Amphiregulin promotes hair regeneration of skin‐derived precursors via the PI3K and MAPK pathways
Objectives There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; ho...
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description | Objectives
There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing.
Materials and Methods
We describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo.
Results
The 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.
Conclusions
By exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.
The 3D co‐culture system reveals that Epi‐SCs and ASCs help SKPs express a higher level of AREG, leading to upregulation of the downstream PI3K and MAPK pathways. As a result, SKP capabilities of proliferation and HF regeneration are promoted. |
doi_str_mv | 10.1111/cpr.13106 |
format | Article |
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There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing.
Materials and Methods
We describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo.
Results
The 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.
Conclusions
By exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.
The 3D co‐culture system reveals that Epi‐SCs and ASCs help SKPs express a higher level of AREG, leading to upregulation of the downstream PI3K and MAPK pathways. As a result, SKP capabilities of proliferation and HF regeneration are promoted.</description><identifier>ISSN: 0960-7722</identifier><identifier>EISSN: 1365-2184</identifier><identifier>DOI: 10.1111/cpr.13106</identifier><identifier>PMID: 34382262</identifier><language>eng</language><publisher>Chichester: John Wiley & Sons, Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; 3D co‐culture system ; Alkaline phosphatase ; Alopecia ; Amphiregulin ; Analysis ; Baldness ; Blood ; Cell culture ; Cell proliferation ; Chemokines ; Dutasteride ; Encyclopedias ; Epidermal growth factor ; Follicles ; Gene expression ; Genes ; Genetic research ; Genomes ; Genomics ; Hair ; hair follicle ; Hair loss ; Immunofluorescence ; Immunosuppressive agents ; Kinases ; Laboratory animals ; MAP kinase ; MAPK ; Morphogenesis ; Original ; Penicillin ; Phosphatases ; PI3K ; Precursors ; Protein kinase ; Protein kinases ; Proteins ; Recombinant proteins ; Regeneration ; RNA-mediated interference ; Signal transduction ; Skin ; skin‐derived precursors ; Staining ; Stem cells ; Three dimensional models ; Transplantation</subject><ispartof>Cell proliferation, 2021-09, Vol.54 (9), p.e13106-n/a</ispartof><rights>2021 The Authors. published by John Wiley & Sons Ltd.</rights><rights>COPYRIGHT 2021 John Wiley & Sons, Inc.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4876-3a8673c247979135cdd22d39d5335fe0bc6510edb9bf4f6d97d95837287e64323</citedby><cites>FETCH-LOGICAL-c4876-3a8673c247979135cdd22d39d5335fe0bc6510edb9bf4f6d97d95837287e64323</cites><orcidid>0000-0003-3607-7141</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450126/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450126/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1416,11561,27923,27924,45573,45574,46051,46475,53790,53792</link.rule.ids></links><search><creatorcontrib>Lu, Qiumei</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Fan, Zhimeng</creatorcontrib><creatorcontrib>Xiao, Xing</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Si, Yuan</creatorcontrib><creatorcontrib>Kong, Deqiang</creatorcontrib><creatorcontrib>Wang, Shuai</creatorcontrib><creatorcontrib>Liao, Meijian</creatorcontrib><creatorcontrib>Chen, Xiaodong</creatorcontrib><creatorcontrib>Wang, Xusheng</creatorcontrib><creatorcontrib>Chu, Weiwei</creatorcontrib><title>Amphiregulin promotes hair regeneration of skin‐derived precursors via the PI3K and MAPK pathways</title><title>Cell proliferation</title><description>Objectives
There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing.
Materials and Methods
We describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo.
Results
The 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.
Conclusions
By exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.
The 3D co‐culture system reveals that Epi‐SCs and ASCs help SKPs express a higher level of AREG, leading to upregulation of the downstream PI3K and MAPK pathways. As a result, SKP capabilities of proliferation and HF regeneration are promoted.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>3D co‐culture system</subject><subject>Alkaline phosphatase</subject><subject>Alopecia</subject><subject>Amphiregulin</subject><subject>Analysis</subject><subject>Baldness</subject><subject>Blood</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>Chemokines</subject><subject>Dutasteride</subject><subject>Encyclopedias</subject><subject>Epidermal growth factor</subject><subject>Follicles</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic research</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Hair</subject><subject>hair follicle</subject><subject>Hair loss</subject><subject>Immunofluorescence</subject><subject>Immunosuppressive agents</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>MAP kinase</subject><subject>MAPK</subject><subject>Morphogenesis</subject><subject>Original</subject><subject>Penicillin</subject><subject>Phosphatases</subject><subject>PI3K</subject><subject>Precursors</subject><subject>Protein kinase</subject><subject>Protein kinases</subject><subject>Proteins</subject><subject>Recombinant proteins</subject><subject>Regeneration</subject><subject>RNA-mediated interference</subject><subject>Signal transduction</subject><subject>Skin</subject><subject>skin‐derived precursors</subject><subject>Staining</subject><subject>Stem cells</subject><subject>Three dimensional models</subject><subject>Transplantation</subject><issn>0960-7722</issn><issn>1365-2184</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1ks1u1DAUhSMEokNhwRtYYgOLTP0T28kGaTQqULWIEYK15bFvJi6JHexkqtnxCDwjT4LLVKAisBeWrr9zro50iuI5wUuSz5kZ45IwgsWDYkGY4CUldfWwWOBG4FJKSk-KJyldY5whKR4XJ6xiNaWCLgqzGsbORdjNvfNojGEIEyTUaRdRnoKHqCcXPAotSl-c__Htu4Xo9mAzDGaOKcSE9k6jqQO0uWCXSHuL3q82l2jUU3ejD-lp8ajVfYJnd-9p8fnN-af1u_Lqw9uL9eqqNFUtRcl0LSQztJKNbAjjxlpKLWssZ4y3gLdGcILBbpttW7XCNtI2vGaS1hJExSg7LV4ffcd5O4A14KeoezVGN-h4UEE7df_Hu07twl7VFceEimzw8s4ghq8zpEkNLhnoe-0hzElRLnDNMGcyoy_-Qq_DHH2OlylZ4brhUvyhdroH5Xwb8l5za6pWkmCZ8-AqU8t_UPlaGJwJHlqX5_cEr44CE0NKEdrfGQlWt41QuRHqVyMye3Zkb7LJ4f-gWm8-HhU_AV0ktUM</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Lu, Qiumei</creator><creator>Gao, Ying</creator><creator>Fan, Zhimeng</creator><creator>Xiao, Xing</creator><creator>Chen, Yu</creator><creator>Si, Yuan</creator><creator>Kong, Deqiang</creator><creator>Wang, Shuai</creator><creator>Liao, Meijian</creator><creator>Chen, Xiaodong</creator><creator>Wang, Xusheng</creator><creator>Chu, Weiwei</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3607-7141</orcidid></search><sort><creationdate>202109</creationdate><title>Amphiregulin promotes hair regeneration of skin‐derived precursors via the PI3K and MAPK pathways</title><author>Lu, Qiumei ; Gao, Ying ; Fan, Zhimeng ; Xiao, Xing ; Chen, Yu ; Si, Yuan ; Kong, Deqiang ; Wang, Shuai ; Liao, Meijian ; Chen, Xiaodong ; Wang, Xusheng ; Chu, Weiwei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4876-3a8673c247979135cdd22d39d5335fe0bc6510edb9bf4f6d97d95837287e64323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>3D co‐culture system</topic><topic>Alkaline phosphatase</topic><topic>Alopecia</topic><topic>Amphiregulin</topic><topic>Analysis</topic><topic>Baldness</topic><topic>Blood</topic><topic>Cell culture</topic><topic>Cell proliferation</topic><topic>Chemokines</topic><topic>Dutasteride</topic><topic>Encyclopedias</topic><topic>Epidermal growth factor</topic><topic>Follicles</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic research</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Hair</topic><topic>hair follicle</topic><topic>Hair loss</topic><topic>Immunofluorescence</topic><topic>Immunosuppressive agents</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>MAP kinase</topic><topic>MAPK</topic><topic>Morphogenesis</topic><topic>Original</topic><topic>Penicillin</topic><topic>Phosphatases</topic><topic>PI3K</topic><topic>Precursors</topic><topic>Protein kinase</topic><topic>Protein kinases</topic><topic>Proteins</topic><topic>Recombinant proteins</topic><topic>Regeneration</topic><topic>RNA-mediated interference</topic><topic>Signal transduction</topic><topic>Skin</topic><topic>skin‐derived precursors</topic><topic>Staining</topic><topic>Stem cells</topic><topic>Three dimensional models</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Qiumei</creatorcontrib><creatorcontrib>Gao, Ying</creatorcontrib><creatorcontrib>Fan, Zhimeng</creatorcontrib><creatorcontrib>Xiao, Xing</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Si, Yuan</creatorcontrib><creatorcontrib>Kong, Deqiang</creatorcontrib><creatorcontrib>Wang, Shuai</creatorcontrib><creatorcontrib>Liao, Meijian</creatorcontrib><creatorcontrib>Chen, Xiaodong</creatorcontrib><creatorcontrib>Wang, Xusheng</creatorcontrib><creatorcontrib>Chu, Weiwei</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</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>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell proliferation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Qiumei</au><au>Gao, Ying</au><au>Fan, Zhimeng</au><au>Xiao, Xing</au><au>Chen, Yu</au><au>Si, Yuan</au><au>Kong, Deqiang</au><au>Wang, Shuai</au><au>Liao, Meijian</au><au>Chen, Xiaodong</au><au>Wang, Xusheng</au><au>Chu, Weiwei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amphiregulin promotes hair regeneration of skin‐derived precursors via the PI3K and MAPK pathways</atitle><jtitle>Cell proliferation</jtitle><date>2021-09</date><risdate>2021</risdate><volume>54</volume><issue>9</issue><spage>e13106</spage><epage>n/a</epage><pages>e13106-n/a</pages><issn>0960-7722</issn><eissn>1365-2184</eissn><abstract>Objectives
There are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing.
Materials and Methods
We describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo.
Results
The 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.
Conclusions
By exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.
The 3D co‐culture system reveals that Epi‐SCs and ASCs help SKPs express a higher level of AREG, leading to upregulation of the downstream PI3K and MAPK pathways. As a result, SKP capabilities of proliferation and HF regeneration are promoted.</abstract><cop>Chichester</cop><pub>John Wiley & Sons, Inc</pub><pmid>34382262</pmid><doi>10.1111/cpr.13106</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-3607-7141</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 1-Phosphatidylinositol 3-kinase 3D co‐culture system Alkaline phosphatase Alopecia Amphiregulin Analysis Baldness Blood Cell culture Cell proliferation Chemokines Dutasteride Encyclopedias Epidermal growth factor Follicles Gene expression Genes Genetic research Genomes Genomics Hair hair follicle Hair loss Immunofluorescence Immunosuppressive agents Kinases Laboratory animals MAP kinase MAPK Morphogenesis Original Penicillin Phosphatases PI3K Precursors Protein kinase Protein kinases Proteins Recombinant proteins Regeneration RNA-mediated interference Signal transduction Skin skin‐derived precursors Staining Stem cells Three dimensional models Transplantation |
title | Amphiregulin promotes hair regeneration of skin‐derived precursors via the PI3K and MAPK pathways |
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