Endothelial progenitor cell
Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the
History and controversy
Developmentally, the endothelium arises in close contact with the
Recently, controversy has developed over the definition of true endothelial progenitors.
Molecular genetic analysis of early outgrowth putative EPC populations suggests they do indeed have monocyte-like expression patterns, and support the existence of a separate population of progenitors, the late outgrowth, or endothelial colony forming cell (ECFC).[10] Furthermore, early outgrowth cells maintain other monocyte functions such as high Dil-Ac-LDL and India ink uptake and low eNOS expression. These original, early outgrowth, CFU-Hill or CACs are also shown to express CD14, a lipopolysaccharide receptor expressed by monocytes but not endothelial cells.[11]
Classifications
By method of isolation and cell function, three main populations of putative adult EPCs have been described. The behavior of the cells can be found in the following table.[9][13]
Behaviour .. \\ .. Population | Colony forming unit – Hill | Circulating angiogenic cell | Endothelial colony forming cell |
---|---|---|---|
Clonal proliferative status | - | - | + |
Replating ability | - | - | + |
In vitro tube formation | +/- | +/- | + |
In vivo de novo vessel formation | - | - | + |
Homing to ischemic sites in vivo | + | + | + |
Paracrine support of angiogenesis | + | + | + |
EPCs also have variable phenotypic markers used for identification. Unfortunately, there are no unique markers for endothelial progenitors that are not shared with other endothelial or hematopoietic cells, which has contributed to the historical controversy surrounding the field. A detailed overview of current markers can be found in the following table.[2][13]
Marker .. \\ .. Population | Colony forming unit – Hill | Circulating angiogenic cell | Endothelial colony forming cell |
---|---|---|---|
CD34 expression | +/- | +/- | +/- |
CD133 expression | + | + | - |
CD45 expression
|
+/- | +/- | - |
CD146 expression | +/- | +/- | + |
VE-cadherin expression | +/- | +/- | ++ |
CD115 expression
|
+ | + | - |
CD31 (PECAM) expression | + | + | + |
CD14 expression | + | + | - |
CD105 expression
|
+ | + | + |
CD117 (ckit) expression
|
+ | + | +/- |
VEGFR1 expression | + | + | + |
VEGFR2 (KDR/Flk1) expression
|
+ | + | ++ |
TIE-2 expression | + | + | + |
CXCR4 expression | + | + | +/- |
von Willebrand factor expression | +/- | +/- | + |
ALDH
|
Bright | Bright | Bright |
ac LDL uptake
|
+ | + | + |
Colony forming unit – Hill
As originally isolated by Asahara et al., the CFU-Hill population is an early outgrowth, formed by plating peripheral blood mononuclear cells on fibronectin-coated dishes, allowing adhesion and depleting non-adherent cells, and isolating discrete colonies.[8][9]
Circulating angiogenic cell
A similar method is to culture the peripheral blood mononuclear fraction in supplemented endothelial growth medium, removing the non-adherent cells, and isolating the remaining. While these cells display some endothelial characteristics, they do not form colonies.[8][9]
Endothelial colony forming cell
Development
Certain developmental cells may be similar to or the same as other endothelial progenitors, though not typically referred to as EPCs.
Function
Role in tumor growth
Endothelial progenitor cells are likely important in tumour growth and are thought to be critical for metastasis and the angiogenesis.[17][18][19] A large amount of research has been done on CFU-Hill bone marrow-derived putative EPCs. Ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. This indicates that endothelial progenitor cells present novel therapeutic targets.[20] Inhibitor of DNA Binding 1 (ID1) has been used as a marker for these cells;[21] this allows for tracking EPCs from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature.
Recently it has been found that miRNAs regulate EPC biology and tumour angiogenesis. This work by Plummer et al. found that in particular targeting of the miRNAs miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth by decreasing the mobilization of proangiogenic EPCs to the tumour. These findings indicate that directed targeting these miRNAs in EPCs may result in a novel strategy for inhibiting tumor angiogenesis.[22]
Studies have shown ECFCs and
Role in cardiovascular disease
Higher levels of circulating "endothelial progenitor cells" were detected in the bloodstream of patients, predicted better outcomes, and patients experienced fewer repeat heart attacks,
A number of small phase clinical trials have begun to point to EPCs as a potential treatment for various cardiovascular diseases (CVDs). For instance, the year long "Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction" (TOPCARE-AMI) studied the therapeutic effect of infusing ex-vivo expanded bone marrow EPCs and culture enriched EPCs derived from peripheral blood into 20 patients with acute myocardial infarction (MI). After four months, significant enhancements were found in ventricular ejection fraction, cardiac geometry, coronary blood flow reserve, and myocardial viability (Shantsila, Watson, & Lip). A similar study looked at the therapeutic effects of EPCs on leg ischemia caused by severe peripheral artery disease. The study injected a sample of EPC rich blood into the gastrocnemius muscles of 25 patients. After 24 weeks an increased number of collateral vessels and improved recovery in blood perfusion was observed. Rest pain and pain-free walking were also noted to have improved [25]
Role in wound healing
The role of endothelial progenitor cells in
Role in endometriosis
In endometriosis, it appears that up to 37% of the microvascular endothelium of the ectopic endometrial tissue originates from endothelial progenitor cells.[27]
See also
References
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Further reading
- Aird, William C. "Blood Endothelial Cells" in Endothelial Cells In Health and Disease. Boca Raton: Taylor & Francis, 2005.
- Milosevic, V., Edelmann, R.J., Fosse, J.H., Östman, A., Akslen, L.A. (2022). Molecular Phenotypes of Endothelial Cells in Malignant Tumors. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_3