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Endothelial progenitor cells (EPC) are a population of rare cells that circulate in the blood with the ability to differentiate into endothelial cells, the cells that make up the lining of blood vessels. The process by which blood vessels are born de novo from endothelial progenitor cells is known as vasculogenesis. Endothelial progenitor cells participate in pathologic angiogenesis such as that found in retinopathy and tumor growth.

Various cytokines, growth factors, and hormones cause hematopoietic cells, and by association endothelial progenitor cells, to be mobilized into the peripheral circulation, ultimately homing to regions of blood vessel formation.[1]

Endothelial progenitor cells can be marked using the Inhibitor of DNA Binding 1 (ID1).[2] This allows for tracking endothelial progenitor cells from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature.

Role in tumor growth[edit]

Endothelial progenitor cells are important in tumour growth and are critical for metastasis and the angiogenesis.[3][4]

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.[5]

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 EPCs to the tumour. These findings indicate that directed targeting these miRNAs in EPCs may result in a novel strategy for inhibiting tumor angiogenesis.[6]

Role in cardiovascular disease[edit]

Higher levels of circulating "endothelial progenitor cells" were detected in the bloodstream of patients, predicted better outcomes, and patients experienced fewer repeat heart attacks,[7] though statistical correlations between these outcomes and circulating endothelial progenitor cell numbers were scant in the original research. Endothelial progenitor cells are mobilized after a myocardial infarction, and that they function to restore the lining of blood vessels that are damaged during the heart attack.

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 suffering from 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 [8]

Role in endometriosis[edit]

In endometriosis, it appears that that up to 37% of the microvascular endothelium of the ectopic endometrial tissue originates from endothelial progenitor cells.[9]

Role in wound healing[edit]

The role of endothelial progenitor cells in wound healing remains unclear. Blood vessels have been seen entering ischemic tissue in a process driven by mechanically forced ingress of existing capillaries into the avascular region, and importantly, instead of through sprouting angiogenesis. These observations contradict sprouting angiogenesis driven by EPCs. Taken together with the inability to find bone-marrow derived endothelium in new vasculature, there is now little material support for postnatal vasculogenesis. Instead, angiogenesis is likely driven by a process of physical force.[10]

History of discovery[edit]

Most of vasculogenesis occurs in utero during embryologic development. Endothelial progenitor cells, were therefore first believed to be angioblasts, which are the stem cells that form blood vessels during embryogenesis.

While embryonic angioblasts have been known to exist for many years, adult endothelial progenitor cells were first believed to be characterized in the 1990s after Asahara and colleagues published that a purified population of CD34-expressing cells isolated from the blood of adult mice could purportedly differentiate into endothelial cells in vitro.[11]

References[edit]

  1. ^ Asahara T, et al. (1999). "Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization". Circulation Research 85 (6): 221–8. doi:10.1161/01.res.85.3.221. PMID 10436164. 
  2. ^ Lyden, D.; Hattori, K.; Dias, S.; Costa, C.; Blaikie, P.; Butros, L.; Chadburn, A.; Heissig, B.; Marks, W.; Witte, L.; Wu, Y.; Hicklin, D.; Zhu, Z.; Hackett, N. R.; Crystal, R. G.; Moore, M. A. S.; Hajjar, K. A.; Manova, K.; Benezra, R.; Rafii, S. (2001). "Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth". Nature Medicine 7 (11): 1194–1201. doi:10.1038/nm1101-1194. PMID 11689883.  edit
  3. ^ Gao D et al. (2008). "Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis". Science 319 (5860): 195–198. doi:10.1126/science.1150224. PMID 18187653. 
  4. ^ Nolan DJ et al. (2007). "Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization". Genes & Development 21 (12): 1546–1558. doi:10.1101/gad.436307. PMC 1891431. PMID 17575055. 
  5. ^ Mellick As, Plummer PN et al. (2010). "Using the Transcription Factor Inhibitor of DNA Binding 1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth". Cancer Research 70 (18): 7273–7282. doi:10.1158/0008-5472.CAN-10-1142. PMC 3058751. PMID 20807818. 
  6. ^ Plummer PN et al. (2012). "MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.". Cancer Research 73 (1): 341–52. doi:10.1158/0008-5472.CAN-12-0271. PMID 22836757. 
  7. ^ Werner N, et al. (2005). "Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes". New England Journal of Medicine 353 (10): 999–1007. doi:10.1056/NEJMoa043814. PMID 16148285. 
  8. ^ Shantsila E, et al (2007). "Endothelial progenitor cells in cardiovascular disorders". Journal of the American College of Cardiology 49 (7): 741–52. doi:10.1016/j.jacc.2006.09.050. PMID 17306702. 
  9. ^ Laschke, M. W.; Giebels, C.; Menger, M. D. (2011). "Vasculogenesis: A new piece of the endometriosis puzzle". Human Reproduction Update 17 (5): 628–636. doi:10.1093/humupd/dmr023. PMID 21586449.  edit
  10. ^ Kilarski WW, et al. (2009). "Biomechanical regulation of blood vessel growth during tissue vascularization". Nature Medicine 15 (6): 657–664. doi:10.1038/nm.1985. PMID 19483693. 
  11. ^ Asahara T, et al. (1997). "Isolation of putative progenitor endothelial cells for angiogenesis". Science 275 (5302): 964–7. doi:10.1126/science.275.5302.964. PMID 9020076. 

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