Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 292

muscle or endothelial cells. The adult heart contains a pool of resident SCFR +

pluripotent cardiovascular progenitor cells for its regeneration [ 556 ]. 39
Tripotent progenitor cells from the secondary heart fields express transcrip-
tion factors Islet-1 and NKx2-5 as well as vascular endothelial growth factor
receptor VEGFR2 [ 545 ]. Certain cardiac tripotent progenitor cells express the
marker brachyury at a specific stage of embryogenesis [ 546 ]. SCFR + , NKx2-

5 , differentiated embryonic stem cells that serve as cardiac progenitors create

cardiac and smooth myocytes, but not endothelial cells [ 547 ]. Factor Isl1 is required
for differentiation of multipotent cardiac progenitor cells into cardiac and smooth
myocytes, but not endothelial cells [ 548 ].
Human pluripotent stem cells, such as embryonic and induced pluripotent
stem cells generate cardiomyocytes. Cardiomyocyte specification requires Wnt
signaling [ 549 ]. However, cardiomyocyte differentiation is sensitive to the timing
and dose of supplied Wnt.
Vascular endothelial growth factor is one of the most important angiogenic
growth factors. It has pleiotropic activities, as it influences non-endothelial cell
types derived from all 3 embryonic lineages, such as pneumocytes, renal podocytes,
cardiomyocytes, various neuron types, hematopoietic and cardiac stem cells, among
others. The Wnt pathway triggers production of various developmental messengers,
such as Nodal, BMP2 and BMP4, Noggin, Wnt3a, an Wnt8a, as well as transcription
factors involved in cardiomyocyte differentiation, such as NKx2-5, TBx5, and
MEF2c factors, as well as insulin gene enhancer protein Isl LIM domain-containing
protein IsL1, a marker for cardiac progenitors of the secondary heart field, and Mix
paired-like MixL1 homeodomain-containing protein.
Cardiac implantation of multipotent mesenchymal stem cells that express VEGF
stimulates revascularization, thereby reducing infarct size. These stem cells secrete
numerous paracrine factors, such as VEGF, FGF2, IGF1, HGF, and CXCL12
chemokine. They can differentiate into cardiomyocytes and endothelial cells. Their
liberated paracrine factors support survival of implanted mesenchymal stem cells
as well as mobilization and migration of stem cells. VEGF

+

mesenchymal stem
cells are characterized by PKB activation that enables mesenchymal stem cell
engraftment in the ischemic heart and cardiac stem cell migration [ 550 ]. Moreover,
VEGF

+

mesenchymal stem cells recruit resident, adult, cardiac stem cells to
ischemic regions. Factor VEGF fosters cell migration via VEGFR1 and VEGFR3,
but not VEGFR2, although cardiac stem cells synthesize the 3 receptor types.
In addition, VEGF recruits CXCR4

+

+ cardiac stem cells via CXCL12 that targets

its CXCR4 receptor [ 550 ].

39 Among markers that identify cardiac stem cells (VEGFR2, also called KDR and Flk1, and tran-
scription factors Islet-1 and NKx2-5), stem cell factor receptor (SCFR or KIT) is also expressed
during various stages of cell lineage commitment in germ, mast, stellate, epithelial, endothelial,
and smooth muscle cells [ 557 ].