Abstract
Purpose of Review
Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) emerged as an important source of cells for cardiovascular regeneration. This review summarizes protocols for generating hPSC-ECs and provides an overview of the current state of the research in clinical application of hPSC-derived ECs.
Recent Findings
Various systems were developed for differentiating hPSCs into the EC lineage. Stepwise two-dimensional systems are now well established, in which various growth factors, small molecules, and coating materials are used at specific developmental stages. Moreover, studies made significant advances in clinical applicability of hPSC-ECs by removing undefined components from the differentiation system, improving the differentiation efficiency, and proving their direct vascular incorporating effects, which contrast with adult stem cells and their therapeutic effects in vivo. Finally, by using biomaterial-mediated delivery, investigators improved the survival of hPSC-ECs to more than 10 months in ischemic tissues and described long-term behavior and safety of in vivo transplanted hPSC-ECs at the histological level.
Summary
hPSC-derived ECs can be as a critical source of cells for treating advanced cardiovascular diseases. Over the past two decades, substantial improvement has been made in the differentiation systems and their clinical compatibility. In the near future, establishment of fully defined differentiation systems and proof of the advantages of biomaterial-mediated cell delivery, with some additional pre-clinical studies, will move this therapy into a vital option for treating those diseases that cannot be managed by currently available therapies.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
McDermott MM, Guralnik JM, Tian L, Liu K, Ferrucci L, Liao Y, et al. Associations of borderline and low normal ankle-brachial index values with functional decline at 5-year follow-up: the WALCS (Walking and Leg Circulation Study). J Am Coll Cardiol. 2009;53(12):1056–62. https://doi.org/10.1016/j.jacc.2008.09.063.
Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation. 2004;109(22):2692–7. https://doi.org/10.1161/01.CIR.0000128596.49339.05.
Ziegelhoeffer T, Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A, et al. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res. 2004;94(2):230–8. https://doi.org/10.1161/01.RES.0000110419.50982.1C.
Lee S, Yoon YS. Revisiting cardiovascular regeneration with bone marrow-derived angiogenic and vasculogenic cells. Br J Pharmacol. 2013;169(2):290–303. https://doi.org/10.1111/j.1476-5381.2012.01857.x.
Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367(9505):113–21. https://doi.org/10.1016/S0140-6736(05)67861-0.
Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1199–209. https://doi.org/10.1056/NEJMoa055706.
Cho SW, Moon SH, Lee SH, Kang SW, Kim J, Lim JM, et al. Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation. 2007;116(21):2409–19. https://doi.org/10.1161/CIRCULATIONAHA.106.687038.
•• Lee SJ, Sohn YD, Andukuri A, Kim S, Byun J, Han JW, et al. Enhanced therapeutic and long-term dynamic vascularization effects of human pluripotent stem cell-derived endothelial cells encapsulated in a nanomatrix gel. Circulation. 2017;136(20):1939–54. https://doi.org/10.1161/CIRCULATIONAHA.116.026329. This study addresses a clinicall compatible system that can differentiate hPSC into EC and therapeutic and long-term vessel-forming effects of hPSC-EC
Park C, Lee JY, Lee SJ, Lee E, Yoon YS. Differentiation of human embryonic stem cells and induced pluripotent stem cells into lymphatic endothelial cells. Circulation. 2010;122(21 Supplement):A13136.
Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M, et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000;6(2):88–95.
Adams WJ, Zhang Y, Cloutier J, Kuchimanchi P, Newton G, Sehrawat S, et al. Functional vascular endothelium derived from human induced pluripotent stem cells. Stem Cell Reports. 2013;1(2):105–13. https://doi.org/10.1016/j.stemcr.2013.06.007.
Goldman O, Feraud O, Boyer-Di Ponio J, Driancourt C, Clay D, Le Bousse-Kerdiles MC, et al. A boost of BMP4 accelerates the commitment of human embryonic stem cells to the endothelial lineage. Stem Cells. 2009;27(8):1750–9. https://doi.org/10.1002/stem.100.
James D, Nam HS, Seandel M, Nolan D, Janovitz T, Tomishima M, et al. Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol. 2010;28(2):161–6. https://doi.org/10.1038/nbt.1605.
Levenberg S, Ferreira LS, Chen-Konak L, Kraehenbuehl TP, Langer R. Isolation, differentiation and characterization of vascular cells derived from human embryonic stem cells. Nat Protoc. 2010;5(6):1115–26. https://doi.org/10.1038/nprot.2010.31.
Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R. Endothelial cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2002;99(7):4391–6. https://doi.org/10.1073/pnas.032074999.
Li Z, Hu S, Ghosh Z, Han Z, Wu JC. Functional characterization and expression profiling of human induced pluripotent stem cell- and embryonic stem cell-derived endothelial cells. Stem Cells Dev. 2011;20(10):1701–10. https://doi.org/10.1089/scd.2010.0426.
Nourse MB, Halpin DE, Scatena M, Mortisen DJ, Tulloch NL, Hauch KD, et al. VEGF induces differentiation of functional endothelium from human embryonic stem cells: implications for tissue engineering. Arterioscler Thromb Vasc Biol. 2010;30(1):80–9. https://doi.org/10.1161/ATVBAHA.109.194233.
Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, et al. Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart. J Exp Med. 2007;204(13):3257–69. https://doi.org/10.1084/jem.20070166.
Taura D, Sone M, Homma K, Oyamada N, Takahashi K, Tamura N, et al. Induction and isolation of vascular cells from human induced pluripotent stem cells—brief report. Arterioscler Thromb Vasc Biol. 2009;29(7):1100–3. https://doi.org/10.1161/ATVBAHA.108.182162.
Wang ZZ, Au P, Chen T, Shao Y, Daheron LM, Bai H, et al. Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nat Biotechnol. 2007;25(3):317–8. https://doi.org/10.1038/nbt1287.
• Patsch C, Challet-Meylan L, Thoma EC, Urich E, Heckel T, O'Sullivan JF, et al. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol. 2015;17(8):994–1003. https://doi.org/10.1038/ncb3205. This study reports a fast and efficient protocol to differentiate hPSC into EC and vascular smooth muscle cell
White MP, Rufaihah AJ, Liu L, Ghebremariam YT, Ivey KN, Cooke JP, et al. Limited gene expression variation in human embryonic stem cell and induced pluripotent stem cell-derived endothelial cells. Stem Cells. 2013;31(1):92–103. https://doi.org/10.1002/stem.1267.
Orlova VV, Drabsch Y, Freund C, Petrus-Reurer S, van den Hil FE, Muenthaisong S, et al. Functionality of endothelial cells and pericytes from human pluripotent stem cells demonstrated in cultured vascular plexus and zebrafish xenografts. Arterioscler Thromb Vasc Biol. 2014;34(1):177–86. https://doi.org/10.1161/ATVBAHA.113.302598.
Rufaihah AJ, Huang NF, Kim J, Herold J, Volz KS, Park TS, et al. Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. Am J Transl Res. 2013;5(1):21–35.
Orlova VV, van den Hil FE, Petrus-Reurer S, Drabsch Y, Ten Dijke P, Mummery CL. Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells. Nat Protoc. 2014;9(6):1514–31. https://doi.org/10.1038/nprot.2014.102.
Lee SJ, Park C, Lee JY, Kim S, Kwon PJ, Kim W, et al. Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair. Sci Rep. 2015;5:11019. https://doi.org/10.1038/srep11019.
Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648–59. https://doi.org/10.1634/stemcells.2007-0226.
Morbidelli L, Ziche M. The rabbit corneal pocket assay. Methods Mol Biol. 2016;1430:299–310. https://doi.org/10.1007/978-1-4939-3628-1_20.
Morbidelli L, Ziche M. The rabbit corneal pocket assay for the study of angiogenesis. Cancer Treat Res. 2004;117:147–51.
Yamanaka S. A fresh look at iPS cells. Cell. 2009;137(1):13–7. https://doi.org/10.1016/j.cell.2009.03.034.
Li Z, Suzuki Y, Huang M, Cao F, Xie X, Connolly AJ, et al. Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells. 2008;26(4):864–73. https://doi.org/10.1634/stemcells.2007-0843.
van der Bogt KE, Sheikh AY, Schrepfer S, Hoyt G, Cao F, Ransohoff KJ, et al. Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation. 2008;118(14 Suppl):S121–9. https://doi.org/10.1161/CIRCULATIONAHA.107.759480.
Li Z, Wilson KD, Smith B, Kraft DL, Jia F, Huang M, et al. Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS One. 2009;4(12):e8443. https://doi.org/10.1371/journal.pone.0008443.
Ong SG, Huber BC, Lee WH, Kodo K, Ebert AD, Ma Y, et al. Microfluidic single-cell analysis of transplanted human induced pluripotent stem cell-derived cardiomyocytes after acute myocardial infarction. Circulation. 2015;132(8):762–71. https://doi.org/10.1161/CIRCULATIONAHA.114.015231.
Hoffmann J, Glassford AJ, Doyle TC, Robbins RC, Schrepfer S, Pelletier MP. Angiogenic effects despite limited cell survival of bone marrow-derived mesenchymal stem cells under ischemia. Thorac Cardiovasc Surg. 2010;58(3):136–42. https://doi.org/10.1055/s-0029-1240758.
van der Bogt KE, Hellingman AA, Lijkwan MA, Bos E-JJ, de Vries MR, van Rappard JR, et al. Molecular imaging of bone marrow mononuclear cell survival and homing in murine peripheral artery disease. JACC Cardiovasc Imaging. 2012;5(1):46–55. https://doi.org/10.1016/j.jcmg.2011.07.011.
Rufaihah AJ, Huang NF, Jame S, Lee JC, Nguyen HN, Byers B, et al. Endothelial cells derived from human iPSCS increase capillary density and improve perfusion in a mouse model of peripheral arterial disease. Arterioscler Thromb Vasc Biol. 2011;31(11):e72–9. https://doi.org/10.1161/ATVBAHA.111.230938.
Mooney DJ, Vandenburgh H. Cell delivery mechanisms for tissue repair. Cell Stem Cell. 2008;2(3):205–13. https://doi.org/10.1016/j.stem.2008.02.005.
Segers VF, Lee RT. Biomaterials to enhance stem cell function in the heart. Circ Res. 2011;109(8):910–22. https://doi.org/10.1161/CIRCRESAHA.111.249052.
Webber MJ, Tongers J, Renault MA, Roncalli JG, Losordo DW, Stupp SI. Development of bioactive peptide amphiphiles for therapeutic cell delivery. Acta Biomater. 2010;6(1):3–11. https://doi.org/10.1016/j.actbio.2009.07.031.
Ban K, Park HJ, Kim S, Andukuri A, Cho KW, Hwang JW, et al. Cell therapy with embryonic stem cell-derived cardiomyocytes encapsulated in injectable nanomatrix gel enhances cell engraftment and promotes cardiac repair. ACS Nano. 2014;8(10):10815–25. https://doi.org/10.1021/nn504617g.
Boopathy AV, Che PL, Somasuntharam I, Fiore VF, Cabigas EB, Ban K, et al. The modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation. Biomaterials. 2014;35(28):8103–12. https://doi.org/10.1016/j.biomaterials.2014.05.082.
Mulyasasmita W, Cai L, Dewi RE, Jha A, Ullmann SD, Luong RH, et al. Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J Control Release. 2014;191:71–81. https://doi.org/10.1016/j.jconrel.2014.05.015.
Anderson JM, Andukuri A, Lim DJ, Jun H-WW. Modulating the gelation properties of self-assembling peptide amphiphiles. ACS Nano. 2009;3(11):3447–54. https://doi.org/10.1021/nn900884n.
Anderson JM, Patterson JL, Vines JB, Javed A, Gilbert SR, Jun HW. Biphasic peptide amphiphile nanomatrix embedded with hydroxyapatite nanoparticles for stimulated osteoinductive response. ACS Nano. 2011;5(12):9463–79. https://doi.org/10.1021/nn203247m.
Acknowledgments
This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI16C2211 and HI15C2782), the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (No. 2015M3A9C6031514 and 2016R1D1A1B03933154), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (No. DP3-DK094346 and DP3-DK108245), and the National Heart, Lung, PHS Grant UL1TR000454 from Clinical and Translational Science Award Program, National Institutes of Health, National Center for Advancing Translational Sciences, and Blood Institute (NHLBI) (No. R01HL127759 and R01HL129511).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Shin-Jeong Lee, Kyung Hee Kim, and Young-sup Yoon declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Regenerative Medicine
Rights and permissions
About this article
Cite this article
Lee, SJ., Kim, K.H. & Yoon, Ys. Generation of Human Pluripotent Stem Cell-derived Endothelial Cells and Their Therapeutic Utility. Curr Cardiol Rep 20, 45 (2018). https://doi.org/10.1007/s11886-018-0985-8
Published:
DOI: https://doi.org/10.1007/s11886-018-0985-8