanism for ensuring robust cell migration.
Lau et al. quantify endogenous concentrations of the chemokine Cxcl12 and its binding affinity for its cognate receptor Cxcr4 in zebrafish embryos, uncovering a negative-feedback loop governing directional cell migration in vivo.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/s41556-020-0465-4</identifier><identifier>PMID: 32042179</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14 ; 14/35 ; 631/136 ; 631/80/84/1372 ; 631/80/84/2334 ; 631/80/86/820 ; 64 ; 64/116 ; Animals ; Animals, Genetically Modified ; Biomedical and Life Sciences ; Buffers ; Cancer Research ; Cell adhesion & migration ; Cell Biology ; Cell Line ; Cell migration ; Cell Movement ; Chemokine CXCL12 - metabolism ; Chemokines ; Chemokines - metabolism ; CXCL12 protein ; CXCR4 protein ; Danio rerio ; Developmental Biology ; Embryonic development ; Embryos ; Feedback ; Feedback loops ; Feedback, Physiological ; Health aspects ; Humans ; Lateral line ; Letter ; Life Sciences ; Negative feedback ; Phosphorylation ; Receptors, CXCR - metabolism ; Receptors, CXCR4 - metabolism ; Robustness ; SDF-1 protein ; Stem Cells ; Zebrafish ; Zebrafish - embryology ; Zebrafish - genetics ; Zebrafish - metabolism ; Zebrafish Proteins - metabolism</subject><ispartof>Nature cell biology, 2020-03, Vol.22 (3), p.266-273</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>2020© The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c637t-5140a321917efeac1ae4933551424702d3e437a347463b055d922a2be4a0c4ed3</citedby><cites>FETCH-LOGICAL-c637t-5140a321917efeac1ae4933551424702d3e437a347463b055d922a2be4a0c4ed3</cites><orcidid>0000-0002-8754-6377 ; 0000-0002-8399-8720 ; 0000-0003-1352-8923</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41556-020-0465-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41556-020-0465-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32042179$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lau, Stephanie</creatorcontrib><creatorcontrib>Feitzinger, Anna</creatorcontrib><creatorcontrib>Venkiteswaran, Gayatri</creatorcontrib><creatorcontrib>Wang, John</creatorcontrib><creatorcontrib>Lewellis, Stephen W.</creatorcontrib><creatorcontrib>Koplinski, Chad A.</creatorcontrib><creatorcontrib>Peterson, Francis C.</creatorcontrib><creatorcontrib>Volkman, Brian F.</creatorcontrib><creatorcontrib>Meier-Schellersheim, Martin</creatorcontrib><creatorcontrib>Knaut, Holger</creatorcontrib><title>A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Chemoattractant gradients frequently guide migrating cells. To achieve the most directional signal, such gradients should be maintained with concentrations around the dissociation constant (
K
d
)
1
–
6
of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range to achieve robust migration. We find that the Cxcl12 (also known as Sdf1) attractant gradient ranges from 0 to 12 nM, values similar to the 3.4 nM
K
d
of its receptor Cxcr4. When we increase the
K
d
of Cxcl12 for Cxcr4, primordium migration is less directional. Furthermore, a negative-feedback loop between Cxcl12 and its clearance receptor Ackr3 (also known as Cxcr7) regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of the cytoplasmic tail of Ackr3 also results in less directional primordium migration. Thus, directed migration of the primordium is dependent on a close match between the Cxcl12 concentration and the
K
d
of Cxcl12 for Cxcr4, which is maintained by buffering of the chemokine levels. Quantitative modelling confirms the plausibility of this mechanism. We anticipate that buffering of attractant concentration is a general mechanism for ensuring robust cell migration.
Lau et al. quantify endogenous concentrations of the chemokine Cxcl12 and its binding affinity for its cognate receptor Cxcr4 in zebrafish embryos, uncovering a negative-feedback loop governing directional cell migration in vivo.</description><subject>14</subject><subject>14/35</subject><subject>631/136</subject><subject>631/80/84/1372</subject><subject>631/80/84/2334</subject><subject>631/80/86/820</subject><subject>64</subject><subject>64/116</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Biomedical and Life Sciences</subject><subject>Buffers</subject><subject>Cancer Research</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology</subject><subject>Cell Line</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>Chemokines</subject><subject>Chemokines - metabolism</subject><subject>CXCL12 protein</subject><subject>CXCR4 protein</subject><subject>Danio rerio</subject><subject>Developmental Biology</subject><subject>Embryonic development</subject><subject>Embryos</subject><subject>Feedback</subject><subject>Feedback loops</subject><subject>Feedback, Physiological</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Lateral line</subject><subject>Letter</subject><subject>Life Sciences</subject><subject>Negative feedback</subject><subject>Phosphorylation</subject><subject>Receptors, CXCR - metabolism</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Robustness</subject><subject>SDF-1 protein</subject><subject>Stem Cells</subject><subject>Zebrafish</subject><subject>Zebrafish - embryology</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish - metabolism</subject><subject>Zebrafish Proteins - metabolism</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kl1r1UAQhhdRbD36A7yRgDd6kXY_s8mNcCi2FgpC1etls5mk2ybZ425S9N93QvrhESWEbGaemX1neAl5y-gRo6I8TpIpVeSU05zKQuXyGTlkUhe5LHT1fDljUIuKH5BXKV1TyqSk-iU5EJxKznR1SOptNkJnJ38LeQvQ1NbdZH0Iu2ywfpzwTVnYTX6wfeauYAg3foTMhdHBOEWsCwi0IWaNj-CW3wWEvs8G36351-RFa_sEb-6_G_Lj9PP3ky_5xdez85PtRe4KoadcMUmt4KxiGlqwjlmQlRAK41xqyhsBUmgrpJaFqKlSTcW55TVIS52ERmzIp7Xvbq4HaFaBvdlFFB9_m2C92c-M_sp04dboklYKr9qQD_cNYvg5Q5rM4NMyix0hzMlwoYQqNQpE9P1f6HWYI86-UJqXBUfRT1RnezB-bAPe65amZluwkquikhSpo39Q-DQweNw0tB7jewUf9wqQmeDX1Nk5JXP-7XKfZSvrYkgpQvu4D0bNYiKzmsigicxiIrPIfvfnIh8rHlyDAF-BhKmxg_g0_f-73gERlNCi</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Lau, Stephanie</creator><creator>Feitzinger, Anna</creator><creator>Venkiteswaran, Gayatri</creator><creator>Wang, John</creator><creator>Lewellis, Stephen W.</creator><creator>Koplinski, Chad A.</creator><creator>Peterson, Francis C.</creator><creator>Volkman, Brian F.</creator><creator>Meier-Schellersheim, Martin</creator><creator>Knaut, Holger</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8754-6377</orcidid><orcidid>https://orcid.org/0000-0002-8399-8720</orcidid><orcidid>https://orcid.org/0000-0003-1352-8923</orcidid></search><sort><creationdate>20200301</creationdate><title>A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration</title><author>Lau, Stephanie ; Feitzinger, Anna ; Venkiteswaran, Gayatri ; Wang, John ; Lewellis, Stephen W. ; Koplinski, Chad A. ; Peterson, Francis C. ; Volkman, Brian F. ; Meier-Schellersheim, Martin ; Knaut, Holger</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c637t-5140a321917efeac1ae4933551424702d3e437a347463b055d922a2be4a0c4ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>14</topic><topic>14/35</topic><topic>631/136</topic><topic>631/80/84/1372</topic><topic>631/80/84/2334</topic><topic>631/80/86/820</topic><topic>64</topic><topic>64/116</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Biomedical and Life Sciences</topic><topic>Buffers</topic><topic>Cancer Research</topic><topic>Cell adhesion & migration</topic><topic>Cell Biology</topic><topic>Cell Line</topic><topic>Cell migration</topic><topic>Cell Movement</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>Chemokines</topic><topic>Chemokines - metabolism</topic><topic>CXCL12 protein</topic><topic>CXCR4 protein</topic><topic>Danio rerio</topic><topic>Developmental Biology</topic><topic>Embryonic development</topic><topic>Embryos</topic><topic>Feedback</topic><topic>Feedback loops</topic><topic>Feedback, Physiological</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Lateral line</topic><topic>Letter</topic><topic>Life Sciences</topic><topic>Negative feedback</topic><topic>Phosphorylation</topic><topic>Receptors, CXCR - metabolism</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Robustness</topic><topic>SDF-1 protein</topic><topic>Stem Cells</topic><topic>Zebrafish</topic><topic>Zebrafish - embryology</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish - metabolism</topic><topic>Zebrafish Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lau, Stephanie</creatorcontrib><creatorcontrib>Feitzinger, Anna</creatorcontrib><creatorcontrib>Venkiteswaran, Gayatri</creatorcontrib><creatorcontrib>Wang, John</creatorcontrib><creatorcontrib>Lewellis, Stephen W.</creatorcontrib><creatorcontrib>Koplinski, Chad A.</creatorcontrib><creatorcontrib>Peterson, Francis C.</creatorcontrib><creatorcontrib>Volkman, Brian F.</creatorcontrib><creatorcontrib>Meier-Schellersheim, Martin</creatorcontrib><creatorcontrib>Knaut, Holger</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lau, Stephanie</au><au>Feitzinger, Anna</au><au>Venkiteswaran, Gayatri</au><au>Wang, John</au><au>Lewellis, Stephen W.</au><au>Koplinski, Chad A.</au><au>Peterson, Francis C.</au><au>Volkman, Brian F.</au><au>Meier-Schellersheim, Martin</au><au>Knaut, Holger</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>22</volume><issue>3</issue><spage>266</spage><epage>273</epage><pages>266-273</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>Chemoattractant gradients frequently guide migrating cells. To achieve the most directional signal, such gradients should be maintained with concentrations around the dissociation constant (
K
d
)
1
–
6
of the chemoreceptor. Whether this actually occurs in animals is unknown. Here we investigate whether a moving tissue, the zebrafish posterior lateral line primordium, buffers its attractant in this concentration range to achieve robust migration. We find that the Cxcl12 (also known as Sdf1) attractant gradient ranges from 0 to 12 nM, values similar to the 3.4 nM
K
d
of its receptor Cxcr4. When we increase the
K
d
of Cxcl12 for Cxcr4, primordium migration is less directional. Furthermore, a negative-feedback loop between Cxcl12 and its clearance receptor Ackr3 (also known as Cxcr7) regulates the Cxcl12 concentrations. Breaking this negative feedback by blocking the phosphorylation of the cytoplasmic tail of Ackr3 also results in less directional primordium migration. Thus, directed migration of the primordium is dependent on a close match between the Cxcl12 concentration and the
K
d
of Cxcl12 for Cxcr4, which is maintained by buffering of the chemokine levels. Quantitative modelling confirms the plausibility of this mechanism. We anticipate that buffering of attractant concentration is a general mechanism for ensuring robust cell migration.
Lau et al. quantify endogenous concentrations of the chemokine Cxcl12 and its binding affinity for its cognate receptor Cxcr4 in zebrafish embryos, uncovering a negative-feedback loop governing directional cell migration in vivo.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32042179</pmid><doi>10.1038/s41556-020-0465-4</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-8754-6377</orcidid><orcidid>https://orcid.org/0000-0002-8399-8720</orcidid><orcidid>https://orcid.org/0000-0003-1352-8923</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-7392 |
| ispartof | Nature cell biology, 2020-03, Vol.22 (3), p.266-273 |
| issn | 1465-7392 1476-4679 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7809593 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 14 14/35 631/136 631/80/84/1372 631/80/84/2334 631/80/86/820 64 64/116 Animals Animals, Genetically Modified Biomedical and Life Sciences Buffers Cancer Research Cell adhesion & migration Cell Biology Cell Line Cell migration Cell Movement Chemokine CXCL12 - metabolism Chemokines Chemokines - metabolism CXCL12 protein CXCR4 protein Danio rerio Developmental Biology Embryonic development Embryos Feedback Feedback loops Feedback, Physiological Health aspects Humans Lateral line Letter Life Sciences Negative feedback Phosphorylation Receptors, CXCR - metabolism Receptors, CXCR4 - metabolism Robustness SDF-1 protein Stem Cells Zebrafish Zebrafish - embryology Zebrafish - genetics Zebrafish - metabolism Zebrafish Proteins - metabolism |
| title | A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration |
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