Therapeutic Potential of Endothelial Colony Forming Cells Derived from Human Umbilical Cord Blood

Author(s): Jing Jia, Baitao Ma, Shaoshuai Wang*, Ling Feng*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 6 , 2019

Become EABM
Become Reviewer


Endothelial progenitor cells (EPCs) are implicated in multiple biologic processes such as vascular homeostasis, neovascularization and tissue regeneration, and tumor angiogenesis. A subtype of EPCs is referred to as endothelial colony-forming cells (ECFCs), which display robust clonal proliferative potential and can form durable and functional blood vessels in animal models. In this review, we provide a brief overview of EPCs’ characteristics, classification and origins, a summary of the progress in preclinical studies with regard to the therapeutic potential of human umbilical cord blood derived ECFCs (CB-ECFCs) for ischemia repair, tissue engineering and tumor, and highlight the necessity to select high proliferative CB-ECFCs and to optimize their recovery and expansion conditions.

Keywords: Endothelial colony forming cells (ECFCs), neovascularization, tissue engineering, tumor angiogenesis, vascular homeostasis, peripheral blood.

Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275(5302): 964-7.
Urbich C, Dimmeler S. Endothelial progenitor cells: Characterization and role in vascular biology. Circ Res 2004; 95(4): 343-53.
Bertagnolli M, Nuyt AM, Thebaud B, Luu TM. Endothelial Progenitor Cells as Prognostic Markers of Preterm Birth-Associated Complications. Stem Cells Transl Med 2017; 6(1): 7-13.
Yoder MC. Human endothelial progenitor cells. Cold Spring Harb Perspect Med 2012; 2(7)a006692
Rehman J, Li J, Orschell C, March K. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107(8): 1164-9.
Hill J, Zalos G, Halcox J, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348(7): 593-600.
Ingram DA, Mead LE, Tanaka H, et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104(9): 2752-60.
Alphonse RS, Vadivel A, Fung M, et al. Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 2014; 129(21): 2144-57.
Melero-Martin JM, De Obaldia ME, Kang SY, et al. Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 2008; 103(2): 194-202.
Prasain N, Lee MR, Vemula S, et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat Biotechnol 2014; 32(11): 1151-7.
Shelley W, Leapley A, Huang L, et al. Changes in the frequency and in vivo vessel-forming ability of rhesus monkey circulating endothelial colony-forming cells across the lifespan (birth to aged). Pediatr Res 2012; 71(2): 156-61.
Leicht S, Schwarz T, Hermann P, Seissler J, Aicher A, Heeschen C. Adiponectin pretreatment counteracts the detrimental effect of a diabetic environment on endothelial progenitors. Diabetes 2011; 60(2): 652-61.
Lee H, Kim W, Kim W, et al. Circulating endothelial progenitor cell levels predict cardiovascular events in end-stage renal disease patients on maintenance hemodialysis. Nephron 2015; 130(3): 151-8.
Simard T, Jung RG, Motazedian P, et al. Progenitor cells for arterial repair: Incremental advancements towards therapeutic reality. Stem Cells Int 2017; 20178270498
Edwards N, Langford-Smith AWW, Wilkinson FL, Alexander MY. Endothelial progenitor cells: New targets for therapeutics for inflammatory conditions with high cardiovascular risk. Front Med 2018; 5: 200.
Takahashi K, Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016; 17(3): 183-93.
Duong Van Huyen JP, Smadja DM, Bruneval P, et al. Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia. Mod Pathol 2008; 21(7): 837-46.
Sarlon G, Zemani F, David L, et al. Therapeutic effect of fucoidan-stimulated endothelial colony-forming cells in peripheral ischemia. J Thromb Haemost 2012; 10(1): 38-48.
Moubarik C, Guillet B, Youssef B, et al. Transplanted Late Outgrowth Endothelial Progenitor Cells as Cell Therapy Product for Stroke. Stem Cell Rev 2010; 7(1): 208-20.
Lee SH, Lee JH, Asahara T, et al. Genistein promotes endothelial colony-forming cell (ECFC) bioactivities and cardiac regeneration in myocardial infarction. PloS One 2014; 9(5)e96155
Milbauer LC, Enenstein JA, Roney M, et al. Blood outgrowth endothelial cell migration and trapping in vivo: a window into gene therapy. Transl Res 2009; 153(4): 179-89.
Kim S, Jin H, Kang S, et al. Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol 2016; 203: 498-507.
Huang X, Zhang Y, Li S, et al. Intracerebroventricular transplantation of ex vivo expanded endothelial colony-forming cells restores blood brain barrier integrity and promotes angiogenesis of mice with traumatic brain injury. J Neurotrauma 2013; 30(24): 2080-8.
Lee J, Lee S, Choi S, Asahara T, Kwon S. The sulfated polysaccharide fucoidan rescues senescence of endothelial colony forming cells for ischemic repair. Stem Cells 2014; 33(6): 1939-51.
Bennis Y, Sarlon-Bartoli G, Guillet B, et al. Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential. J Thromb Haemost 2012; 10(9): 1914-28.
Garrigue P, Hache G, Bennis Y, et al. Erythropoietin pretreatment of transplanted endothelial colony-forming cells enhances recovery in a cerebral ischemia model by increasing their homing ability: A SPECT/CT study. J Nucl Med 2016; 57(11): 1798-804.
Lee S, Lee J, Yoo S, Hur J, Kim H, Kwon S. Hypoxia inhibits cellular senescence to restore the therapeutic potential of old human endothelial progenitor cells via the hypoxia-inducible factor-1α-TWIST-p21 axis. Arterioscler Thromb Vasc Biol 2013; 33(10): 2407-14.
Lee S, Lee J, Han Y, Ryu J, Yoon Y, Han H. Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis. Stem Cell Res Ther 2015; 6(139): 1-13.
Mena HA, Lokajczyk A, Dizier B, et al. Acidic preconditioning improves the proangiogenic responses of endothelial colony forming cells. Angiogenesis 2014; 17(4): 867-79.
Lee SH, Lee KB, Lee JH, et al. Selective interference targeting of lnk in umbilical cord-derived late endothelial progenitor cells improves vascular repair, following hind limb ischemic injury, via regulation of JAK2/STAT3 signaling. Stem Cells 2015; 33(5): 1490-500.
Lin R, Moreno-Luna R, Li D, Jaminet S, Greene A, Melero-Martin J. Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling. Proc Natl Acad Sci USA 2014; 111(28): 10137-42.
Burger D, Viñas J, Akbari S, et al. Human Endothelial Colony-Forming Cells Protect against Acute Kidney Injury: role of exosomes. Am J Pathol 2015; 185(8): 2309-23.
Viñas J, Burger D, Zimpelmann J, et al. Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury. Kidney Int 2016; 90(6): 1238-50.
Ichim TE, Zhong Z, Kaushal S, et al. Exosomes as a tumor immune escape mechanism: possible therapeutic implications. J Transl Med 2008; 6: 37.
Schrepfer S, Deuse T, Reichenspurner H, Fischbein M, Robbins R, Pelletier M. Stem cell transplantation: the lung barrier. Transplant Proc 2007; 39(2): 573-6.
Shen Q, Goderie S, Jin L, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 2004; 304(5675): 1338-40.
Ding BS, Cao Z, Lis R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 2014; 505(7481): 97-102.
Chen YC, Lin RZ, Qi H, et al. Functional human vascular network generated in photocrosslinkable gelatin methacrylate hydrogels. Adv Funct Mater 2012; 22(10): 2027-39.
Traktuev DO, Prater DN, Merfeld-Clauss S, et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ Res 2009; 104(12): 1410-20.
Souidi N, Stolk M, Rudeck J, et al. Stromal cells act as guardians for endothelial progenitors by reducing their immunogenicity after cotransplantation. Stem Cells 2017; 35(5): 1233-45.
Jung HS, Kim MJ, Hong SH, et al. The potential of endothelial colony-forming cells to improve early graft loss after intraportal islet transplantation. Cell Transplant 2014; 23(3): 273-83.
Peters EB. Endothelial Progenitor cells for the vascularization of engineered tissues. Tissue Eng Part B Rev 2018; 24(1): 1-24.
Moccia F, Zuccolo E, Poletto V, et al. Endothelial progenitor cells support tumour growth and metastatisation: Implications for the resistance to anti-angiogenic therapy. Tumor Biol 2015; 36(9): 6603-14.
Peters BA, Diaz LA, Polyak K, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 2005; 11(3): 261-2.
McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 2014; 16(8): 717-27.
Dragoni S, Laforenza U, Bonetti E, et al. Vascular endothelial growth factor stimulates endothelial colony forming cells proliferation and tubulogenesis by inducing oscillations in intracellular Ca2+ concentration. Stem Cells 2011; 29(11): 1898-907.
Lodola F, Laforenza U, Bonetti E, et al. Store-operated Ca2+ entry is remodelled and controls in vitro angiogenesis in endothelial progenitor cells isolated from tumoral patients. PLoS One 2012; 7(9)e42541
Laurenzana A, Biagioni A, D’Alessio S, et al. Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme. Oncotarget 2014; 5(11): 3711-27.
Margheri G, Zoppi A, Olmi R, et al. Tumor-tropic endothelial colony forming cells (ECFCs) loaded with near-infrared sensitive Au nanoparticles: A “cellular stove” approach to the photoablation of melanoma. Oncotarget 2016; 7(26): 39846-60.
Munoz-Hernandez R, Miranda ML, Stiefel P, et al. Decreased Level of Cord Blood Circulating Endothelial Colony-Forming Cells in Preeclampsia. Hypertension 2014; 64(1): 165-71.
Gui J, Rohrbach A, Borns K, et al. Vitamin D rescues dysfunction of fetal endothelial colony forming cells from individuals with gestational diabetes. Placenta 2015; 36(4): 410-8.
Baker CD, Ryan SL, Ingram DA, Seedorf GJ, Abman SH, Balasubramaniam V. Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia. Am J Respir Crit Care Med 2009; 180(5): 454-61.
Fujinaga H, Fujinaga H, Watanabe N, et al. Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 2016; 310(11): L1143-54.
Oh B, Kim D, Kim B, et al. Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells. Biochem Biophys Res Commun 2010; 398(4): 627-33.
Green L, Njoku V, Mund J, et al. Endogenous transmembrane TNF-alpha protects against premature senescence in endothelial colony forming cells. Circ Res 2016; 118(10): 1512-24.
Sakimoto S, Marchetti V, Aguilar E, et al. CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect. JCI insight 2017; 2(2)e89906
Ferratge S, Ha G, Carpentier G, et al. Initial clonogenic potential of human endothelial progenitor cells is predictive of their further properties and establishes a functional hierarchy related to immaturity. Stem Cell Res 2017; 21: 148-59.
Coldwell K, Lee S, Kean J, et al. Effects of obstetric factors and storage temperatures on the yield of endothelial colony forming cells from umbilical cord blood. Angiogenesis 2011; 14(3): 381-92.
Chevalier F, Lavergne M, Negroni E, et al. Glycosaminoglycan mimetic improves enrichment and cell functions of human endothelial progenitor cell colonies. Stem Cell Res 2014; 12(3): 703-15.
Burnouf T, Strunk D, Koh MB, Schallmoser K. Human platelet lysate: Replacing fetal bovine serum as a gold standard for human cell propagation? Biomaterials 2016; 76: 371-87.
Huang L, Critser P, Grimes B, Yoder M. Human umbilical cord blood plasma can replace fetal bovine serum for in vitro expansion of functional human endothelial colony-forming cells. Cytotherapy 2011; 13(6): 712-21.
Nuzzolo E, Capodimonti S, Martini M, et al. Adult and cord blood endothelial progenitor cells have different gene expression profiles and immunogenic potential. Blood Transfus 2014; 12: s367-74.
Flex A, Biscetti F, Iachininoto M, et al. Human cord blood endothelial progenitors promote post-ischemic angiogenesis in immunocompetent mouse model. Thromb Res 2016; 141: 106-11.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [460 - 465]
Pages: 6
DOI: 10.2174/1574888X14666190214162453
Price: $58

Article Metrics

PDF: 47