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Vascular stem/progenitor cells: functions and signaling pathways

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Abstract

Vascular stem/progenitor cells (VSCs) are an important source of all types of vascular cells needed to build, maintain, repair, and remodel blood vessels. VSCs, therefore, play critical roles in the development, normal physiology, and pathophysiology of numerous diseases. There are four major types of VSCs, including endothelial progenitor cells (EPCs), smooth muscle progenitor cells (SMPCs), pericytes, and mesenchymal stem cells (MSCs). VSCs can be found in bone marrow, circulating blood, vessel walls, and other extravascular tissues. During the past two decades, considerable progress has been achieved in the understanding of the derivation, surface markers, and differentiation of VSCs. Yet, the mechanisms regulating their functions and maintenance under normal and pathological conditions, such as in eye diseases, remain to be further elucidated. Owing to the essential roles of blood vessels in human tissues and organs, understanding the functional properties and the underlying molecular basis of VSCs is of critical importance for both basic and translational research.

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References

  1. Qian H, Yang Y, Li J, Huang J, Dou K, Yang G (2007) The role of vascular stem cells in atherogenesis and post-angioplasty restenosis. Ageing Res Rev 6:109–127

    Article  PubMed  Google Scholar 

  2. van Dijk CG, Nieuweboer FE, Pei JY, Xu YJ, Burgisser P, van Mulligen E et al (2015) The complex mural cell: pericyte function in health and disease. Int J Cardiol 190:75–89

    Article  PubMed  Google Scholar 

  3. Pacilli A, Pasquinelli G (2009) Vascular wall resident progenitor cells: a review. Exp Cell Res 315:901–914

    Article  CAS  PubMed  Google Scholar 

  4. Bobryshev YV, Orekhov AN, Chistiakov DA (2015) Vascular stem/progenitor cells: current status of the problem. Cell Tissue Res 362:1–7

    Article  CAS  PubMed  Google Scholar 

  5. Marcola M, Rodrigues CE (2015) Endothelial progenitor cells in tumor angiogenesis: another brick in the wall. Stem Cells Int 2015:832649

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  CAS  PubMed  Google Scholar 

  7. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F et al (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109:1801–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Keskek SO, Bozkirli-Ersozlu ED, Kozanoglu I, Yucel AE (2017) High levels of circulating endothelial progenitor cells are associated with acrotism in patients with takayasu arteritis. Med Princ Pract 26:132–138

    Article  PubMed  Google Scholar 

  9. Bitterli L, Afan S, Buhler S, DiSanto S, Zwahlen M, Schmidlin K et al (2016) Endothelial progenitor cells as a biological marker of peripheral artery disease. Vasc Med 21:3–11

    Article  CAS  PubMed  Google Scholar 

  10. Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169

    Article  PubMed  Google Scholar 

  11. Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD (2012) Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Investig 122:1567–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801

    Article  CAS  PubMed  Google Scholar 

  13. Esner M, Meilhac SM, Relaix F, Nicolas JF, Cossu G, Buckingham ME (2006) Smooth muscle of the dorsal aorta shares a common clonal origin with skeletal muscle of the myotome. Development 133:737–749

    Article  CAS  PubMed  Google Scholar 

  14. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616

    CAS  PubMed  Google Scholar 

  15. Orlandi A, Bennett M (2010) Progenitor cell-derived smooth muscle cells in vascular disease. Biochem Pharmacol 79:1706–1713

    Article  CAS  PubMed  Google Scholar 

  16. Bentzon JF, Falk E (2010) Circulating smooth muscle progenitor cells in atherosclerosis and plaque rupture: current perspective and methods of analysis. Vasc Pharmacol 52:11–20

    Article  CAS  Google Scholar 

  17. Merkulova-Rainon T, Broqueres-You D, Kubis N, Silvestre JS, Levy BI (2012) Towards the therapeutic use of vascular smooth muscle progenitor cells. Cardiovasc Res 95:205–214

    Article  CAS  PubMed  Google Scholar 

  18. Alexander MR, Owens GK (2012) Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu Rev Physiol 74:13–40

    Article  CAS  PubMed  Google Scholar 

  19. Rouget C (1873) Mémoire sur le développement, la structure et les propriétés physiologiques des capillaires sanguins et lymphatiques. Arch Physiol Norm Pathol 5:603–663

    Google Scholar 

  20. Zimmermann KW (1923) Der feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch 68:29–109

    Article  Google Scholar 

  21. Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314:15–23

    Article  PubMed  Google Scholar 

  22. Pallone TL, Silldorff EP (2001) Pericyte regulation of renal medullary blood flow. Exp Nephrol 9:165–170

    Article  CAS  PubMed  Google Scholar 

  23. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H et al (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245

    Article  CAS  PubMed  Google Scholar 

  25. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stapor PC, Sweat RS, Dashti DC, Betancourt AM, Murfee WL (2014) Pericyte dynamics during angiogenesis: new insights from new identities. J Vasc Res 51:163–174

    Article  PubMed  PubMed Central  Google Scholar 

  27. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215

    Article  CAS  PubMed  Google Scholar 

  28. Lin CS, Lue TF (2013) Defining vascular stem cells. Stem Cells Dev 22:1018–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Torsney E, Xu Q (2011) Resident vascular progenitor cells. J Mol Cell Cardiol 50:304–311

    Article  CAS  PubMed  Google Scholar 

  30. Guimaraes-Camboa N, Cattaneo P, Sun Y, Moore-Morris T, Gu Y, Dalton ND et al (2017) Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20(345–359):e345

    Article  CAS  Google Scholar 

  31. Volz KS, Jacobs AH, Chen HI, Poduri A, McKay AS, Riordan DP et al (2015) Pericytes are progenitors for coronary artery smooth muscle. eLife 4. doi:10.7554/eLife.10036

    Google Scholar 

  32. Billaud M, Donnenberg VS, Ellis BW, Meyer EM, Donnenberg AD, Hill JC et al (2017) Classification and functional characterization of vasa vasorum-associated perivascular progenitor cells in human aorta. Stem cell Rep 9:292–303

    Article  CAS  Google Scholar 

  33. Hashemian SJ, Kouhnavard M, Nasli-Esfahani E (2015) Mesenchymal stem cells: rising concerns over their application in treatment of type one diabetes mellitus. J Diabetes Res 2015:675103

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25:2739–2749

    Article  CAS  PubMed  Google Scholar 

  35. Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74

    Article  CAS  PubMed  Google Scholar 

  36. Oswald J, Boxberger S, Jorgensen B, Feldmann S, Ehninger G, Bornhauser M et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384

    Article  PubMed  Google Scholar 

  37. Kashiwakura Y, Katoh Y, Tamayose K, Konishi H, Takaya N, Yuhara S et al (2003) Isolation of bone marrow stromal cell-derived smooth muscle cells by a human SM22alpha promoter: in vitro differentiation of putative smooth muscle progenitor cells of bone marrow. Circulation 107:2078–2081

    Article  PubMed  Google Scholar 

  38. Loibl M, Binder A, Herrmann M, Duttenhoefer F, Richards RG, Nerlich M et al (2014) Direct cell-cell contact between mesenchymal stem cells and endothelial progenitor cells induces a pericyte-like phenotype in vitro. Biomed Res Int 2014:395781

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Tanaka Y, Shirasawa B, Takeuchi Y, Kawamura D, Nakamura T, Samura M et al (2016) Autologous preconditioned mesenchymal stem cell sheets improve left ventricular function in a rabbit old myocardial infarction model. Am J Trans Res 8:2222–2233

    Google Scholar 

  40. Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C et al (2017) Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 8:45200–45212

    PubMed  PubMed Central  Google Scholar 

  41. Volarevic V, Arsenijevic N, Lukic ML, Stojkovic M (2011) Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 29:5–10

    Article  CAS  PubMed  Google Scholar 

  42. Leasher JL, Bourne RR, Flaxman SR, Jonas JB, Keeffe J, Naidoo K et al (2016) Global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010. Diabetes Care 39:1643–1649

    Article  PubMed  Google Scholar 

  43. Medina RJ, O’Neill CL, Humphreys MW, Gardiner TA, Stitt AW (2010) Outgrowth endothelial cells: characterization and their potential for reversing ischemic retinopathy. Invest Ophthalmol Vis Sci 51:5906–5913

    Article  PubMed  Google Scholar 

  44. Sakimoto S, Marchetti V, Aguilar E, Lee K, Usui Y, Murinello S et al (2017) CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect. JCI Insight 2:e89906

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shaw LC, Neu MB, Grant MB (2011) Cell-based therapies for diabetic retinopathy. Curr DiabRep 11:265–274

    Article  Google Scholar 

  46. Tan K, Lessieur E, Cutler A, Nerone P, Vasanji A, Asosingh K et al (2010) Impaired function of circulating CD34(+) CD45(−) cells in patients with proliferative diabetic retinopathy. Exp Eye Res 91:229–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tikhonenko M, Lydic TA, Opreanu M, Li Calzi S, Bozack S, McSorley KM et al (2013) N-3 polyunsaturated fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS One 8:e55177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang Y, Fan L, Meng X, Jiang F, Chen Q, Zhang Z et al (2016) Transplantation of IL-10-transfected endothelial progenitor cells improves retinal vascular repair via suppressing inflammation in diabetic rats. Graefe’s Arch Clin Exp Ophthalmol 254:1957–1965

    Article  CAS  Google Scholar 

  49. Caballero S, Hazra S, Bhatwadekar A, Li Calzi S, Paradiso LJ, Miller LP et al (2013) Circulating mononuclear progenitor cells: differential roles for subpopulations in repair of retinal vascular injury. Invest Ophthalmol Vis Sci 54:3000–3009

    Article  PubMed  PubMed Central  Google Scholar 

  50. Majesky MW, Horita H, Ostriker A, Lu S, Regan JN, Bagchi A et al (2017) Differentiated smooth muscle cells generate a subpopulation of resident vascular progenitor cells in the adventitia regulated by Klf4. Circ Res 120:296–311

    Article  CAS  PubMed  Google Scholar 

  51. Zhao T, Zhang ZN, Westenskow PD, Todorova D, Hu Z, Lin T et al (2015) Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17:353–359

    Article  CAS  PubMed  Google Scholar 

  52. Mendel TA, Clabough EB, Kao DS, Demidova-Rice TN, Durham JT, Zotter BC et al (2013) Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy. PLoS One 8:e65691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hajmousa G, Elorza AA, Nies VJ, Jensen EL, Nagy RA, Harmsen MC (2016) Hyperglycemia induces bioenergetic changes in adipose-derived stromal cells while their pericytic function is retained. Stem Cells Dev 25:1444–1453

    Article  CAS  PubMed  Google Scholar 

  54. Kim JM, Hong KS, Song WK, Bae D, Hwang IK, Kim JS et al (2016) Perivascular progenitor cells derived from human embryonic stem cells exhibit functional characteristics of pericytes and improve the retinal vasculature in a rodent model of diabetic retinopathy. Stem Cells Trans Med 5:1268–1276

    Article  CAS  Google Scholar 

  55. Mathew B, Poston JN, Dreixler JC, Torres L, Lopez J, Zelkha R et al (2017) Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats. Graefe’s Arch Clin Exp Ophthalmol 255:1581–1592

    Article  CAS  Google Scholar 

  56. Wang JD, An Y, Zhang JS, Wan XH, Jonas JB, Xu L et al (2017) Human bone marrow mesenchymal stem cells for retinal vascular injury. Acta Ophthalmol 95(6):e453–e461. doi: 10.1111/aos.13154

    Article  CAS  PubMed  Google Scholar 

  57. Ezquer F, Ezquer M, Arango-Rodriguez M, Conget P (2014) Could donor multipotent mesenchymal stromal cells prevent or delay the onset of diabetic retinopathy? Acta Ophthalmol 92:e86–e95

    Article  PubMed  Google Scholar 

  58. Ezquer M, Urzua CA, Montecino S, Leal K, Conget P, Ezquer F (2016) Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem Cell Res Ther 7:42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Moisseiev E, Anderson JD, Oltjen S, Goswami M, Zawadzki RJ, Nolta JA et al (2017) Protective effect of intravitreal administration of exosomes derived from mesenchymal stem cells on retinal ischemia. Curr Eye Res 1–10. doi:10.1080/02713683.2017.1319491

  60. Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd et al (2017) Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med 376:1047–1053

    Article  PubMed  PubMed Central  Google Scholar 

  61. Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y (2016) Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study. Stem Cell Res Ther 7:178

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ferrara N, Adamis AP (2016) Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 15:385–403

    Article  CAS  PubMed  Google Scholar 

  63. Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21:154–165

    Article  CAS  PubMed  Google Scholar 

  64. Liao YY, Tsai HC, Chou PY, Wang SW, Chen HT, Lin YM et al (2016) CCL3 promotes angiogenesis by dysregulation of miR-374b/VEGF-A axis in human osteosarcoma cells. Oncotarget 7(4):4310–4325. doi:10.18632/oncotarget.6708

    Article  PubMed  Google Scholar 

  65. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H et al (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E et al (2000) Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 86:1198–1202

    Article  CAS  PubMed  Google Scholar 

  67. Ball SG, Shuttleworth CA, Kielty CM (2007) Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol 177:489–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Katare R, Riu F, Mitchell K, Gubernator M, Campagnolo P, Cui Y et al (2011) Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ Res 109:894–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang F, Tang Z, Hou X, Lennartsson J, Li Y, Koch AW et al (2009) VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 106:6152–6157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lakkisto P, Kyto V, Forsten H, Siren JM, Segersvard H, Voipio-Pulkki LM et al (2010) Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of HIF-1alpha, SDF-1alpha and VEGF-B. Eur J Pharmacol 635:156–164

    Article  CAS  PubMed  Google Scholar 

  71. Yu Y, Gao Y, Qin J, Kuang CY, Song MB, Yu SY et al (2010) CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury. Basic Res Cardiol 105:713–724

    Article  CAS  PubMed  Google Scholar 

  72. Bauer SM, Bauer RJ, Liu ZJ, Chen H, Goldstein L, Velazquez OC (2005) Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in three-dimensional collagen gels. J Vasc Surg 41:699–707

    Article  PubMed  Google Scholar 

  73. Conrad C, Niess H, Huss R, Huber S, von Luettichau I, Nelson PJ et al (2009) Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 119:281–289

    Article  PubMed  Google Scholar 

  74. Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T et al (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96

    Article  CAS  PubMed  Google Scholar 

  75. Suzuki H, Watabe T, Kato M, Miyazawa K, Miyazono K (2005) Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells. Blood 105:2372–2379

    Article  CAS  PubMed  Google Scholar 

  76. Cimato T, Beers J, Ding S, Ma M, McCoy JP, Boehm M et al (2009) Neuropilin-1 identifies endothelial precursors in human and murine embryonic stem cells before CD34 expression. Circulation 119:2170–2178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yamamizu K, Kawasaki K, Katayama S, Watabe T, Yamashita JK (2009) Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1. Blood 114:3707–3716

    Article  CAS  PubMed  Google Scholar 

  78. Bai Y, Wang X, Shen L, Jiang K, Ding X, Cappetta D et al (2016) Mechanical stress regulates endothelial progenitor cell angiogenesis through VEGF receptor endocytosis. Int Heart J 57:356–362

    Article  PubMed  Google Scholar 

  79. Li T, Wang GD, Tan YZ, Wang HJ (2014) Inhibition of lymphangiogenesis of endothelial progenitor cells with VEGFR-3 siRNA delivered with PEI-alginate nanoparticles. Int J Biol Sci 10:160–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee C, Zhang F, Tang Z, Liu Y, Li X (2013) PDGF-C: a new performer in the neurovascular interplay. Trends Mol Med 19:474–486

    Article  CAS  PubMed  Google Scholar 

  81. Li X, Eriksson U (2003) Novel PDGF family members: PDGF-C and PDGF-D. Cytokine Growth Factor Rev 14:91–98

    Article  CAS  PubMed  Google Scholar 

  82. Homsi J, Daud AI (2007) Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control 14:285–294

    Article  PubMed  Google Scholar 

  83. Vazao H, das Neves RP, Graos M, Ferreira L (2011) Towards the maturation and characterization of smooth muscle cells derived from human embryonic stem cells. PLoS One 6:e17771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yu J, Li Y, Li M, Qu Z, Ruan Q (2010) Oxidized low density lipoprotein-induced transdifferentiation of bone marrow-derived smooth muscle-like cells into foam-like cells in vitro. Int J Exp Pathol 91:24–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055

    CAS  PubMed  Google Scholar 

  86. Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Investig 112:1142–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tang B, Gong JP, Sun JM, Luo WJ, Chen YK, Liu ZJ et al (2013) Construction of a plasmid for expression of rat platelet-derived growth factor C and its effects on proliferation, migration and adhesion of endothelial progenitor cells. Plasmid 69:195–201

    Article  CAS  PubMed  Google Scholar 

  88. Li X, Tjwa M, Moons L, Fons P, Noel A, Ny A et al (2005) Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors. J Clin Investig 115:118–127

    Article  CAS  PubMed  Google Scholar 

  89. Guo S, Yu L, Cheng Y, Li C, Zhang J, An J et al (2012) PDGFRbeta triggered by bFGF promotes the proliferation and migration of endothelial progenitor cells via p-ERK signalling. Cell Biol Int 36:945–950

    Article  CAS  PubMed  Google Scholar 

  90. Wang H, Yin Y, Li W, Zhao X, Yu Y, Zhu J et al (2012) Over-expression of PDGFR-beta promotes PDGF-induced proliferation, migration, and angiogenesis of EPCs through PI3K/Akt signaling pathway. PLoS One 7:e30503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ball SG, Shuttleworth CA, Kielty CM (2007) Platelet-derived growth factor receptor-alpha is a key determinant of smooth muscle alpha-actin filaments in bone marrow-derived mesenchymal stem cells. Int J Biochem Cell Biol 39:379–391

    Article  CAS  PubMed  Google Scholar 

  92. Andersson ER, Sandberg R, Lendahl U (2011) Notch signaling: simplicity in design, versatility in function. Development 138:3593–3612

    Article  CAS  PubMed  Google Scholar 

  93. Gu JW, Rizzo P, Pannuti A, Golde T, Osborne B, Miele L (2012) Notch signals in the endothelium and cancer “stem-like” cells: opportunities for cancer therapy. Vascular Cell 4:7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196–208

    Article  CAS  PubMed  Google Scholar 

  95. Kwon SM, Eguchi M, Wada M, Iwami Y, Hozumi K, Iwaguro H et al (2008) Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation 118:157–165

    Article  PubMed  Google Scholar 

  96. Jiang H, Cheng XW, Shi GP, Hu L, Inoue A, Yamamura Y et al (2014) Cathepsin K-mediated Notch1 activation contributes to neovascularization in response to hypoxia. Nat Commun 5:3838

    CAS  PubMed  Google Scholar 

  97. Ran QS, Yu YH, Fu XH, Wen YC (2015) Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury. Neural Regener Res 10:1258–1264

    Article  Google Scholar 

  98. Sukmawati D, Tanaka R, Ito-Hirano R, Fujimura S, Hayashi A, Itoh S et al (2016) The role of Notch signaling in diabetic endothelial progenitor cells dysfunction. J Diabetes Complic 30:12–20

    Article  Google Scholar 

  99. Doi H, Iso T, Sato H, Yamazaki M, Matsui H, Tanaka T et al (2006) Jagged1-selective notch signaling induces smooth muscle differentiation via a RBP-Jkappa-dependent pathway. J Biol Chem 281:28555–28564

    Article  CAS  PubMed  Google Scholar 

  100. Lin CH, Lilly B (2014) Endothelial cells direct mesenchymal stem cells toward a smooth muscle cell fate. Stem Cells Dev 23:2581–2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M et al (2012) Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc Natl Acad Sci USA 109:6993–6998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Arboleda-Velasquez JF, Primo V, Graham M, James A, Manent JD, Amore PA (2014) Notch signaling functions in retinal pericyte survival. Invest Ophthalmol Vis Sci 55:5191–5199

    Article  PubMed  PubMed Central  Google Scholar 

  103. Wang Y, Pan L, Moens CB, Appel B (2014) Notch3 establishes brain vascular integrity by regulating pericyte number. Development 141:307–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kofler NM, Cuervo H, Uh MK, Murtomaki A, Kitajewski J (2015) Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations. Sci Rep 5:16449

    Article  PubMed  PubMed Central  Google Scholar 

  105. Patenaude A, Woerher S, Umlandt P, Wong F, Ibrahim R, Kyle A et al (2015) A novel population of local pericyte precursor cells in tumor stroma that require Notch signaling for differentiation. Microvasc Res 101:38–47

    Article  CAS  PubMed  Google Scholar 

  106. Guichet PO, Guelfi S, Teigell M, Hoppe L, Bakalara N, Bauchet L et al (2015) Notch1 stimulation induces a vascularization switch with pericyte-like cell differentiation of glioblastoma stem cells. Stem Cells 33:21–34

    Article  CAS  PubMed  Google Scholar 

  107. Schadler KL, Zweidler-McKay PA, Guan H, Kleinerman ES (2010) Delta-like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing’s sarcoma. Clin Cancer Res 16:848–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Stewart KS, Zhou Z, Zweidler-McKay P, Kleinerman ES (2011) Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. Blood 117:719–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nguyen NQ, Castermans K, Berndt S, Herkenne S, Tabruyn SP, Blacher S et al (2011) The antiangiogenic 16 K prolactin impairs functional tumor neovascularization by inhibiting vessel maturation. PLoS One 6:e27318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Song JL, Nigam P, Tektas SS, Selva E (2015) microRNA regulation of Wnt signaling pathways in development and disease. Cell Signal 27:1380–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. von Maltzahn J, Chang NC, Bentzinger CF, Rudnicki MA (2012) Wnt signaling in myogenesis. Trends Cell Biol 22:602–609

    Article  CAS  Google Scholar 

  112. Qi W, Yang C, Dai Z, Che D, Feng J, Mao Y et al (2015) High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling. Diabetes 64:1407–1419

    Article  CAS  PubMed  Google Scholar 

  113. Yang DH, Yoon JY, Lee SH, Bryja V, Andersson ER, Arenas E et al (2009) Wnt5a is required for endothelial differentiation of embryonic stem cells and vascularization via pathways involving both Wnt/beta-catenin and protein kinase Calpha. Circ Res 104:372–379

    Article  CAS  PubMed  Google Scholar 

  114. Gherghe CM, Duan J, Gong J, Rojas M, Klauber-Demore N, Majesky M et al (2011) Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner. FASEB J 25:1836–1843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hu J, Dong A, Fernandez-Ruiz V, Shan J, Kawa M, Martinez-Anso E et al (2009) Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma. Can Res 69:6951–6959

    Article  CAS  Google Scholar 

  116. Keats EC, Dominguez JM 2nd, Grant MB, Khan ZA (2014) Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis. Stem Cells 32:1649–1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Leroux L, Descamps B, Tojais NF, Seguy B, Oses P, Moreau C et al (2010) Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a Wnt4-dependent pathway. Mol Ther 18:1545–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dufourcq P, Descamps B, Tojais NF, Leroux L, Oses P, Daret D et al (2008) Secreted frizzled-related protein-1 enhances mesenchymal stem cell function in angiogenesis and contributes to neovessel maturation. Stem Cells 26:2991–3001

    Article  PubMed  CAS  Google Scholar 

  119. Ren S, Johnson BG, Kida Y, Ip C, Davidson KC, Lin SL et al (2013) LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc Natl Acad Sci USA 110:1440–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Campagnolo P, Tsai TN, Hong X, Kirton JP, So PW, Margariti A et al (2015) c-Kit+ progenitors generate vascular cells for tissue-engineered grafts through modulation of the Wnt/Klf4 pathway. Biomaterials 60:53–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Srivastava R, Zhang J, Go GW, Narayanan A, Nottoli TP, Mani A (2015) Impaired LRP6-TCF7L2 activity enhances smooth muscle cell plasticity and causes coronary artery disease. Cell Rep 13:746–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Trowe MO, Airik R, Weiss AC, Farin HF, Foik AB, Bettenhausen E et al (2012) Canonical Wnt signaling regulates smooth muscle precursor development in the mouse ureter. Development 139:3099–3108

    Article  CAS  PubMed  Google Scholar 

  123. Kwiatkowski W, Gray PC, Choe S (2014) Engineering TGF-beta superfamily ligands for clinical applications. Trends Pharmacol Sci 35:648–657

    Article  CAS  PubMed  Google Scholar 

  124. Oshimori N, Fuchs E (2012) The harmonies played by TGF-beta in stem cell biology. Cell Stem Cell 11:751–764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim J, Kim M, Jeong Y, Lee WB, Park H, Kwon JY et al (2015) BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1. Arterioscler Thromb Vasc Biol 35:2020–2031

    Article  CAS  PubMed  Google Scholar 

  126. Smadja DM, Bieche I, Silvestre JS, Germain S, Cornet A, Laurendeau I et al (2008) Bone morphogenetic proteins 2 and 4 are selectively expressed by late outgrowth endothelial progenitor cells and promote neoangiogenesis. Arterioscler Thromb Vasc Biol 28:2137–2143

    Article  CAS  PubMed  Google Scholar 

  127. Imamura H, Ohta T, Tsunetoshi K, Doi K, Nozaki K, Takagi Y et al (2010) Transdifferentiation of bone marrow-derived endothelial progenitor cells into the smooth muscle cell lineage mediated by tansforming growth factor-beta1. Atherosclerosis 211:114–121

    Article  CAS  PubMed  Google Scholar 

  128. Zuo K, Li M, Zhang X, Lu C, Wang S, Zhi K et al (2015) MiR-21 suppresses endothelial progenitor cell proliferation by activating the TGFbeta signaling pathway via downregulation of WWP1. Int J Clin Exp Pathol 8:414–422

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Kinner B, Zaleskas JM, Spector M (2002) Regulation of smooth muscle actin expression and contraction in adult human mesenchymal stem cells. Exp Cell Res 278:72–83

    Article  CAS  PubMed  Google Scholar 

  130. Jian H, Shen X, Liu I, Semenov M, He X, Wang XF (2006) Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20:666–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ai WJ, Li J, Lin SM, Li W, Liu CZ, Lv WM (2015) R-Smad signaling-mediated VEGF expression coordinately regulates endothelial cell differentiation of rat mesenchymal stem cells. Stem Cells Dev 24:1320–1331

    Article  CAS  PubMed  Google Scholar 

  132. Takahashi Y, Maki T, Liang AC, Itoh K, Lok J, Osumi N et al (2014) p38 MAP kinase mediates transforming-growth factor-beta1-induced upregulation of matrix metalloproteinase-9 but not -2 in human brain pericytes. Brain Res 1593:1–8

    Article  CAS  PubMed  Google Scholar 

  133. Xie WB, Li Z, Shi N, Guo X, Tang J, Ju W et al (2013) Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells. Circ Res 113:e76–e86

    Article  CAS  PubMed  Google Scholar 

  134. Qu Z, Yu J, Ruan Q (2012) TGF-beta1-induced LPP expression dependant on Rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells. J Huazhong Univ Sci Technol Med Sci 32:459–465

    Article  CAS  PubMed  Google Scholar 

  135. Westerweel PE, van Velthoven CT, Nguyen TQ, den Ouden K, de Kleijn DP, Goumans MJ et al (2010) Modulation of TGF-beta/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model. Cardiovasc Diabetol 9:55

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Sahara M, Hansson EM, Wernet O, Lui KO, Spater D, Chien KR (2014) Manipulation of a VEGF-Notch signaling circuit drives formation of functional vascular endothelial progenitors from human pluripotent stem cells. Cell Res 24:820–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Koyanagi M, Bushoven P, Iwasaki M, Urbich C, Zeiher AM, Dimmeler S (2007) Notch signaling contributes to the expression of cardiac markers in human circulating progenitor cells. Circ Res 101:1139–1145

    Article  CAS  PubMed  Google Scholar 

  138. Manderfield LJ, Aghajanian H, Engleka KA, Lim LY, Liu F, Jain R et al (2015) Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest. Development 142:2962–2971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kurpinski K, Lam H, Chu J, Wang A, Kim A, Tsay E et al (2010) Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 28:734–742

    Article  CAS  PubMed  Google Scholar 

  140. Mooney CJ, Hakimjavadi R, Fitzpatrick E, Kennedy E, Walls D, Morrow D et al (2015) Hedgehog and resident vascular stem cell fate. Stem Cells Int 2015:468428

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F et al (2011) Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev Cell 20:291–302

    Article  CAS  PubMed  Google Scholar 

  142. Torihashi S, Hattori T, Hasegawa H, Kurahashi M, Ogaeri T, Fujimoto T (2009) The expression and crucial roles of BMP signaling in development of smooth muscle progenitor cells in the mouse embryonic gut. Differ Res Biol Diver 77:277–289

    Article  CAS  Google Scholar 

  143. Yao Q, Renault MA, Chapouly C, Vandierdonck S, Belloc I, Jaspard-Vinassa B et al (2014) Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation. Blood 123:2429–2437

    Article  CAS  PubMed  Google Scholar 

  144. Stratman AN, Schwindt AE, Malotte KM, Davis GE (2010) Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 116:4720–4730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kim SW, Jin HL, Kang SM, Kim S, Yoo KJ, Jang Y et al (2016) Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol 203:498–507

    Article  PubMed  Google Scholar 

  146. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY et al (2012) Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308:2369–2379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Melero-Martin JM, Dudley AC (2011) Concise review: vascular stem cells and tumor angiogenesis. Stem Cells. 29:163–168

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This review was supported by the State Key Laboratory of Ophthalmology (SKLO) at the Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; a key program of the National Natural Science Foundation of China (NSFC; 81330021) to X. Li; an NSFC Grant (81670855) to X. Li; an NSFC–Swedish Research Foundation International Collaboration Grant (81611130082) to X. Li; a Guangdong Province Leading Expert Program Grant to X. Li; an NSFC Grant (31601179) to W. Lu; a Natural Science Foundation of Guangdong Province, China, Grant (2016A030310209) to W. Lu, and a Fundamental Research Funds of SKLO Grant (2016QN04) to W. Lu.

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Lu, W., Li, X. Vascular stem/progenitor cells: functions and signaling pathways. Cell. Mol. Life Sci. 75, 859–869 (2018). https://doi.org/10.1007/s00018-017-2662-2

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