CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells.
The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5). The cardiogenic defects in Cited2-depleted cells were rescued by treatment with recombinant CITED2 protein. We showed that Cited2 expression is enriched in cardiac progenitors either derived from ESC or mouse embryonic hearts. Finally, we demonstrated that CITED2 and ISL1 proteins interact physically and cooperate to promote ESC differentiation toward cardiomyocytes. Collectively, our results show that Cited2 plays a pivotal role in cardiac commitment of ESC.
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Ivette
I
Pacheco-Leyva
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Ana Catarina
AC
Matias
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Daniel V
DV
Oliveira
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
João M A
JM
Santos
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Rita
R
Nascimento
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Eduarda
E
Guerreiro
Division of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Anna C
AC
Michell
Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3200, 185 Cambridge Street, Boston, MA 02114-2790, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA; Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Annebel M
AM
van De Vrugt
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Gisela
G
Machado-Oliveira
DSM Biotechnology Center, Alexander Fleminglaan 1, 2613 AX Delft, the Netherlands.
Guilherme
G
Ferreira
Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3200, 185 Cambridge Street, Boston, MA 02114-2790, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.
Ibrahim
I
Domian
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal; ABC - Algarve Biomedical Centre, 8005-139 Faro, Portugal. Electronic address: jebraganca@ualg.pt.
José
J
Bragança
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
C110087:Cited2 protein, mouse; D060850:LIM-Homeodomain Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1
Cited2; Isl1; cardiac progenitor; differentiation; embryonic stem cell; transcriptional regulation