Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair

Mesenchymal progenitor cells are broadly distributed across perivascular niches—an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populate...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Stem cells (Dayton, Ohio) Ohio), 2021-11, Vol.39 (11), p.1427-1434
Hauptverfasser: Xu, Jiajia, Wang, Yiyun, Gomez‐Salazar, Mario A., Hsu, Ginny Ching‐Yun, Negri, Stefano, Li, Zhao, Hardy, Winters, Ding, Lijun, Peault, Bruno, James, Aaron W.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1434
container_issue 11
container_start_page 1427
container_title Stem cells (Dayton, Ohio)
container_volume 39
creator Xu, Jiajia
Wang, Yiyun
Gomez‐Salazar, Mario A.
Hsu, Ginny Ching‐Yun
Negri, Stefano
Li, Zhao
Hardy, Winters
Ding, Lijun
Peault, Bruno
James, Aaron W.
description Mesenchymal progenitor cells are broadly distributed across perivascular niches—an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+, CD107alow, and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering. Mesenchymal progenitor cells in the tunica adventitia have a hierarchy of differentiation and proliferation potential. On top of the hierarchy, platelet‐derived growth factor receptor (PDGFR)α+ and aldehyde dehydrogenase (ALDH)High cells show a bipotent differentiation potential into osteogenic and adipogenic cell lineages with high proliferative rate. Conversely, CD10 and CD107a expression separate osteogenic progenitors from adipogenic progenitors, respectively. Moreover, osteoprogenitors can transition into adipogenic phenotype.
doi_str_mv 10.1002/stem.3436
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8830593</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2551207440</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4436-e0f91635ac580e43bbcd12b22cd85876ee557c84c9c59d56489cccdbf42665203</originalsourceid><addsrcrecordid>eNp1kcFu1DAQhi0EoqVw4AVQJC5wSGs7HsfmgASr0iIVcWg5W44z2bpK4sVOivbGI_CMPAlOt1QtEqfxyN_8849-Ql4yesgo5UdpwuGwEpV8RPYZCF0KzdTj_KZSlkC13iPPUrqilAlQ6inZqwQHziXdJ-cfw4i_f_7qQhz8uC42GP21TW7ubSwc9n16V6xyuekvccIY1jiin7aFHdtiTljk0WLyKc1YRNxYH5-TJ53tE764rQfk26fji9Vpefb15PPqw1npRPZaIu00kxVYB4qiqJrGtYw3nLtWgaolIkDtlHDagW5BCqWdc23TCS4lcFodkPc73c3cDNg6HKdoe7OJfrBxa4L15uHP6C_NOlwbpSoKusoCb24FYvg-Y5rM4NNytB0xzMlwAMZpLcSy6_U_6FWY45jPy5SSIKAWdabe7igXQ0oRuzszjJolKrNEZZaoMvvqvvs78m82GTjaAT98j9v_K5nzi-MvN5J_AKOhoHU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2586545747</pqid></control><display><type>article</type><title>Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Xu, Jiajia ; Wang, Yiyun ; Gomez‐Salazar, Mario A. ; Hsu, Ginny Ching‐Yun ; Negri, Stefano ; Li, Zhao ; Hardy, Winters ; Ding, Lijun ; Peault, Bruno ; James, Aaron W.</creator><creatorcontrib>Xu, Jiajia ; Wang, Yiyun ; Gomez‐Salazar, Mario A. ; Hsu, Ginny Ching‐Yun ; Negri, Stefano ; Li, Zhao ; Hardy, Winters ; Ding, Lijun ; Peault, Bruno ; James, Aaron W.</creatorcontrib><description>Mesenchymal progenitor cells are broadly distributed across perivascular niches—an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+, CD107alow, and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering. Mesenchymal progenitor cells in the tunica adventitia have a hierarchy of differentiation and proliferation potential. On top of the hierarchy, platelet‐derived growth factor receptor (PDGFR)α+ and aldehyde dehydrogenase (ALDH)High cells show a bipotent differentiation potential into osteogenic and adipogenic cell lineages with high proliferative rate. Conversely, CD10 and CD107a expression separate osteogenic progenitors from adipogenic progenitors, respectively. Moreover, osteoprogenitors can transition into adipogenic phenotype.</description><identifier>ISSN: 1066-5099</identifier><identifier>EISSN: 1549-4918</identifier><identifier>DOI: 10.1002/stem.3436</identifier><identifier>PMID: 34252260</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley &amp; Sons, Inc</publisher><subject>adipogenesis ; adipose stem cell ; Aldehyde dehydrogenase ; Aldehydes ; ALDH ; Animals ; Antigens ; Bioengineering ; Biomedical materials ; Blood vessels ; Bone growth ; CD10 ; CD107a ; CD140a ; Cell Differentiation ; Cells (biology) ; Cytology ; exocytosis ; Heterogeneity ; Isoforms ; LAMP1 ; Mammals ; mesenchymal stem cell ; Mesenchymal Stem Cells ; mesenchymal stromal cell ; Mesenchyme ; Morphology ; Niches ; Osteogenesis ; Pericytes ; perivascular stem cell ; Progenitor cells ; Repair ; Stem cells ; Tissue Engineering ; tunica adventitia ; Wound Healing</subject><ispartof>Stem cells (Dayton, Ohio), 2021-11, Vol.39 (11), p.1427-1434</ispartof><rights>2021 The Authors. STEM CELLS published by Wiley Periodicals LLC on behalf of AlphaMed Press.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc/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-c4436-e0f91635ac580e43bbcd12b22cd85876ee557c84c9c59d56489cccdbf42665203</citedby><cites>FETCH-LOGICAL-c4436-e0f91635ac580e43bbcd12b22cd85876ee557c84c9c59d56489cccdbf42665203</cites><orcidid>0000-0003-0775-4377 ; 0000-0002-2002-622X ; 0000-0002-6084-2029 ; 0000-0002-6330-7945 ; 0000-0001-5923-3413</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34252260$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Jiajia</creatorcontrib><creatorcontrib>Wang, Yiyun</creatorcontrib><creatorcontrib>Gomez‐Salazar, Mario A.</creatorcontrib><creatorcontrib>Hsu, Ginny Ching‐Yun</creatorcontrib><creatorcontrib>Negri, Stefano</creatorcontrib><creatorcontrib>Li, Zhao</creatorcontrib><creatorcontrib>Hardy, Winters</creatorcontrib><creatorcontrib>Ding, Lijun</creatorcontrib><creatorcontrib>Peault, Bruno</creatorcontrib><creatorcontrib>James, Aaron W.</creatorcontrib><title>Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair</title><title>Stem cells (Dayton, Ohio)</title><addtitle>Stem Cells</addtitle><description>Mesenchymal progenitor cells are broadly distributed across perivascular niches—an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+, CD107alow, and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering. Mesenchymal progenitor cells in the tunica adventitia have a hierarchy of differentiation and proliferation potential. On top of the hierarchy, platelet‐derived growth factor receptor (PDGFR)α+ and aldehyde dehydrogenase (ALDH)High cells show a bipotent differentiation potential into osteogenic and adipogenic cell lineages with high proliferative rate. Conversely, CD10 and CD107a expression separate osteogenic progenitors from adipogenic progenitors, respectively. Moreover, osteoprogenitors can transition into adipogenic phenotype.</description><subject>adipogenesis</subject><subject>adipose stem cell</subject><subject>Aldehyde dehydrogenase</subject><subject>Aldehydes</subject><subject>ALDH</subject><subject>Animals</subject><subject>Antigens</subject><subject>Bioengineering</subject><subject>Biomedical materials</subject><subject>Blood vessels</subject><subject>Bone growth</subject><subject>CD10</subject><subject>CD107a</subject><subject>CD140a</subject><subject>Cell Differentiation</subject><subject>Cells (biology)</subject><subject>Cytology</subject><subject>exocytosis</subject><subject>Heterogeneity</subject><subject>Isoforms</subject><subject>LAMP1</subject><subject>Mammals</subject><subject>mesenchymal stem cell</subject><subject>Mesenchymal Stem Cells</subject><subject>mesenchymal stromal cell</subject><subject>Mesenchyme</subject><subject>Morphology</subject><subject>Niches</subject><subject>Osteogenesis</subject><subject>Pericytes</subject><subject>perivascular stem cell</subject><subject>Progenitor cells</subject><subject>Repair</subject><subject>Stem cells</subject><subject>Tissue Engineering</subject><subject>tunica adventitia</subject><subject>Wound Healing</subject><issn>1066-5099</issn><issn>1549-4918</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAQhi0EoqVw4AVQJC5wSGs7HsfmgASr0iIVcWg5W44z2bpK4sVOivbGI_CMPAlOt1QtEqfxyN_8849-Ql4yesgo5UdpwuGwEpV8RPYZCF0KzdTj_KZSlkC13iPPUrqilAlQ6inZqwQHziXdJ-cfw4i_f_7qQhz8uC42GP21TW7ubSwc9n16V6xyuekvccIY1jiin7aFHdtiTljk0WLyKc1YRNxYH5-TJ53tE764rQfk26fji9Vpefb15PPqw1npRPZaIu00kxVYB4qiqJrGtYw3nLtWgaolIkDtlHDagW5BCqWdc23TCS4lcFodkPc73c3cDNg6HKdoe7OJfrBxa4L15uHP6C_NOlwbpSoKusoCb24FYvg-Y5rM4NNytB0xzMlwAMZpLcSy6_U_6FWY45jPy5SSIKAWdabe7igXQ0oRuzszjJolKrNEZZaoMvvqvvs78m82GTjaAT98j9v_K5nzi-MvN5J_AKOhoHU</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Xu, Jiajia</creator><creator>Wang, Yiyun</creator><creator>Gomez‐Salazar, Mario A.</creator><creator>Hsu, Ginny Ching‐Yun</creator><creator>Negri, Stefano</creator><creator>Li, Zhao</creator><creator>Hardy, Winters</creator><creator>Ding, Lijun</creator><creator>Peault, Bruno</creator><creator>James, Aaron W.</creator><general>John Wiley &amp; Sons, Inc</general><general>Oxford University Press</general><scope>24P</scope><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>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0775-4377</orcidid><orcidid>https://orcid.org/0000-0002-2002-622X</orcidid><orcidid>https://orcid.org/0000-0002-6084-2029</orcidid><orcidid>https://orcid.org/0000-0002-6330-7945</orcidid><orcidid>https://orcid.org/0000-0001-5923-3413</orcidid></search><sort><creationdate>202111</creationdate><title>Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair</title><author>Xu, Jiajia ; Wang, Yiyun ; Gomez‐Salazar, Mario A. ; Hsu, Ginny Ching‐Yun ; Negri, Stefano ; Li, Zhao ; Hardy, Winters ; Ding, Lijun ; Peault, Bruno ; James, Aaron W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4436-e0f91635ac580e43bbcd12b22cd85876ee557c84c9c59d56489cccdbf42665203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>adipogenesis</topic><topic>adipose stem cell</topic><topic>Aldehyde dehydrogenase</topic><topic>Aldehydes</topic><topic>ALDH</topic><topic>Animals</topic><topic>Antigens</topic><topic>Bioengineering</topic><topic>Biomedical materials</topic><topic>Blood vessels</topic><topic>Bone growth</topic><topic>CD10</topic><topic>CD107a</topic><topic>CD140a</topic><topic>Cell Differentiation</topic><topic>Cells (biology)</topic><topic>Cytology</topic><topic>exocytosis</topic><topic>Heterogeneity</topic><topic>Isoforms</topic><topic>LAMP1</topic><topic>Mammals</topic><topic>mesenchymal stem cell</topic><topic>Mesenchymal Stem Cells</topic><topic>mesenchymal stromal cell</topic><topic>Mesenchyme</topic><topic>Morphology</topic><topic>Niches</topic><topic>Osteogenesis</topic><topic>Pericytes</topic><topic>perivascular stem cell</topic><topic>Progenitor cells</topic><topic>Repair</topic><topic>Stem cells</topic><topic>Tissue Engineering</topic><topic>tunica adventitia</topic><topic>Wound Healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Jiajia</creatorcontrib><creatorcontrib>Wang, Yiyun</creatorcontrib><creatorcontrib>Gomez‐Salazar, Mario A.</creatorcontrib><creatorcontrib>Hsu, Ginny Ching‐Yun</creatorcontrib><creatorcontrib>Negri, Stefano</creatorcontrib><creatorcontrib>Li, Zhao</creatorcontrib><creatorcontrib>Hardy, Winters</creatorcontrib><creatorcontrib>Ding, Lijun</creatorcontrib><creatorcontrib>Peault, Bruno</creatorcontrib><creatorcontrib>James, Aaron W.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Stem cells (Dayton, Ohio)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Jiajia</au><au>Wang, Yiyun</au><au>Gomez‐Salazar, Mario A.</au><au>Hsu, Ginny Ching‐Yun</au><au>Negri, Stefano</au><au>Li, Zhao</au><au>Hardy, Winters</au><au>Ding, Lijun</au><au>Peault, Bruno</au><au>James, Aaron W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair</atitle><jtitle>Stem cells (Dayton, Ohio)</jtitle><addtitle>Stem Cells</addtitle><date>2021-11</date><risdate>2021</risdate><volume>39</volume><issue>11</issue><spage>1427</spage><epage>1434</epage><pages>1427-1434</pages><issn>1066-5099</issn><eissn>1549-4918</eissn><abstract>Mesenchymal progenitor cells are broadly distributed across perivascular niches—an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+, CD107alow, and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering. Mesenchymal progenitor cells in the tunica adventitia have a hierarchy of differentiation and proliferation potential. On top of the hierarchy, platelet‐derived growth factor receptor (PDGFR)α+ and aldehyde dehydrogenase (ALDH)High cells show a bipotent differentiation potential into osteogenic and adipogenic cell lineages with high proliferative rate. Conversely, CD10 and CD107a expression separate osteogenic progenitors from adipogenic progenitors, respectively. Moreover, osteoprogenitors can transition into adipogenic phenotype.</abstract><cop>Hoboken, USA</cop><pub>John Wiley &amp; Sons, Inc</pub><pmid>34252260</pmid><doi>10.1002/stem.3436</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-0775-4377</orcidid><orcidid>https://orcid.org/0000-0002-2002-622X</orcidid><orcidid>https://orcid.org/0000-0002-6084-2029</orcidid><orcidid>https://orcid.org/0000-0002-6330-7945</orcidid><orcidid>https://orcid.org/0000-0001-5923-3413</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1066-5099
ispartof Stem cells (Dayton, Ohio), 2021-11, Vol.39 (11), p.1427-1434
issn 1066-5099
1549-4918
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8830593
source Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects adipogenesis
adipose stem cell
Aldehyde dehydrogenase
Aldehydes
ALDH
Animals
Antigens
Bioengineering
Biomedical materials
Blood vessels
Bone growth
CD10
CD107a
CD140a
Cell Differentiation
Cells (biology)
Cytology
exocytosis
Heterogeneity
Isoforms
LAMP1
Mammals
mesenchymal stem cell
Mesenchymal Stem Cells
mesenchymal stromal cell
Mesenchyme
Morphology
Niches
Osteogenesis
Pericytes
perivascular stem cell
Progenitor cells
Repair
Stem cells
Tissue Engineering
tunica adventitia
Wound Healing
title Bone‐forming perivascular cells: Cellular heterogeneity and use for tissue repair
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T18%3A24%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Bone%E2%80%90forming%20perivascular%20cells:%20Cellular%20heterogeneity%20and%20use%20for%20tissue%20repair&rft.jtitle=Stem%20cells%20(Dayton,%20Ohio)&rft.au=Xu,%20Jiajia&rft.date=2021-11&rft.volume=39&rft.issue=11&rft.spage=1427&rft.epage=1434&rft.pages=1427-1434&rft.issn=1066-5099&rft.eissn=1549-4918&rft_id=info:doi/10.1002/stem.3436&rft_dat=%3Cproquest_pubme%3E2551207440%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2586545747&rft_id=info:pmid/34252260&rfr_iscdi=true