Age-related inflammation triggers skeletal stem/progenitor cell dysfunction
Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulatin...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (14), p.6995-7004 |
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| creator | Josephson, Anne Marie Bradaschia-Correa, Vivian Lee, Sooyeon Leclerc, Kevin Patel, Karan S. Lopez, Emma Muinos Litwa, Hannah P. Neibart, Shane S. Kadiyala, Manasa Wong, Madeleine Z. Mizrahi, Matthew M. Yim, Nury L. Ramme, Austin J. Egol, Kenneth A. Leucht, Philipp |
| description | Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal. |
| doi_str_mv | 10.1073/pnas.1810692116 |
| format | Article |
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Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1810692116</identifier><identifier>PMID: 30894483</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Age ; Aging ; Aging - genetics ; Aging - metabolism ; Aging - pathology ; Animal models ; Animals ; Biocompatibility ; Biological Sciences ; Biomedical materials ; Bone healing ; Cell number ; Cells (biology) ; Decoupling ; Female ; Fracture Healing ; Fractures, Bone - metabolism ; Fractures, Bone - pathology ; Gene sequencing ; Genomes ; Healing ; Humans ; Inflammation ; Inflammation - genetics ; Inflammation - metabolism ; Inflammation - pathology ; Male ; Mice ; Mice, Knockout ; NF-kappa B p50 Subunit - genetics ; NF-kappa B p50 Subunit - metabolism ; NF-κB protein ; Osteogenesis ; Pharmacology ; Phenotypes ; PNAS Plus ; Progenitor cells ; Regeneration ; Restoration ; Ribonucleic acid ; RNA ; Senescence ; Stem cells ; Stem Cells - metabolism ; Stem Cells - pathology ; Tissue engineering ; Transgenic mice</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2019-04, Vol.116 (14), p.6995-7004</ispartof><rights>Copyright National Academy of Sciences Apr 2, 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-d32bfa60141843af39c70c8cad88d0e57c1ba25b7d3d4f36a9f4aa138be8d3803</citedby><cites>FETCH-LOGICAL-c509t-d32bfa60141843af39c70c8cad88d0e57c1ba25b7d3d4f36a9f4aa138be8d3803</cites><orcidid>0000-0002-8409-8513</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26698604$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26698604$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30894483$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Josephson, Anne Marie</creatorcontrib><creatorcontrib>Bradaschia-Correa, Vivian</creatorcontrib><creatorcontrib>Lee, Sooyeon</creatorcontrib><creatorcontrib>Leclerc, Kevin</creatorcontrib><creatorcontrib>Patel, Karan S.</creatorcontrib><creatorcontrib>Lopez, Emma Muinos</creatorcontrib><creatorcontrib>Litwa, Hannah P.</creatorcontrib><creatorcontrib>Neibart, Shane S.</creatorcontrib><creatorcontrib>Kadiyala, Manasa</creatorcontrib><creatorcontrib>Wong, Madeleine Z.</creatorcontrib><creatorcontrib>Mizrahi, Matthew M.</creatorcontrib><creatorcontrib>Yim, Nury L.</creatorcontrib><creatorcontrib>Ramme, Austin J.</creatorcontrib><creatorcontrib>Egol, Kenneth A.</creatorcontrib><creatorcontrib>Leucht, Philipp</creatorcontrib><title>Age-related inflammation triggers skeletal stem/progenitor cell dysfunction</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.</description><subject>Age</subject><subject>Aging</subject><subject>Aging - genetics</subject><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Biological Sciences</subject><subject>Biomedical materials</subject><subject>Bone healing</subject><subject>Cell number</subject><subject>Cells (biology)</subject><subject>Decoupling</subject><subject>Female</subject><subject>Fracture Healing</subject><subject>Fractures, Bone - metabolism</subject><subject>Fractures, Bone - pathology</subject><subject>Gene sequencing</subject><subject>Genomes</subject><subject>Healing</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>NF-kappa B p50 Subunit - genetics</subject><subject>NF-kappa B p50 Subunit - metabolism</subject><subject>NF-κB protein</subject><subject>Osteogenesis</subject><subject>Pharmacology</subject><subject>Phenotypes</subject><subject>PNAS Plus</subject><subject>Progenitor cells</subject><subject>Regeneration</subject><subject>Restoration</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Senescence</subject><subject>Stem cells</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - pathology</subject><subject>Tissue engineering</subject><subject>Transgenic mice</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUuP1DAQhC0EYoeFMydQJC5cstN-xLEvSKsVL7ESFzhbjt0JGRJ7sB2k_fckmmV4nPrQX5e6qgh5TuGKQsv3x2DzFVUUpGaUygdkR0HTWgoND8kOgLW1EkxckCc5HwBANwoekwsOSguh-I58uh6wTjjZgr4aQz_ZebZljKEqaRwGTLnK33HCYqcqF5z3xxQHDGOJqXI4TZW_y_0S3HbylDzq7ZTx2f28JF_fvf1y86G-_fz-4831be0a0KX2nHW9lUAFVYLbnmvXglPOeqU8YNM62lnWdK3nXvRcWt0LaylXHSrPFfBL8uake1y6Gb3DUJKdzDGNs013JtrR_LsJ4zczxJ9Gioa1QFeB1_cCKf5YMBczj3lzYwPGJRtGdcOaLasVffUfeohLCqs9wxijjIOUcqX2J8qlmHPC_vwMBbMVZbaizJ-i1ouXf3s487-bWYEXJ-CQ16zPeyalVhIE_wWyyJqU</recordid><startdate>20190402</startdate><enddate>20190402</enddate><creator>Josephson, Anne Marie</creator><creator>Bradaschia-Correa, Vivian</creator><creator>Lee, Sooyeon</creator><creator>Leclerc, Kevin</creator><creator>Patel, Karan S.</creator><creator>Lopez, Emma Muinos</creator><creator>Litwa, Hannah P.</creator><creator>Neibart, Shane S.</creator><creator>Kadiyala, Manasa</creator><creator>Wong, Madeleine Z.</creator><creator>Mizrahi, Matthew M.</creator><creator>Yim, Nury L.</creator><creator>Ramme, Austin J.</creator><creator>Egol, Kenneth A.</creator><creator>Leucht, Philipp</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8409-8513</orcidid></search><sort><creationdate>20190402</creationdate><title>Age-related inflammation triggers skeletal stem/progenitor cell dysfunction</title><author>Josephson, Anne Marie ; Bradaschia-Correa, Vivian ; Lee, Sooyeon ; Leclerc, Kevin ; Patel, Karan S. ; Lopez, Emma Muinos ; Litwa, Hannah P. ; Neibart, Shane S. ; Kadiyala, Manasa ; Wong, Madeleine Z. ; Mizrahi, Matthew M. ; Yim, Nury L. ; Ramme, Austin J. ; Egol, Kenneth A. ; Leucht, Philipp</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-d32bfa60141843af39c70c8cad88d0e57c1ba25b7d3d4f36a9f4aa138be8d3803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Age</topic><topic>Aging</topic><topic>Aging - 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metabolism</topic><topic>Stem Cells - pathology</topic><topic>Tissue engineering</topic><topic>Transgenic mice</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Josephson, Anne Marie</creatorcontrib><creatorcontrib>Bradaschia-Correa, Vivian</creatorcontrib><creatorcontrib>Lee, Sooyeon</creatorcontrib><creatorcontrib>Leclerc, Kevin</creatorcontrib><creatorcontrib>Patel, Karan S.</creatorcontrib><creatorcontrib>Lopez, Emma Muinos</creatorcontrib><creatorcontrib>Litwa, Hannah P.</creatorcontrib><creatorcontrib>Neibart, Shane S.</creatorcontrib><creatorcontrib>Kadiyala, Manasa</creatorcontrib><creatorcontrib>Wong, Madeleine Z.</creatorcontrib><creatorcontrib>Mizrahi, Matthew M.</creatorcontrib><creatorcontrib>Yim, Nury L.</creatorcontrib><creatorcontrib>Ramme, Austin J.</creatorcontrib><creatorcontrib>Egol, Kenneth A.</creatorcontrib><creatorcontrib>Leucht, Philipp</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</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>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Josephson, Anne Marie</au><au>Bradaschia-Correa, Vivian</au><au>Lee, Sooyeon</au><au>Leclerc, Kevin</au><au>Patel, Karan S.</au><au>Lopez, Emma Muinos</au><au>Litwa, Hannah P.</au><au>Neibart, Shane S.</au><au>Kadiyala, Manasa</au><au>Wong, Madeleine Z.</au><au>Mizrahi, Matthew M.</au><au>Yim, Nury L.</au><au>Ramme, Austin J.</au><au>Egol, Kenneth A.</au><au>Leucht, Philipp</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Age-related inflammation triggers skeletal stem/progenitor cell dysfunction</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2019-04-02</date><risdate>2019</risdate><volume>116</volume><issue>14</issue><spage>6995</spage><epage>7004</epage><pages>6995-7004</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30894483</pmid><doi>10.1073/pnas.1810692116</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-8409-8513</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Age Aging Aging - genetics Aging - metabolism Aging - pathology Animal models Animals Biocompatibility Biological Sciences Biomedical materials Bone healing Cell number Cells (biology) Decoupling Female Fracture Healing Fractures, Bone - metabolism Fractures, Bone - pathology Gene sequencing Genomes Healing Humans Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Male Mice Mice, Knockout NF-kappa B p50 Subunit - genetics NF-kappa B p50 Subunit - metabolism NF-κB protein Osteogenesis Pharmacology Phenotypes PNAS Plus Progenitor cells Regeneration Restoration Ribonucleic acid RNA Senescence Stem cells Stem Cells - metabolism Stem Cells - pathology Tissue engineering Transgenic mice |
| title | Age-related inflammation triggers skeletal stem/progenitor cell dysfunction |
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