Transcriptional Regulation of Cardiac Progenitor Cell Populations

Transcriptome-wide analysis of dynamically regulated progenitor cell populations has the potential to elucidate key aspects of cardiac development. The heart, as the first organ to develop in the mammal, is a technically challenging but clinically relevant target for study. To define the transcriptional program of the cardiac progenitor, we used a novel transgenic strategy and fluorescence-activated cell sorting to reliably label and isolate cardiac progenitors directly from mouse embryos. Pure populations of cardiac progenitor cells were isolated from the cardiac crescent and 2 subsequent stages of heart development: the linear heart tube and the looping heart. RNA was isolated from stage-specific cardiac progenitors and subjected to transcriptome analysis by oligonucleotide array hybridization. The cardiac transcriptional regulatory programs were compared with the molecular programs of age-matched noncardiac embryonic cells, embryonic stem cells, adult cardiomyocytes, and each other to identify sets of genes exhibiting differential expression in the cardiac progenitor cell population. These results define the transcriptional profile of mammalian cardiac progenitor cells and provide insight into the molecular regulation of the earliest periods of heart development.

[1]  J. D. Engel,et al.  Erythroid transcription factor GATA-1 is abundantly transcribed in mouse testis , 1993, Nature.

[2]  Daniel J Garry,et al.  Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. , 2004, Developmental biology.

[3]  R. P. Thompson,et al.  Expression of homeobox genes Msx‐1 (Hox‐7) and Msx‐2 (Hox‐8) during cardiac development in the chick , 1993, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  R. Markwald,et al.  The outflow tract of the heart is recruited from a novel heart-forming field. , 2001, Developmental biology.

[5]  A. Lassar,et al.  A role for bone morphogenetic proteins in the induction of cardiac myogenesis. , 1997, Genes & development.

[6]  M. C. DeRuiter,et al.  Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the great elastic arteries and ductus arteriosus , 2000, Virchows Archiv.

[7]  D. Simon,et al.  Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. , 1995, Development.

[8]  G. Swart.  Activated leukocyte cell adhesion molecule (CD166/ALCAM): developmental and mechanistic aspects of cell clustering and cell migration. , 2002, European journal of cell biology.

[9]  G. Vogel,et al.  Renovating the Heart , 2004, Science.

[10]  A. Bradley,et al.  Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. , 1996, Development.

[11]  G. Vogel,et al.  Cell therapy. Renovating the heart. , 2004, Science.

[12]  C. Begley,et al.  The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. , 1996, The EMBO journal.

[13]  M. Kirby,et al.  Conotruncal myocardium arises from a secondary heart field. , 2001, Development.

[14]  A. Joyner,et al.  Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. , 1997, Development.

[15]  K. Devriendt,et al.  Progressive AV‐block and anomalous venous return among cardiac anomalies associated with two novel missense mutations in the CSX/NKX2‐5 Gene , 2002, Human mutation.

[16]  F. Sabin.  Studies on the origin of blood vessels and of red corpuscles as seen in the living blastoderm of the chick during the second day of incubation , 1920 .

[17]  P. Kaufmann.  The anatomical basis of mouse development , 1999 .

[18]  J. Seidman,et al.  Congenital heart disease caused by mutations in the transcription factor NKX2-5. , 1998, Science.

[19]  Dhammika Gunasekera,et al.  Genomic organization, 5'flanking region and tissue-specific expression of mouse phosphofructokinase C gene. , 2000, Gene.

[20]  K Sigrist,et al.  GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. , 1997, Genes & development.

[21]  P. Chambon,et al.  Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. , 1996, Development.

[22]  D. Srivastava,et al.  A Subclass of bHLH Proteins Required for Cardiac Morphogenesis , 1995, Science.

[23]  J. Richardson,et al.  Microsomal triglyceride transfer protein expression during mouse development. , 2000, Journal of lipid research.

[24]  M. Mercola,et al.  Wnt antagonism initiates cardiogenesis in Xenopus laevis. , 2001, Genes & development.

[25]  D. Elliott,et al.  Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. , 2003, Journal of the American College of Cardiology.

[26]  J. Rubenstein,et al.  Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. , 1995, Genes & development.

[27]  K. Remes.  Cell therapy , 2002, Journal of the Neurological Sciences.

[28]  E. Olson,et al.  Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. , 1997, Genes & development.

[29]  J. Visvader,et al.  Differential expression of the LYL, SCL and E2A helix-loop-helix genes within the hemopoietic system. , 1991, Oncogene.

[30]  C. Mickanin,et al.  Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): alternatively spliced, functionally distinct isoforms expressed during mammalian cardiovascular development. , 1994, Development.

[31]  G. Cossu,et al.  Mesoangioblasts--vascular progenitors for extravascular mesodermal tissues. , 2003, Current opinion in genetics & development.

[32]  Daniel J Garry,et al.  RNA amplification and transcriptional profiling for analysis of stem cell populations , 2003, Genesis.

[33]  M. Mercola,et al.  An inductive role for the endoderm in Xenopus cardiogenesis. , 1995, Development.

[34]  S. Izumo,et al.  The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. , 1999, Development.

[35]  A. Lassar,et al.  Induction of avian cardiac myogenesis by anterior endoderm. , 1995, Development.

[36]  Y. Hiroi,et al.  Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease. , 2002, Circulation journal : official journal of the Japanese Circulation Society.

[37]  A. Lassar,et al.  Inhibition of Wnt activity induces heart formation from posterior mesoderm. , 2001, Genes & development.

[38]  Kyunghee Choi.  The hemangioblast: a common progenitor of hematopoietic and endothelial cells. , 2002, Journal of hematotherapy & stem cell research.

[39]  N. Oppenheimer-Marks,et al.  Expression of the TAL1 proto-oncogene in cultured endothelial cells and blood vessels of the spleen. , 1993, Oncogene.

[40]  A. Lassar,et al.  Wnt signals from the neural tube block ectopic cardiogenesis. , 2001, Genes & development.

[41]  L. Moreland.  Platelet-endothelial cell adhesion molecule-1 , 2004 .

[42]  M. Buckingham,et al.  Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo. , 1988, Development.

[43]  M. Buckingham,et al.  The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. , 2001, Developmental cell.

[44]  G. Lyons,et al.  Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. , 1994, Development.

[45]  C. Lien,et al.  Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. , 1999, Development.

[46]  B. Herrmann,et al.  Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos. , 1991, Development.

[47]  J. Visvader,et al.  SCL is coexpressed with GATA-1 in hemopoietic cells but is also expressed in developing brain. , 1992, Oncogene.

[48]  M. Baiocchi,et al.  The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. , 2002, Development.

[49]  P. Kingsley,et al.  Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression , 2002, Development.

[50]  L Hartley,et al.  Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. , 1995, Genes & Development.

[51]  S. Orkin,et al.  Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. , 1998, Genes & development.

[52]  E. Olson.  The Path to the Heart and the Road Not Taken , 2001, Science.