doi: 10.1161/ATVBAHA.108.163246
© 2008 American Heart Association, Inc.
Editorials |
"Priming" Endothelial Progenitor Cells
A New Strategy to Improve Cell Based Therapeutics
From the Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, Calif.
Correspondence to Dr Geoffrey C. Gurtner, MD, Department of Surgery, Division of Plastic and Reconstructive Surgery, Hagey Laboratory of Regenerative Medicine, Rm GK201, 257 Campus Drive, Stanford University, Stanford, CA 94305. E-mail ggurtner{at}stanford.edu
It is believed that this new century will be the century of regenerative medicine in which chronic diseases will be reversed by therapeutics which can repair and restore function in situ.1 One prerequisite for tissue regeneration is a readily available population of cells that are both highly renewable and highly differentiable. Commonly known as stem or precursor cells, the theoretical appeal of these cells dates back more than 100 years2 but gained traction in the latter half of the 20th century with the isolation and identification of hematopoietic stem cells,3 mesenchymal stem cells,4 and human embryonic stem cells.5,6 In vascular biology progenitor cells able to initiate neovascularization, known as endothelial precursor cells (EPCs), were first identified by Isner and Asahara7 in 1997.
See ATVB 2008;28:644–650
Since then, a number of studies have indicated a strong correlation between cardiovascular risk factors and EPC numbers and function.8 Diabetes mellitus,9,10 hypercholesterolemia,11 coronary artery disease,12 and cigarette smoking13,14 have all been shown to adversely affect EPC number and function, and it has been suggested that EPC number might be useful as a surrogate measure of vascular health.8 There has also been enthusiasm for the use of EPCs as therapeutic agents. Ex vivo isolation of EPCs and local delivery has been used to treat hindlimb ischemia,15 neointimal hyperplasia,16 and pulmonary hypertension17 in animal models. In addition, EPCs have been shown to significantly decrease left ventricular scarring and increase vascular density in animal models of myocardial infarction.18
Despite this, significant problems exist that have prevented rapid translation into the clinic. One problem is that the prevalence of EPCs in blood or bone marrow is typically low and thus the cellular yield per unit of autologous tissue is disappointing. EPCs also tend to differentiate readily in cell culture limiting attempts to perform ex vivo expansion of the cells. Because the cellular yield is so low, large blood volumes typically need to be obtained which complicates clinical application of this strategy. Attempts to use soluble factors such as VEGF, SDF-1
, and erythropoietin (EPO) to mobilize EPCs in vivo have also been disappointing with mostly equivocal results in trials.19 Gene therapy approaches have also been unimpressive.20
Given these frustrations, Zemani et al21 tried a new approach to improve the functionality of existing progenitor cells. They reasoned that if the few cells available were more robust in their ability to incorporate into vessels or release angiogenic factors, fewer cells might be sufficient to produce a therapeutic effect. Because it is known that the chemokine SDF-1 is able to mobilize EPCs, and because EPCs are known to have receptors for SDF-1, there must be a direct interaction to activate these cells in vivo. They exploited this observation by taking EPCs ex vivo and pretreating or "priming" them with the chemokine SDF-1. They demonstrate that SDF-1–primed EPCs exhibit increased adhesion to HUVECs, a greater resistance to shear stress, an enhanced capacity to tubulize in Matrigel, and were more able to incorporate into new vessels in a murine model of hindlimb ischemia. The authors conclude that the pretreatment of EPCs by SDF-1 was able to initiate an activation program within the EPCs, resulting in more efficient incorporation into sites of neovascularization. Because EPCs can be activated by other factors, such as VEGF, angiopoietin, G colony–stimulating factor (CSF), and erythropoietin, there are many potential variants of this approach.
The Zemani et al 21 article combines 2 previously distinct strategies, the use of exogenous cells and exogenous soluble factor delivery, to produce activated EPCs that appear to be more robust than unactivated cells. This in part is able to overcome the problem of EPC scarcity. Unlike prior studies examining the therapeutic use of soluble factors, the targets here are the ex vivo precursor cells which are exposed to much higher doses than would occur in vivo during the "priming process" (see Figure). Although further work is needed, the approach of activating the progenitor cell (and not the host tissue) may have relevance in other areas of regenerative medicine. This strategy may circumvent the problems of insufficient cell number and low efficiency of incorporation that have plagued recent clinical pilot studies.
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In addition, this work demonstrates the importance of continuing to invest in a clearer understanding of the cytokine and growth factor milieu which regulates progenitor cell behavior. Such work will undoubtedly uncover new mechanisms to maintain, expand, and differentiate progenitor cells in vitro. These insights will result in new tools to manipulate precursor and stem cells in vivo and provide new translational avenues to improve for cell based therapeutics.
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Gurtner GC, Callaghan MJ, Longaker MT. Progress and potential for regenerative medicine. Annu Rev Med. 2007; 58: 299–312.[CrossRef][Medline] [Order article via Infotrieve]
2. Weissman A. Essays Upon Heredity. 1889, Claredon Press: Oxford.
3. Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol. 2001; 17: 387–403.[CrossRef][Medline] [Order article via Infotrieve]
4. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, Ruadkow IA. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974; 2 (2): 83–92.[Medline] [Order article via Infotrieve]
5. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282: 1145–1147.
6. Gearhart J. Cell biology: new potential for human embryonic stem cells. Science. 1998; 282: 1061–1062.
7. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997: 275: 964–967.
8. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003; 348: 593–600.
9. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002; 106: 2781–2786.
10. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004; 53: 195–199.
11. Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH. Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clin Sci (Lond). 2004; 107: 273–280.[Medline] [Order article via Infotrieve]
12. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001; 89: e1–e7.[CrossRef][Medline] [Order article via Infotrieve]
13. Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol. 2004; 24: 1442–1447.
14. Wang X, Zhu J, Chen J, Shang Y. Effects of nicotine on the number and activity of circulating endothelial progenitor cells. J Clin Pharmacol. 2004; 44: 881–888.
15. Kalka C, Masuda H, Takahashi T, Kalka-Moll W, Silver M, Kearney M, Li T, J Isner J, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA. 2000; 97: 3422–3427.
16. Kaushal S, Amiel GE, Guleserian KJ, Shapira OM, Perry T. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med. 2001; 7: 1035–1040.[CrossRef][Medline] [Order article via Infotrieve]
17. Takahashi M, Nakamura T, Toba T, Kajiwara N, Kato H. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng. 2004; 10: 771–779.[CrossRef][Medline] [Order article via Infotrieve]
18. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isne JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103: 634–637.
19. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza L, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation. 2003; 107: 1359–1365.
20. Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nature Medicine. 2000; 6: 1102–1103.[CrossRef][Medline] [Order article via Infotrieve]
21. Zemani F, Silvestre JS, Fauvel-Lafeve F, Bruel A, Vilar J, Bieche I, Laurendeau I, Galy-Fauroux I, Fischer AM, Boisson-Vidal C. Ex vivo priming of EPC with SDF-1 before transplantation could increase their porangiogenic potential. Arterioscler Thromb Vasc Biol. 2008; 28: 644–650.
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