Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 293

6.1.9.1 Resident Coronary Vascular Progenitors

VEGFR2 , resident coronary progenitor cells reside in vascular niches

inside the human myocardium [ 551 ]. Vascular progenitor cells are located in the
proepicardium, from whence they migrate into the myocardium. They are connected
by gap junctions to vascular endothelial and smooth muscle cells as well as
fibroblasts. These self-renewing cells differentiate predominantly into endothelial
and smooth muscle cells and partly into cardiomyocytes.
On the other hand, myocyte progenitor cells distributed in the cardiac
crescent and pharyngeal mesoderm differentiate into cardiomyocytes to progres-
sively constitute, together with coronary vessels, the 4-chambered heart [ 551 ].

+ ,SCFR +

6.1.9.2 Notch and Wnt Morphogens

Niche-resident cardiac progenitors and supporting cells express Notch-1 receptors
and Notch ligand Jagged-1, respectively. The intracellular domain of Notch-1
(Notch ICD ) translocates to the nucleus and activates the NKX2-5 gene [ 552 ].
Notch ICD

that binds to NKX2-5 promoter, hence initiating
transcription and cardiomyocyte differentiation, whereas Jagged-1 activation of the
Notch1 pathway downregulates transcription factors of vascular cells.
During early stage of development, when the transcription factor NKx2-5 is
not expressed, the Notch pathway mediates a coordinated regulation between bone
morphogenetic proteins, such as BMP2, BMP6, and BMP7, that are required
for cardiogenesis, and Wnt pathways. 40

connects to RBPJ κ

This action can generate cardiomyocytes

from VEGFR2 hemangioblasts rather than cells of the hematopoietic, vascular

endothelial, or smooth muscle lineages [ 553 ].
Wnt signaling regulates NKx2-5

+

+ ,Isl1 + multipotent cardiac progenitor cells.

The Wnt- -catenin signaling promotes expansion of multipotent cardiac progenitor

cells. Notch-1 impedes accumulation of phosphorylated

β

β -catenins in these progen-

itors [ 548 ]. Notch-1 and -catenin regulate positively and negatively, respectively,

the expression of cardiac transcription factors Isl1, myocardin, and SET and MYND
domain-containing protein SMYD1.
During later stages of cardiogenesis, Notch-4 inhibits the maturation of the
cardiac lineage. Active Notch-1 receptor in embryonic stem cells reduces their
cardiac potential at late differentiation stage. Notch-4 receptor, the expression of
which is restricted to the heart endothelium, promotes cardiac development from
cardiac mesoderm and is able to respecify VEGFR2

β

hemangioblasts to a cardiac
cell fate by activating BMP signaling and inhibiting the Wnt-

+

-catenin pathway.
Certain cardiomyocyte progenitors derive from proepicardial cells that express
T-box TBx18 transcription factor. These progenitors migrate onto the outer cardiac

β

40 Protein Wnt2 induces cardiac differentiation from mesoderm, whereas Wnt4 acts via the
β -catenin-independent pathway that inhibits the β -catenin-dependent pathway for cardiac spec-

ification of mesoderm.