A role for Tbx5 in proepicardial cell migration during cardiogenesis

Transcriptional regulatory cascades during epicardial and coronary vascular development from proepicardial progenitor cells remain to be defined. We have used immunohistochemistry of human embryonic tissues to demonstrate that the TBX5 transcription factor is expressed not only in the myocardium, but also throughout the embryonic epicardium and coronary vasculature. TBX5 is not expressed in other human fetal vascular beds. Furthermore, immunohistochemical analyses of human embryonic tissues reveals that unlike their epicardial counterparts, delaminating epicardial-derived cells do not express TBX5 as they migrate through the subepicardium before undergoing epithelial-mesenchymal transformation required for coronary vasculogenesis. In the chick, Tbx5 is expressed in the embryonic proepicardial organ (PEO), which is composed of the epicardial and coronary vascular progenitor cells. Retrovirus-mediated overexpression of human TBX5 inhibits cell incorporation of infected proepicardial cells into the nascent chick epicardium and coronary vasculature. TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration. Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium. Culture of explanted PEOs demonstrates that untreated chick proepicardial cells downregulate Tbx5 expression during cell migration. Therefore, we propose that Tbx5 participates in regulation of proepicardial cell migration, a critical event in the establishment of the epicardium and coronary vasculature.

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Abstract 14044: Engineering Bioactive Nanoparticles to Rejuvenate Vascular Progenitor Cells

Circulation ◽

10.1161/circ.142.suppl_3.14044 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Loan T Bui ◽

Shanique Edwards ◽

Laura Alderfer ◽

Laura Haneline ◽

Donny Hanjaya-putra

Keyword(s):

Cell Migration ◽

Progenitor Cells ◽

De Novo ◽

Cardiovascular Complications ◽

Release Kinetic ◽

Future Health ◽

Immunodeficient Mice ◽

Vascular Progenitor Cells

Introduction: Fetal exposure to gestational diabetes mellitus (GDM) predisposes children to future health complications including hypertension and cardiovascular disease. A key mechanism by which these complications occur is through stress-induced dysfunction of vascular progenitor cells, including endothelial colony-forming cells (ECFCs). In particular, overexpression of transgelin (TAGLN), also known as SM22α, in GDM-ECFCs is associated with actin cytoskeletal rearrangement, which results in reduced cell migration and impaired vasculogenesis. We hypothesized that bioactive nanoparticles (NPs) conjugated on the surface of GDM-ECFCs can provide a sustained pseudo-autocrine stimulation to improve in vitro and in vivo vasculogenesis. Methods & Results: We designed multilamellar lipid NPs with an average size of 147±63 nm in diameter to deliver small molecules SB-431542 (TGF-β inhibitor) directly to the surface of GDM-ECFCs. Bioactive NPs can be robustly conjugated to the surface of ECFCs using thiol-maleimide coupling without altering cell viability and key progenitor phenotypes. By controlling the release kinetic of TGF-β inhibitor from the NPs, we can normalize TAGLN expression and improve cell migration, a critical key step in establishing functional vascular networks. Moreover, bioactive NPs can restore the vasculogenic potential of GDM-ECFCs in both 2D Matrigel and 3D collagen assays. Finally, when transplanted into immunodeficient mice, GDM-ECFCs conjugated with bioactive NPs exhibit robust de novo blood vessel formation with high engraftment rate, comparable to normal ECFCs. Conclusions: Collectively, these findings highlight a simple, yet promising strategy to rejuvenate GDM-ECFCs and improve their therapeutic potentials, which can be clinically-translated to address various cardiovascular complications, as well as toward a range of approaches in tissue repair and regenerative medicine.

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Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

Developmental Cell ◽

10.1016/j.devcel.2017.08.008 ◽

2017 ◽

Vol 42 (6) ◽

pp. 655-666.e3 ◽

Cited By ~ 36

Author(s):

Bikram Sharma ◽

Lena Ho ◽

Gretchen Hazel Ford ◽

Heidi I. Chen ◽

Andrew B. Goldstone ◽

...

Keyword(s):

Progenitor Cells ◽

Coronary Vasculature

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Resident vascular progenitor cells

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2010.09.006 ◽

2011 ◽

Vol 50 (2) ◽

pp. 304-311 ◽

Cited By ~ 99

Author(s):

Evelyn Torsney ◽

Qingbo Xu

Keyword(s):

Progenitor Cells ◽

Vascular Progenitor Cells

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Abstract 327: Apelin-13 Increases Myocardial Progenitor Cells and Improves Myocardial Remodeling of Post-myocardial Infarction.

Hypertension ◽

10.1161/hyp.60.suppl_1.a327 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

lanfang Li ◽

Heng Zeng ◽

Jian-Xiong Chen

Keyword(s):

Myocardial Infarction ◽

Progenitor Cells ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cxcr4 Expression ◽

Post Myocardial Infarction ◽

Coronary Artery Ligation ◽

Vascular Progenitor Cells

ABSTRACT: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and has beneficial effects against hypertension and myocardial ischemia/reperfusion injury. Little is known about the role of apelin in the homing of vascular progenitor cells (PCs) and cardiac remodeling post-myocardial infarction (MI). The present study investigates whether apelin affects PCs homing to the infarcted myocardium thereby mediating cardiac remodeling post-MI. Mice were infarcted by coronary artery ligation and apelin-13 (1 mg/kg.d) was injected for three days prior to MI and for either 24 hours or 14 days post MI. Homing of vascular progenitor cell (CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and CD133 + /CXCR4 + ) into the ischemic area were examined at 24 hours and 14 days post-MI. Myocardial Akt, eNOS, VEGF, Jagged1, Notch3, SDF-1α and CXCR4 expression were assessed. Functional analyses were performed at day 14 after MI. Mice receiving apelin-13 treatment demonstrated upregulation of SDF-1α/CXCR4 expression and dramatically increased the number of CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and c-kit + /CXCR4 + cells in the infarcted hearts. Apelin-13 also significantly increased Akt and eNOS phosphorylation and upregulated VEGF, Jagged1, Notch3 expression in the ischemic hearts. This was accompanied by a significant reduction of myocardial apoptosis. Further, treatment with apelin-13 promoted myocardial angiogenesis, attenuated cardiac fibrosis and hypertrophy together with a significant improvement of cardiac function at 14 days post-MI mice. Apelin-13 increases angiogenesis and improves cardiac remodeling by a mechanism involving upregulation of SDF-1α/CXCR4 and homing of vascular progenitor cells.

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Abstract 479: Dickkopf-3 Binds to CXCR7 of Vascular Progenitor Cells to Enhance Degradable Graft Regeneration

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.38.suppl_1.479 ◽

2018 ◽

Vol 38 (Suppl_1) ◽

Author(s):

Shirin Issa Bhaloo ◽

Yifan Wu ◽

Alexandra Le Bras ◽

Yanhua Hu ◽

Qingbo Xu ◽

...

Keyword(s):

Progenitor Cells ◽

Vascular Progenitor Cells

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TGF-β receptor kinase inhibitor enhances growth and integrity of embryonic stem cell–derived endothelial cells

The Journal of Cell Biology ◽

10.1083/jcb.200305147 ◽

2003 ◽

Vol 163 (6) ◽

pp. 1303-1311 ◽

Cited By ~ 117

Author(s):

Tetsuro Watabe ◽

Ayako Nishihara ◽

Koichi Mishima ◽

Jun Yamashita ◽

Kiyoshi Shimizu ◽

...

Keyword(s):

Endothelial Cells ◽

Progenitor Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Kinase Inhibitor ◽

Embryonic Stem ◽

Vascular Growth ◽

Vascular Progenitor Cells ◽

Β Receptor ◽

Synthetic Molecule

Recent findings have shown that embryonic vascular progenitor cells are capable of differentiating into mural and endothelial cells. However, the molecular mechanisms that regulate their differentiation, proliferation, and endothelial sheet formation remain to be elucidated. Here, we show that members of the transforming growth factor (TGF)-β superfamily play important roles during differentiation of vascular progenitor cells derived from mouse embryonic stem cells (ESCs) and from 8.5–days postcoitum embryos. TGF-β and activin inhibited proliferation and sheet formation of endothelial cells. Interestingly, SB-431542, a synthetic molecule that inhibits the kinases of receptors for TGF-β and activin, facilitated proliferation and sheet formation of ESC-derived endothelial cells. Moreover, SB-431542 up-regulated the expression of claudin-5, an endothelial specific component of tight junctions. These results suggest that endogenous TGF-β/activin signals play important roles in regulating vascular growth and permeability.

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