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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Veröffentlicht in:Cell proliferation 2021-09, Vol.54 (9), p.e13106-n/a
Hauptverfasser: Lu, Qiumei, Gao, Ying, Fan, Zhimeng, Xiao, Xing, Chen, Yu, Si, Yuan, Kong, Deqiang, Wang, Shuai, Liao, Meijian, Chen, Xiaodong, Wang, Xusheng, Chu, Weiwei
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container_end_page n/a
container_issue 9
container_start_page e13106
container_title Cell proliferation
container_volume 54
creator Lu, Qiumei
Gao, Ying
Fan, Zhimeng
Xiao, Xing
Chen, Yu
Si, Yuan
Kong, Deqiang
Wang, Shuai
Liao, Meijian
Chen, Xiaodong
Wang, Xusheng
Chu, Weiwei
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
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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 &amp; 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 &amp; Sons Ltd.</rights><rights>COPYRIGHT 2021 John Wiley &amp; 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 &amp; 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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 &amp; 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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