Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth
We previously developed and validated a strategy for stimulating heart regeneration by administration of recombinant neuregulin (rNRG1), a growth factor, in mice. rNRG1 stimulated proliferation of heart muscle cells, cardiomyocytes, and was most effective when administration began during the neonata...
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| Veröffentlicht in: | PloS one 2016-05, Vol.11 (5), p.e0155456 |
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| creator | Ganapathy, Balakrishnan Nandhagopal, Nikitha Polizzotti, Brian D Bennett, David Asan, Alparslan Wu, Yijen Kühn, Bernhard |
| description | We previously developed and validated a strategy for stimulating heart regeneration by administration of recombinant neuregulin (rNRG1), a growth factor, in mice. rNRG1 stimulated proliferation of heart muscle cells, cardiomyocytes, and was most effective when administration began during the neonatal period. Our results suggested the use of rNRG1 to treat pediatric patients with heart failure. However, administration in this age group may stimulate growth outside of the heart.
NRG1 and ErbB receptor expression was determined by RT-PCR. rNRG1 concentrations in serum were quantified by ELISA. Mice that received protocols of recombinant neuregulin1-β1 administration (rNRG1, 100 ng/g body weight, daily subcutaneous injection for the first month of life), previously shown to induce cardiac regeneration, were examined at pre-determined intervals. Somatic growth was quantified by weighing. Organ growth was quantified by MRI and by weighing. Neoplastic growth was examined by MRI, visual inspection, and histopathological analyses. Phospho-ERK1/2 and S6 kinase were analyzed with Western blot and ELISA, respectively.
Lung, spleen, liver, kidney, brain, and breast gland exhibited variable expression of the NRG1 receptors ErbB2, ErbB3, ErbB4, and NRG1. Body weight and tibia length were not altered in mice receiving rNRG1. MRI showed that administration of rNRG1 did not alter the volume of the lungs, liver, kidneys, brain, or spinal cord. Administration of rNRG1 did not alter the weight of the lungs, spleen, liver, kidneys, or brain. MRI, visual inspection, and histopathological analyses showed no neoplastic growth. Follow-up for 6 months showed no alteration of somatic or organ growth. rNRG1 treatment increased the levels of phospho-ERK1/2, but not phospho-S6 kinase.
Administration protocols of rNRG1 for stimulating cardiac regeneration in mice during the first month of life did not induce unwanted growth effects. Further studies may be required to determine whether this is the case in a corresponding human population. |
| doi_str_mv | 10.1371/journal.pone.0155456 |
| format | Article |
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NRG1 and ErbB receptor expression was determined by RT-PCR. rNRG1 concentrations in serum were quantified by ELISA. Mice that received protocols of recombinant neuregulin1-β1 administration (rNRG1, 100 ng/g body weight, daily subcutaneous injection for the first month of life), previously shown to induce cardiac regeneration, were examined at pre-determined intervals. Somatic growth was quantified by weighing. Organ growth was quantified by MRI and by weighing. Neoplastic growth was examined by MRI, visual inspection, and histopathological analyses. Phospho-ERK1/2 and S6 kinase were analyzed with Western blot and ELISA, respectively.
Lung, spleen, liver, kidney, brain, and breast gland exhibited variable expression of the NRG1 receptors ErbB2, ErbB3, ErbB4, and NRG1. Body weight and tibia length were not altered in mice receiving rNRG1. MRI showed that administration of rNRG1 did not alter the volume of the lungs, liver, kidneys, brain, or spinal cord. Administration of rNRG1 did not alter the weight of the lungs, spleen, liver, kidneys, or brain. MRI, visual inspection, and histopathological analyses showed no neoplastic growth. Follow-up for 6 months showed no alteration of somatic or organ growth. rNRG1 treatment increased the levels of phospho-ERK1/2, but not phospho-S6 kinase.
Administration protocols of rNRG1 for stimulating cardiac regeneration in mice during the first month of life did not induce unwanted growth effects. Further studies may be required to determine whether this is the case in a corresponding human population.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0155456</identifier><identifier>PMID: 27175488</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging - physiology ; Amino acids ; Animals ; Animals, Newborn ; Antineoplastic agents ; Biology ; Biology and Life Sciences ; Body weight ; Brain ; Cancer ; Cardiac muscle ; Cardiology ; Cardiomyocytes ; Cardiovascular disease ; Care and treatment ; Cell cycle ; Cell proliferation ; Clinical trials ; Cynops pyrrhogaster ; Dosage and administration ; Enzyme-linked immunosorbent assay ; Epidermal growth factor ; ErbB protein ; ErbB Receptors - genetics ; ErbB Receptors - metabolism ; ErbB-2 protein ; ErbB-3 protein ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Gene Expression Regulation - drug effects ; Health aspects ; Heart ; Heart - drug effects ; Heart - physiology ; Heart diseases ; Heart failure ; Hospitals ; Human populations ; Humans ; Inspection ; Kidney - drug effects ; Kidney - enzymology ; Kidneys ; Kinases ; Liver ; Lungs ; Magnetic resonance imaging ; Medicine ; Medicine and Health Sciences ; Mice ; Morphogenesis - drug effects ; Muscles ; Neonates ; Neoplasms - pathology ; Neuregulin ; Neuregulin 1 ; Neuregulin-1 - administration & dosage ; Neuregulin-1 - blood ; Neuregulin-1 - genetics ; Neuregulin-1 - pharmacology ; Organ Size - drug effects ; Pediatrics ; Phosphorylation - drug effects ; Physical Sciences ; Polymerase chain reaction ; Receptors ; Recombinant Proteins - pharmacology ; Regeneration ; Regeneration - drug effects ; Research and Analysis Methods ; Ribosomal Protein S6 Kinases - metabolism ; Rodents ; Spinal cord ; Spleen ; Studies ; Tibia ; Weighing</subject><ispartof>PloS one, 2016-05, Vol.11 (5), p.e0155456</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Ganapathy 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 Ganapathy et al 2016 Ganapathy et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3995aa210e24444f5ac84342805e430c9f01f975747808cac7ed9e7f3bfdfc013</citedby><cites>FETCH-LOGICAL-c692t-3995aa210e24444f5ac84342805e430c9f01f975747808cac7ed9e7f3bfdfc013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866786/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866786/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27175488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Calvert, John</contributor><creatorcontrib>Ganapathy, Balakrishnan</creatorcontrib><creatorcontrib>Nandhagopal, Nikitha</creatorcontrib><creatorcontrib>Polizzotti, Brian D</creatorcontrib><creatorcontrib>Bennett, David</creatorcontrib><creatorcontrib>Asan, Alparslan</creatorcontrib><creatorcontrib>Wu, Yijen</creatorcontrib><creatorcontrib>Kühn, Bernhard</creatorcontrib><title>Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We previously developed and validated a strategy for stimulating heart regeneration by administration of recombinant neuregulin (rNRG1), a growth factor, in mice. rNRG1 stimulated proliferation of heart muscle cells, cardiomyocytes, and was most effective when administration began during the neonatal period. Our results suggested the use of rNRG1 to treat pediatric patients with heart failure. However, administration in this age group may stimulate growth outside of the heart.
NRG1 and ErbB receptor expression was determined by RT-PCR. rNRG1 concentrations in serum were quantified by ELISA. Mice that received protocols of recombinant neuregulin1-β1 administration (rNRG1, 100 ng/g body weight, daily subcutaneous injection for the first month of life), previously shown to induce cardiac regeneration, were examined at pre-determined intervals. Somatic growth was quantified by weighing. Organ growth was quantified by MRI and by weighing. Neoplastic growth was examined by MRI, visual inspection, and histopathological analyses. Phospho-ERK1/2 and S6 kinase were analyzed with Western blot and ELISA, respectively.
Lung, spleen, liver, kidney, brain, and breast gland exhibited variable expression of the NRG1 receptors ErbB2, ErbB3, ErbB4, and NRG1. Body weight and tibia length were not altered in mice receiving rNRG1. MRI showed that administration of rNRG1 did not alter the volume of the lungs, liver, kidneys, brain, or spinal cord. Administration of rNRG1 did not alter the weight of the lungs, spleen, liver, kidneys, or brain. MRI, visual inspection, and histopathological analyses showed no neoplastic growth. Follow-up for 6 months showed no alteration of somatic or organ growth. rNRG1 treatment increased the levels of phospho-ERK1/2, but not phospho-S6 kinase.
Administration protocols of rNRG1 for stimulating cardiac regeneration in mice during the first month of life did not induce unwanted growth effects. Further studies may be required to determine whether this is the case in a corresponding human population.</description><subject>Aging - physiology</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Antineoplastic agents</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Body weight</subject><subject>Brain</subject><subject>Cancer</subject><subject>Cardiac muscle</subject><subject>Cardiology</subject><subject>Cardiomyocytes</subject><subject>Cardiovascular disease</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cell proliferation</subject><subject>Clinical trials</subject><subject>Cynops pyrrhogaster</subject><subject>Dosage and administration</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Epidermal growth factor</subject><subject>ErbB protein</subject><subject>ErbB Receptors - genetics</subject><subject>ErbB Receptors - metabolism</subject><subject>ErbB-2 protein</subject><subject>ErbB-3 protein</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart - drug effects</subject><subject>Heart - physiology</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Hospitals</subject><subject>Human populations</subject><subject>Humans</subject><subject>Inspection</subject><subject>Kidney - drug effects</subject><subject>Kidney - enzymology</subject><subject>Kidneys</subject><subject>Kinases</subject><subject>Liver</subject><subject>Lungs</subject><subject>Magnetic resonance imaging</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Morphogenesis - drug effects</subject><subject>Muscles</subject><subject>Neonates</subject><subject>Neoplasms - pathology</subject><subject>Neuregulin</subject><subject>Neuregulin 1</subject><subject>Neuregulin-1 - administration & dosage</subject><subject>Neuregulin-1 - blood</subject><subject>Neuregulin-1 - 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drug effects</topic><topic>Heart - physiology</topic><topic>Heart diseases</topic><topic>Heart failure</topic><topic>Hospitals</topic><topic>Human populations</topic><topic>Humans</topic><topic>Inspection</topic><topic>Kidney - drug effects</topic><topic>Kidney - enzymology</topic><topic>Kidneys</topic><topic>Kinases</topic><topic>Liver</topic><topic>Lungs</topic><topic>Magnetic resonance imaging</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Morphogenesis - drug effects</topic><topic>Muscles</topic><topic>Neonates</topic><topic>Neoplasms - pathology</topic><topic>Neuregulin</topic><topic>Neuregulin 1</topic><topic>Neuregulin-1 - administration & dosage</topic><topic>Neuregulin-1 - blood</topic><topic>Neuregulin-1 - genetics</topic><topic>Neuregulin-1 - pharmacology</topic><topic>Organ Size - drug effects</topic><topic>Pediatrics</topic><topic>Phosphorylation - drug effects</topic><topic>Physical Sciences</topic><topic>Polymerase chain reaction</topic><topic>Receptors</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Regeneration</topic><topic>Regeneration - drug effects</topic><topic>Research and Analysis Methods</topic><topic>Ribosomal Protein S6 Kinases - metabolism</topic><topic>Rodents</topic><topic>Spinal cord</topic><topic>Spleen</topic><topic>Studies</topic><topic>Tibia</topic><topic>Weighing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ganapathy, Balakrishnan</creatorcontrib><creatorcontrib>Nandhagopal, Nikitha</creatorcontrib><creatorcontrib>Polizzotti, Brian D</creatorcontrib><creatorcontrib>Bennett, David</creatorcontrib><creatorcontrib>Asan, Alparslan</creatorcontrib><creatorcontrib>Wu, Yijen</creatorcontrib><creatorcontrib>Kühn, Bernhard</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ganapathy, Balakrishnan</au><au>Nandhagopal, Nikitha</au><au>Polizzotti, Brian D</au><au>Bennett, David</au><au>Asan, Alparslan</au><au>Wu, Yijen</au><au>Kühn, Bernhard</au><au>Calvert, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-05-13</date><risdate>2016</risdate><volume>11</volume><issue>5</issue><spage>e0155456</spage><pages>e0155456-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We previously developed and validated a strategy for stimulating heart regeneration by administration of recombinant neuregulin (rNRG1), a growth factor, in mice. rNRG1 stimulated proliferation of heart muscle cells, cardiomyocytes, and was most effective when administration began during the neonatal period. Our results suggested the use of rNRG1 to treat pediatric patients with heart failure. However, administration in this age group may stimulate growth outside of the heart.
NRG1 and ErbB receptor expression was determined by RT-PCR. rNRG1 concentrations in serum were quantified by ELISA. Mice that received protocols of recombinant neuregulin1-β1 administration (rNRG1, 100 ng/g body weight, daily subcutaneous injection for the first month of life), previously shown to induce cardiac regeneration, were examined at pre-determined intervals. Somatic growth was quantified by weighing. Organ growth was quantified by MRI and by weighing. Neoplastic growth was examined by MRI, visual inspection, and histopathological analyses. Phospho-ERK1/2 and S6 kinase were analyzed with Western blot and ELISA, respectively.
Lung, spleen, liver, kidney, brain, and breast gland exhibited variable expression of the NRG1 receptors ErbB2, ErbB3, ErbB4, and NRG1. Body weight and tibia length were not altered in mice receiving rNRG1. MRI showed that administration of rNRG1 did not alter the volume of the lungs, liver, kidneys, brain, or spinal cord. Administration of rNRG1 did not alter the weight of the lungs, spleen, liver, kidneys, or brain. MRI, visual inspection, and histopathological analyses showed no neoplastic growth. Follow-up for 6 months showed no alteration of somatic or organ growth. rNRG1 treatment increased the levels of phospho-ERK1/2, but not phospho-S6 kinase.
Administration protocols of rNRG1 for stimulating cardiac regeneration in mice during the first month of life did not induce unwanted growth effects. Further studies may be required to determine whether this is the case in a corresponding human population.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27175488</pmid><doi>10.1371/journal.pone.0155456</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-05, Vol.11 (5), p.e0155456 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1788715639 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aging - physiology Amino acids Animals Animals, Newborn Antineoplastic agents Biology Biology and Life Sciences Body weight Brain Cancer Cardiac muscle Cardiology Cardiomyocytes Cardiovascular disease Care and treatment Cell cycle Cell proliferation Clinical trials Cynops pyrrhogaster Dosage and administration Enzyme-linked immunosorbent assay Epidermal growth factor ErbB protein ErbB Receptors - genetics ErbB Receptors - metabolism ErbB-2 protein ErbB-3 protein Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - metabolism Gene Expression Regulation - drug effects Health aspects Heart Heart - drug effects Heart - physiology Heart diseases Heart failure Hospitals Human populations Humans Inspection Kidney - drug effects Kidney - enzymology Kidneys Kinases Liver Lungs Magnetic resonance imaging Medicine Medicine and Health Sciences Mice Morphogenesis - drug effects Muscles Neonates Neoplasms - pathology Neuregulin Neuregulin 1 Neuregulin-1 - administration & dosage Neuregulin-1 - blood Neuregulin-1 - genetics Neuregulin-1 - pharmacology Organ Size - drug effects Pediatrics Phosphorylation - drug effects Physical Sciences Polymerase chain reaction Receptors Recombinant Proteins - pharmacology Regeneration Regeneration - drug effects Research and Analysis Methods Ribosomal Protein S6 Kinases - metabolism Rodents Spinal cord Spleen Studies Tibia Weighing |
| title | Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth |
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