OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells
Mesenchymal stem/stromal cells (MSCs) are in numerous cell therapy clinical trials, including for injured myocardium. Acquisition of cardiomyocyte characteristics by MSCs may improve cardiac regeneration but the mechanisms regulating this process are unclear. Here, we investigated whether the plurip...
| Authors: | ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2017 |
| Country: | Argentina |
| Institution: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repository: | CONICET Digital (CONICET) |
| Language: | English |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/48811 |
| Online Access: | http://hdl.handle.net/11336/48811 |
| Access Level: | Open access |
| Keyword: | MESENCHYMAL STROMAL CELLS CARDIAC REGENERATION OCT4 EPIGENETIC https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 |
| _version_ | 1878404102201802752 |
|---|---|
| author | Yannarelli, Gustavo Gabriel |
| author2 | Pacienza, Natalia Alejandra Montanari, Sonia Santa Cruz, Diego Mario Viswanathan, Sowmya Keating, Armand |
| author2_role | author author author author author |
| author_browse | Keating, Armand Montanari, Sonia Pacienza, Natalia Alejandra Santa Cruz, Diego Mario Viswanathan, Sowmya Yannarelli, Gustavo Gabriel |
| author_facet | Yannarelli, Gustavo Gabriel Pacienza, Natalia Alejandra Montanari, Sonia Santa Cruz, Diego Mario Viswanathan, Sowmya Keating, Armand |
| author_role | author |
| collection | CONICET Digital (CONICET) |
| description | Mesenchymal stem/stromal cells (MSCs) are in numerous cell therapy clinical trials, including for injured myocardium. Acquisition of cardiomyocyte characteristics by MSCs may improve cardiac regeneration but the mechanisms regulating this process are unclear. Here, we investigated whether the pluripotency transcription factor OCT4 is involved in the activation of cardiac lineage genetic programs in MSCs. We employed our established co-culture model of MSCs with rat embryonic cardiomyocytes showing co-expression of cardiac markers on MSCs independent of cell fusion. Bone marrow-derived MSCs were isolated from transgenic mice expressing GFP under the control of the cardiac-specific α-myosin heavy chain promoter. After 5 days of co-culture, MSCs expressed cardiac specific genes, including Nkx2.5, atrial natriuretic factor and α-cardiac actin. The frequency of GFP+ cells was 7.6±1.9%, however, these cells retained the stromal cell phenotype, indicating, as expected, only partial differentiation. Global OCT4 expression increased 2.6±0.7-fold in cocultured MSCs and of interest, 87±5% vs 79±4% of MSCs expressed OCT4 by flow cytometry in controls and after co-culture, respectively. Consistent with the latter observation, the GFP+ cells did not express nuclear OCT4 and showed a significant increase in OCT4 promoter methylation compared with undifferentiated MSCs (92% vs 45%), inferring that OCT4 is regulated by an epigenetic mechanism. We further showed that siRNA silencing of OCT4 in MSCs resulted in a reduced frequency of GFP+ cells in co-culture to less than 1%. Our data infer that OCT4 expression may have a direct effect on partial cardiomyocyte reprogramming of MSCs and suggest a new mechanism(s) associated with MSC multipotency and a requirement for crosstalk with the cardiac microenvironment. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | AR_fb9e959efa6da88e8dfcb2ba87d4e577 |
| identifier_str_mv | Yannarelli, Gustavo Gabriel; Pacienza, Natalia Alejandra; Montanari, Sonia; Santa Cruz, Diego Mario; Viswanathan, Sowmya; et al.; OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells; Public Library of Science; Plos One; 12; 12; 12-2017; 1-20 1932-6203 CONICET Digital CONICET |
| institution | Consejo Nacional de Investigaciones Científicas y Técnicas |
| instname_str | Consejo Nacional de Investigaciones Científicas y Técnicas |
| language | eng |
| network_acronym_str | AR |
| network_name_str | Argentina |
| oai_identifier_str | oai:ri.conicet.gov.ar:11336/48811 |
| publishDate | 2017 |
| publishDateSort | 2017 |
| publisher | Public Library of Science |
| publisherStr | Public Library of Science |
| reponame_str | CONICET Digital (CONICET) |
| spelling | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells Yannarelli, Gustavo Gabriel Pacienza, Natalia Alejandra Montanari, Sonia Santa Cruz, Diego Mario Viswanathan, Sowmya Keating, Armand MESENCHYMAL STROMAL CELLS CARDIAC REGENERATION OCT4 EPIGENETIC https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 Mesenchymal stem/stromal cells (MSCs) are in numerous cell therapy clinical trials, including for injured myocardium. Acquisition of cardiomyocyte characteristics by MSCs may improve cardiac regeneration but the mechanisms regulating this process are unclear. Here, we investigated whether the pluripotency transcription factor OCT4 is involved in the activation of cardiac lineage genetic programs in MSCs. We employed our established co-culture model of MSCs with rat embryonic cardiomyocytes showing co-expression of cardiac markers on MSCs independent of cell fusion. Bone marrow-derived MSCs were isolated from transgenic mice expressing GFP under the control of the cardiac-specific α-myosin heavy chain promoter. After 5 days of co-culture, MSCs expressed cardiac specific genes, including Nkx2.5, atrial natriuretic factor and α-cardiac actin. The frequency of GFP+ cells was 7.6±1.9%, however, these cells retained the stromal cell phenotype, indicating, as expected, only partial differentiation. Global OCT4 expression increased 2.6±0.7-fold in cocultured MSCs and of interest, 87±5% vs 79±4% of MSCs expressed OCT4 by flow cytometry in controls and after co-culture, respectively. Consistent with the latter observation, the GFP+ cells did not express nuclear OCT4 and showed a significant increase in OCT4 promoter methylation compared with undifferentiated MSCs (92% vs 45%), inferring that OCT4 is regulated by an epigenetic mechanism. We further showed that siRNA silencing of OCT4 in MSCs resulted in a reduced frequency of GFP+ cells in co-culture to less than 1%. Our data infer that OCT4 expression may have a direct effect on partial cardiomyocyte reprogramming of MSCs and suggest a new mechanism(s) associated with MSC multipotency and a requirement for crosstalk with the cardiac microenvironment. Fil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina. University Health Network; Canadá Fil: Pacienza, Natalia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Montanari, Sonia. University Health Network; Canadá Fil: Santa Cruz, Diego Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentina Fil: Viswanathan, Sowmya. University Health Network; Canadá Fil: Keating, Armand. University Health Network; Canadá Public Library of Science http://hdl.handle.net/11336/48811 Yannarelli, Gustavo Gabriel; Pacienza, Natalia Alejandra; Montanari, Sonia; Santa Cruz, Diego Mario; Viswanathan, Sowmya; et al.; OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells; Public Library of Science; Plos One; 12; 12; 12-2017; 1-20 1932-6203 CONICET Digital CONICET |
| spellingShingle | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells Yannarelli, Gustavo Gabriel MESENCHYMAL STROMAL CELLS CARDIAC REGENERATION OCT4 EPIGENETIC https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 |
| status_str | publishedVersion |
| title | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| title_full | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| title_fullStr | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| title_full_unstemmed | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| title_short | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| title_sort | OCT4 expression mediates partial cardiomyocyte reprogramming of mesenchymal stromal cells |
| topic | MESENCHYMAL STROMAL CELLS CARDIAC REGENERATION OCT4 EPIGENETIC https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 |
| topic_facet | MESENCHYMAL STROMAL CELLS CARDIAC REGENERATION OCT4 EPIGENETIC https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3 |
| url | http://hdl.handle.net/11336/48811 |