Abstract
Postnatal neovascular formation was originally thought to be mediated by angiogenesis, which is defined as the formation of new blood vessels from pre-existing endothelial cells (ECs). However, over the last decade, it has been proposed that vasculogenesis, that is, de novo blood vessel generation from endothelial progenitor cells (EPCs) derived from bone marrow, may persist into adult life. Nonetheless, it is still a matter of debate as to what extent the EPCs contribute to new vessel formation in the adult.
In the peripheral blood vessels, the presence of different stem and progenitor cell types residing in the media and adventitia of the vascular wall has been suggested. These stem/progenitor cells were reported to have the ability to differentiate into ECs in culture and form capillary-like microvessels in ex vivo assays. However, the precise roles of these cells during angiogenic growth are not well defined. We recently isolated a novel endothelial stem/progenitor-like cells from the intima of adult murine blood vessels using the Hoechst method in which stem cell populations are identified as side populations. This vascular endothelial side population cell possesses colony-forming ability, generates large numbers of ECs, and when transplanted into ischemic lesions, these cells contribute to the newly formed long-term surviving blood vessels and restore blood flow completely. Our discovery of vascular endothelial side population cells that have features of endothelial stem/progenitor cells may lead to the identification of new targets for vascular regeneration therapy as well as vascular disrupting therapy.
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Abbreviations
- BM:
-
Bone marrow
- ECs:
-
Endothelial cells
- EPCs:
-
Endothelial progenitor cells
- FACS:
-
Fluorescence-activated cell sorting
- HAECs:
-
Human aortic endothelial cells
- HC:
-
Hematopoietic cell
- HSC:
-
Hematopoietic stem cell
- HUVECs:
-
Human umbilical vein endothelial cells
- KSL:
-
c-Kit+ Sca-1+, and Lineage−
- MP:
-
Main population
- SMCs:
-
Smooth muscle cells
- SP:
-
Side population
References
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111
Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132(4):598–611
Mimeault M, Batra SK (2008) Recent progress on tissue-resident adult stem cell biology and their therapeutic implications. Stem Cell Rev 4(1):27–49
Lin KK, Goodell MA (2011) Detection of hematopoietic stem cells by flow cytometry. Methods Cell Biol 103:21–30
Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T (1992) In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood 80(12):3044–3050
Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241(4861):58–62
Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121(7):1109–1121
Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, Satake M, Suda T (2000) A role for hematopoietic stem cells in promoting angiogenesis. Cell 102(2):199–209
Christensen JL, Weissman IL (2001) Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A 98(25):14541–14546
Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273(5272):242–245
Pallavicini MG, Summers LJ, Dean PN, Gray JW (1985) Enrichment of murine hemopoietic clonogenic cells by multivariate analyses and sorting. Exp Hematol 13(11):1173–1181
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4):1797–1806
Chaudhary PM, Roninson IB (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66(1):85–94
Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7(9):1028–1034
Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA (2002) Myogenic specification of side population cells in skeletal muscle. J Cell Biol 159(1):123–134
Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA (2002) Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245(1):42–56
Shimano K, Satake M, Okaya A, Kitanaka J, Kitanaka N, Takemura M, Sakagami M, Terada N, Tsujimura T (2003) Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 163(1):3–9
Summer R, Kotton DN, Sun X, Ma B, Fitzsimmons K, Fine A (2003) Side population cells and Bcrp1 expression in lung. Am J Physiol Lung Cell Mol Physiol 285(1):L97–L104
Lassalle B, Bastos H, Louis JP, Riou L, Testart J, Dutrillaux B, Fouchet P, Allemand I (2004) ‘Side Population’ cells in adult mouse testis express Bcrp1 gene and are enriched in spermatogonia and germinal stem cells. Development 131(2):479–487
Redvers RP, Li A, Kaur P (2006) Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci U S A 103(35):13168–13173
Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, Iwanaga K, Takahashi T, Goto M, Mikami Y, Yasuda N, Akazawa H, Uezumi A, Takeda S, Komuro I (2007) Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol 176(3):329–341
Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 101(3):781–786
Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101(39):14228–14233
Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE (1989) The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9(3):1346–1350
Huls M, van den Heuvel JJ, Dijkman HB, Russel FG, Masereeuw R (2006) ABC transporter expression profiling after ischemic reperfusion injury in mouse kidney. Kidney Int 69(12):2186–2193
Miller DS (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier. Trends Pharmacol Sci 31(6):246–254
Golebiewska A, Brons NH, Bjerkvig R, Niclou SP (2011) Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell 8(2):136–147
Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA (2002) The post-natal heart contains a myocardial stem cell population. FEBS Lett 530(1–3):239–243
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 100(21):12313–12318
Martin CM, Meeson AP, Robertson SM, Hawke TJ, Richardson JA, Bates S, Goetsch SC, Gallardo TD, Garry DJ (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265(1):262–275
Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R (2005) CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97(1):52–61
Mouquet F, Pfister O, Jain M, Oikonomopoulos A, Ngoy S, Summer R, Fine A, Liao R (2005) Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circ Res 97(11):1090–1092
Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52(2):237–268
Torsney E, Xu Q (2011) Resident vascular progenitor cells. J Mol Cell Cardiol 50(2):304–311
Majesky MW, Dong XR, Regan JN, Hoglund VJ (2011) Vascular smooth muscle progenitor cells: building and repairing blood vessels. Circ Res 108(3):365–377
Ingram DA, Mead LE, Moore DB, Woodard W, Fenoglio A, Yoder MC (2005) Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 105(7):2783–2786
Naito H, Kidoya H, Sakimoto S, Wakabayashi T, Takakura N (2012) Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J 31(4):842–855
Sainz J, Al Haj Zen A, Caligiuri G, Demerens C, Urbain D, Lemitre M, Lafont A (2006) Isolation of “side population” progenitor cells from healthy arteries of adult mice. Arterioscler Thromb Vasc Biol 26(2):281–286
Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, Wilcox JN (1996) Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 93(12):2178–2187
Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q (2004) Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113(9):1258–1265
Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, Weil J, Reichenspurner H, Kilic N, Ergun S (2006) Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133(8):1543–1551
Passman JN, Dong XR, Wu SP, Maguire CT, Hogan KA, Bautch VL, Majesky MW (2008) A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc Natl Acad Sci U S A 105(27):9349–9354
Pasquinelli G, Tazzari PL, Vaselli C, Foroni L, Buzzi M, Storci G, Alviano F, Ricci F, Bonafe M, Orrico C, Bagnara GP, Stella A, Conte R (2007) Thoracic aortas from multiorgan donors are suitable for obtaining resident angiogenic mesenchymal stromal cells. Stem Cells 25(7):1627–1634
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302):964–967
Asahara T, Kawamoto A, Masuda H (2011) Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells 29(11):1650–1655
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 NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7(11):1194–1201
De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9(6):789–795
De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226
Gothert JR, Gustin SE, van Eekelen JA, Schmidt U, Hall MA, Jane SM, Green AR, Gottgens B, Izon DJ, Begley CG (2004) Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. Blood 104(6):1769–1777
Ziegelhoeffer T, Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A, Schaper W (2004) Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 94(2):230–238
Shinde Patil VR, Friedrich EB, Wolley AE, Gerszten RE, Allport JR, Weissleder R (2005) Bone marrow-derived lin(−)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma. Neoplasia 7(3):234–240
Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Yla-Herttuala S, Alitalo K, Weissman IL, Salven P (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci U S A 105(18):6620–6625
Okuno Y, Nakamura-Ishizu A, Kishi K, Suda T, Kubota Y (2011) Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing. Blood 117(19):5264–5272
Rinkevich Y, Lindau P, Ueno H, Longaker MT, Weissman IL (2011) Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip. Nature 476(7361):409–413
Folkman J, Haudenschild CC, Zetter BR (1979) Long-term culture of capillary endothelial cells. Proc Natl Acad Sci U S A 76(10):5217–5221
Wu Z, Hofman FM, Zlokovic BV (2003) A simple method for isolation and characterization of mouse brain microvascular endothelial cells. J Neurosci Methods 130(1):53–63
Ewing P, Wilke A, Brockhoff G, Andreesen R, Eissner G, Holler E, Gerbitz A (2003) Isolation and transplantation of allogeneic pulmonary endothelium derived from GFP transgenic mice. J Immunol Methods 283(1–2):307–315
van Beijnum JR, Rousch M, Castermans K, van der Linden E, Griffioen AW (2008) Isolation of endothelial cells from fresh tissues. Nat Protoc 3(6):1085–1091
Asakura A, Rudnicki MA (2002) Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp Hematol 30(11):1339–1345
Jonker JW, Freeman J, Bolscher E, Musters S, Alvi AJ, Titley I, Schinkel AH, Dale TC (2005) Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 23(8):1059–1065
Pietras EM, Warr MR, Passegue E (2011) Cell cycle regulation in hematopoietic stem cells. J Cell Biol 195(5):709–720
Bruscia EM, Ziegler EC, Price JE, Weiner S, Egan ME, Krause DS (2006) Engraftment of donor-derived epithelial cells in multiple organs following bone marrow transplantation into newborn mice. Stem Cells 24(10):2299–2308
Simons BD, Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145(6):851–862
McNiece IK, Stewart FM, Deacon DM, Temeles DS, Zsebo KM, Clark SC, Quesenberry PJ (1989) Detection of a human CFC with a high proliferative potential. Blood 74(2):609–612
Takakura N, Huang XL, Naruse T, Hamaguchi I, Dumont DJ, Yancopoulos GD, Suda T (1998) Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9(5):677–686
Rajagopalan S, Mohler ER III, Lederman RJ, Mendelsohn FO, Saucedo JF, Goldman CK, Blebea J, Macko J, Kessler PD, Rasmussen HS, Annex BH (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108(16):1933–1938
Nikol S, Baumgartner I, Van Belle E, Diehm C, Visona A, Capogrossi MC, Ferreira-Maldent N, Gallino A, Wyatt MG, Wijesinghe LD, Fusari M, Stephan D, Emmerich J, Pompilio G, Vermassen F, Pham E, Grek V, Coleman M, Meyer F (2008) Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 16(5):972–978
Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH (2008) Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 118(1):58–65
Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T (2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360(9331):427–435
Minamino T, Toko H, Tateno K, Nagai T, Komuro I (2002) Peripheral-blood or bone-marrow mononuclear cells for therapeutic angiogenesis? Lancet 360(9350):2083–2084
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438(7070):967–974
Kim JY, Song SH, Kim KL, Ko JJ, Im JE, Yie SW, Ahn YK, Kim DK, Suh W (2010) Human cord blood-derived endothelial progenitor cells and their conditioned media exhibit therapeutic equivalence for diabetic wound healing. Cell Transplant 19(12):1635–1644
Yamada Y, Takakura N (2006) Physiological pathway of differentiation of hematopoietic stem cell population into mural cells. J Exp Med 203(4):1055–1065
Biteau B, Hochmuth CE, Jasper H (2011) Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9(5):402–411
Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400
Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603
Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177
Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851
Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887
Chappell JC, Taylor SM, Ferrara N, Bautch VL (2009) Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 17(3):377–386
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and Japan Society for the Promotion of Science of Japan.
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Naito, H., Takakura, N. (2013). Vascular-Resident Endothelial Side Population Cells. In: Dulak, J., Józkowicz, A., Łoboda, A. (eds) Angiogenesis and Vascularisation. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1428-5_3
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