Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death
Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity....
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| description | Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal dif |
| doi_str_mv | 10.1371/journal.pone.0154781 |
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Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0154781</identifier><identifier>PMID: 27144388</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Apoptosis ; Bcl-2 protein ; Biology and Life Sciences ; Biosynthesis ; Boranes - pharmacology ; Brain slice preparation ; Cancer ; Carbon monoxide ; Carbonates - pharmacology ; Caspase ; Caspase 3 - metabolism ; Caspase-3 ; Cell death ; Cell Death - drug effects ; Cell Differentiation - drug effects ; Cell growth ; Cell Line ; Cell lines ; Cell number ; Cell proliferation ; Cell Proliferation - drug effects ; Central nervous system ; Differentiation ; Gene expression ; Heme ; Hippocampus ; Humans ; Inflammation ; Iodides ; Ischemia ; Low concentrations ; Mice ; Mice, Inbred BALB C ; Mortality ; mRNA ; Nestin ; Neurodegenerative diseases ; Neurogenesis ; Neurogenesis - drug effects ; Neurological diseases ; Neuromodulation ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neurotrophin 2 ; Oxygen ; Oxygenase ; Propidium iodide ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Receptors ; Research and Analysis Methods ; Retinoic acid ; Rodents ; Signaling ; Smooth muscle ; Stem cells ; Studies ; Tissues ; Yield</subject><ispartof>PloS one, 2016-05, Vol.11 (5), p.e0154781</ispartof><rights>2016 Almeida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Almeida et al 2016 Almeida et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-f4476b807a01f6ad86400463f81f22ba7ae1b2f36076a48bc88ebb97a5f6c2ae3</citedby><orcidid>0000-0001-9415-3742</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/PMC4856303/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856303/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27144388$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Almeida, Ana S</creatorcontrib><creatorcontrib>Soares, Nuno L</creatorcontrib><creatorcontrib>Vieira, Melissa</creatorcontrib><creatorcontrib>Gramsbergen, Jan Bert</creatorcontrib><creatorcontrib>Vieira, Helena L A</creatorcontrib><title>Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Biology and Life Sciences</subject><subject>Biosynthesis</subject><subject>Boranes - pharmacology</subject><subject>Brain slice preparation</subject><subject>Cancer</subject><subject>Carbon monoxide</subject><subject>Carbonates - pharmacology</subject><subject>Caspase</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase-3</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cell number</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Central nervous system</subject><subject>Differentiation</subject><subject>Gene expression</subject><subject>Heme</subject><subject>Hippocampus</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Iodides</subject><subject>Ischemia</subject><subject>Low concentrations</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mortality</subject><subject>mRNA</subject><subject>Nestin</subject><subject>Neurodegenerative diseases</subject><subject>Neurogenesis</subject><subject>Neurogenesis - drug effects</subject><subject>Neurological diseases</subject><subject>Neuromodulation</subject><subject>Neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurotrophin 2</subject><subject>Oxygen</subject><subject>Oxygenase</subject><subject>Propidium iodide</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Receptors</subject><subject>Research and Analysis Methods</subject><subject>Retinoic acid</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Tissues</subject><subject>Yield</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1UktvEzEQXiEQLYV_gMASFzhs8NsOB6RqeUVqKargwMmyN-PU0WYd7N2I_gV-NQ7ZVu2Bk0cz32PG-qrqOcEzwhR5u45j6m0328YeZpgIrjR5UB2TOaO1pJg9vFMfVU9yXmMsmJbycXVEFeGcaX1c_WlscrFH57GPv8MS0CV0YHPoV6XVQTt2UJ8S9Lq5uDwvxRu02GxT3EFGX2FMcQU95JDfoUXfpsIDFP1hUlZDH4L3kKAfgh1CMfkZoFsid42-Jdjt28Wlga4AwQ5XT6tH3nYZnk3vSfXj08fvzZf67OLzojk9q1tB5VB7zpV0GiuLiZd2qSXHmEvmNfGUOqssEEc9k1hJy7VrtQbn5soKL1tqgZ1ULw-62y5mM31jNkRpqeZUUF0QiwNiGe3abFPY2HRtog3mXyOmlbFpCG0HxjFCiibHreWctMIJj8GJuSJMCK_2bu8nt9FtYNmWs5Pt7onen_ThyqziznAtJMOsCLyaBFL8NUIe_rMyP6DaFHNO4G8dCDb7vNywzD4vZspLob24u90t6SYg7C_Df79w</recordid><startdate>20160504</startdate><enddate>20160504</enddate><creator>Almeida, Ana S</creator><creator>Soares, Nuno L</creator><creator>Vieira, Melissa</creator><creator>Gramsbergen, Jan Bert</creator><creator>Vieira, Helena L A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9415-3742</orcidid></search><sort><creationdate>20160504</creationdate><title>Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death</title><author>Almeida, Ana S ; Soares, Nuno L ; Vieira, Melissa ; Gramsbergen, Jan Bert ; Vieira, Helena L A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-f4476b807a01f6ad86400463f81f22ba7ae1b2f36076a48bc88ebb97a5f6c2ae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Bcl-2 protein</topic><topic>Biology and Life Sciences</topic><topic>Biosynthesis</topic><topic>Boranes - 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Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27144388</pmid><doi>10.1371/journal.pone.0154781</doi><orcidid>https://orcid.org/0000-0001-9415-3742</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1786792528 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Apoptosis Bcl-2 protein Biology and Life Sciences Biosynthesis Boranes - pharmacology Brain slice preparation Cancer Carbon monoxide Carbonates - pharmacology Caspase Caspase 3 - metabolism Caspase-3 Cell death Cell Death - drug effects Cell Differentiation - drug effects Cell growth Cell Line Cell lines Cell number Cell proliferation Cell Proliferation - drug effects Central nervous system Differentiation Gene expression Heme Hippocampus Humans Inflammation Iodides Ischemia Low concentrations Mice Mice, Inbred BALB C Mortality mRNA Nestin Neurodegenerative diseases Neurogenesis Neurogenesis - drug effects Neurological diseases Neuromodulation Neurons Neurons - drug effects Neurons - metabolism Neurotrophin 2 Oxygen Oxygenase Propidium iodide Proto-Oncogene Proteins c-bcl-2 - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Receptors Research and Analysis Methods Retinoic acid Rodents Signaling Smooth muscle Stem cells Studies Tissues Yield |
| title | Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T20%3A54%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Carbon%20Monoxide%20Releasing%20Molecule-A1%20(CORM-A1)%20Improves%20Neurogenesis:%20Increase%20of%20Neuronal%20Differentiation%20Yield%20by%20Preventing%20Cell%20Death&rft.jtitle=PloS%20one&rft.au=Almeida,%20Ana%20S&rft.date=2016-05-04&rft.volume=11&rft.issue=5&rft.spage=e0154781&rft.pages=e0154781-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0154781&rft_dat=%3Cproquest_plos_%3E4044902611%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1786792528&rft_id=info:pmid/27144388&rft_doaj_id=oai_doaj_org_article_b311ae340ca441c5b5f0eb5971355f7e&rfr_iscdi=true |