Stem cells and the vasculature

Article metrics


Unraveling the contribution of stem and progenitor cells to blood vessel formation and, reciprocally, the importance of blood vessels to the production and function of stem and progenitor cells, has been a major focus of vascular research over the last decade, but has spawned many controversies. Here I review how vascular stem and progenitor cells contribute both vascular and nonvascular cells during development and in disease, and how nonvascular stem and progenitor cells might contribute to vascular lineages. I also discuss the role of the vasculature in forming stem and progenitor cell niches. Finally, I highlight the potential relevance of these relationships to disease etiology and treatment.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Proposed interactions of stem and progenitor cells with the vasculature.
Figure 2: Potential developmental relationships of hematopoietic and endothelial cells.


  1. 1

    Carmeliet, P. & Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

  2. 2

    Psaltis, P.J., Harbuzariu, A., Delacroix, S., Holroyd, E. & Simari, R. Resident vascular progenitor cells—diverse origins, phenotype and function. J. Cardiovasc. Transl. Res. 4, 161–176 (2011).

  3. 3

    Hogan, K.A. & Bautch, V.L. Blood vessel patterning at the embryonic midline. Curr. Top. Dev. Biol. 62, 55–85 (2004).

  4. 4

    Majesky, M.W. Developmental basis of vascular smooth muscle diversity. Arterioscler. Thromb. Vasc. Biol. 27, 1248–1258 (2007).

  5. 5

    Gittenberger-de Groot, A.C., DeRuiter, M.C., Bergwerff, M. & Poelmann, R.E. Smooth muscle cell origin and its relation to heterogeneity in development and disease. Arterioscler. Thromb. Vasc. Biol. 19, 1589–1594 (1999).

  6. 6

    Kirby, M.L. & Waldo, K.L. Neural crest and cardiovascular patterning. Circ. Res. 77, 211–215 (1995).

  7. 7

    Cleaver, O., Tonissen, K.F., Saha, M.S. & Krieg, P.A. Neovascularization of the Xenopus embryo. Dev. Dyn. 210, 66–77 (1997).

  8. 8

    Coultas, L., Chawengsaksophak, K. & Rossant, J. Endothelial cells and VEGF in vascular development. Nature 438, 937–945 (2005).

  9. 9

    Ambler, C.A., Nowicki, J.L., Burke, A.C. & Bautch, V.L. Assembly of trunk and limb blood vessels involves extensive migration and vasculogenesis of somite-derived angioblasts. Dev. Biol. 234, 352–364 (2001).

  10. 10

    Pardanaud, L. et al. Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 122, 1363–1371 (1996).

  11. 11

    James, J.M., Gewolb, C. & Bautch, V.L. Neurovascular development uses VEGF-A signaling to regulate blood vessel ingression into the neural tube. Development 136, 833–841 (2009).

  12. 12

    Kurz, H., Torsten, G., Eggli, P.S. & Christ, B. First blood vessels in the avian neural tube are formed by a combination of dorsal angioblast immigration and ventral sprouting of endothelial cells. Dev. Biol. 173, 133–147 (1996).

  13. 13

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

  14. 14

    Esner, M. et al. Smooth muscle of the dorsal aorta shares a common clonal origin with skeletal muscle of the myotome. Development 133, 737–749 (2006).

  15. 15

    Lagha, M. et al. Pax3:Foxc2 reciprocal repression in the somite modulates muscular versus vascular cell fate choice in multipotent progenitors. Dev. Cell 17, 892–899 (2009).

  16. 16

    Majesky, M.W., Dong, X.R., Regan, J. & Hoglund, V. Vascular smooth muscle progenitor cells: building and repairing blood vessels. Circ. Res. 108, 365–377 (2011).

  17. 17

    Wasteson, P. et al. Developmental origin of smooth muscle cells in the descending aorta in mice. Development 135, 1823–1832 (2008).

  18. 18

    Bianco, P., Robey, P.G. & Simmons, P.J. Mesenchymal stem cells: revisiting history, concepts and assays. Cell Stem Cell 2, 313–319 (2008).

  19. 19

    Park, C., Ma, Y.D. & Choi, K. Evidence for the hemangioblast. Exp. Hematol. 33, 965–970 (2005).

  20. 20

    Wu, S.M., Chien, K.R. & Mummery, C. Origins and fates of cardiovascular progenitor cells. Cell 132, 537–543 (2008).

  21. 21

    Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998).

  22. 22

    Vogeli, K.M., Jin, S.-W., Martin, G.R. & Stainier, D.Y.R. A common progenitor for haematopoietic and endothelial lineages in the zebrafish gastrula. Nature 443, 337–339 (2006).

  23. 23

    Sabin, F.R. Studies on the origin of the blood vessels and of red blood corpuscles as seen in the living blastoderm of chick during the second day of incubation. Contrib. Embryol. Carnegie Inst. 9, 215–262 (1920).

  24. 24

    Huber, T.L., Kouskoff, V., Joerg Fehling, H., Palis, J. & Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432, 625–630 (2004).

  25. 25

    de Bruijn, M.F.T.R. et al. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity 16, 673–683 (2002).

  26. 26

    Bertrand, J.Y. & Traver, D. Hematopoietic cell development in the zebrafish embryo. Curr. Opin. Hematol. 16, 243–248 (2009).

  27. 27

    Bertrand, J.Y. et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature 464, 108–111 (2010).

  28. 28

    Boisset, J.-C. et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010).

  29. 29

    Eilken, H.M., Nishikawa, S.-I. & Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009).

  30. 30

    Kissa, K. & Herbomel, P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature 464, 112–115 (2010).

  31. 31

    Zovein, A.C. et al. Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell 3, 625–636 (2008).

  32. 32

    Chen, M.J., Yokomizo, T., Zeigler, B.M., Dzierzak, E. & Speck, N.A. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887–891 (2009).

  33. 33

    Iacovino, M. et al. HoxA3 is an apical regulator of haemogenic endothelium. Nat. Cell Biol. 13, 72–78 (2011).

  34. 34

    Lancrin, C. et al. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457, 892–895 (2009).

  35. 35

    Yamashita, J. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408, 92–96 (2000).

  36. 36

    Bearzi, C. et al. Identification of a coronary vascular progenitor cell in the human heart. Proc. Natl. Acad. Sci. USA 106, 15885–15890 (2009).

  37. 37

    Bu, L. et al. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460, 113–117 (2009).

  38. 38

    Kattman, S.J., Huber, T.L. & Keller, G.M. Multipotent Flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial and vascular smooth muscle lineages. Dev. Cell 11, 723–732 (2006).

  39. 39

    Moretti, A. et al. Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127, 1151–1165 (2006).

  40. 40

    Corselli, M., Chen, C.-W., Crisan, M., Lazzari, L. & Peault, B. Perivascular ancestors of adult multipotent stem cells. Arterioscler. Thromb. Vasc. Biol. 30, 1104–1109 (2010).

  41. 41

    Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol. 9, 255–267 (2007).

  42. 42

    Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

  43. 43

    Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

  44. 44

    Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

  45. 45

    Traktuev, D.O. et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location and stabilize endothelial networks. Circ. Res. 102, 77–85 (2008).

  46. 46

    Feng, J., Mantesso, A., De Bari, C., Nishiyama, A. & Sharpe, P.T. Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proc. Natl. Acad. Sci. USA 108, 6503–6508 (2011).

  47. 47

    Olson, L.E. & Soriano, P. PDGFRβ signaling regulates mural cell plasticity and inhibits fat development. Dev. Cell 20, 815–826 (2011).

  48. 48

    Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

  49. 49

    Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008).

  50. 50

    Jujo, K., Ii, M. & Losordo, D.W. Endothelial progenitor cells in neovascularization of infarcted myocardium. J. Mol. Cell. Cardiol. 45, 530–544 (2008).

  51. 51

    Kerbel, R.S. et al. Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas. Proc. Natl. Acad. Sci. USA 105, E54 (2008).

  52. 52

    Nolan, D.J. et al. Bone marrow–derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev. 21, 1546–1558 (2007).

  53. 53

    Göthert, J.R. et al. Genetically tagging endothelial cells in vivo: bone marrow–derived cells do not contribute to tumor endothelium. Blood 104, 1769–1777 (2004).

  54. 54

    Purhonen, S. et al. Bone marrow–derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl. Acad. Sci. USA 105, 6620–6625 (2008).

  55. 55

    De Palma, M., Venneri, M.A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).

  56. 56

    Dudley, A.C. et al. Bone marrow is a reservoir for proangiogenic myelomonocytic cells but not endothelial cells in spontaneous tumors. Blood 116, 3367–3371 (2010).

  57. 57

    Butler, J.M., Kobayashi, H. & Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat. Rev. Cancer 10, 138–146 (2010).

  58. 58

    Yoder, M.C. Is endothelium the origin of endothelial progenitor cells? Arterioscler. Thromb. Vasc. Biol. 30, 1094–1103 (2010).

  59. 59

    Ingram, D.A. et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104, 2752–2760 (2004).

  60. 60

    Yoder, M.C. et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109, 1801–1809 (2007).

  61. 61

    Au, P., Tam, J., Fukumura, D. & Jain, R.K. Bone marrow derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111, 4551–4558 (2008).

  62. 62

    Melero-Martin, J.M. et al. In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 109, 4761–4768 (2007).

  63. 63

    Arciniegas, E., Frid, M.G., Douglas, I.S. & Stenmark, K.R. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L1–L8 (2007).

  64. 64

    Potenta, S., Zeisberg, E. & Kalluri, R. The role of endothelial-to-mesenchymal transition in cancer progression. Br. J. Cancer 99, 1375–1379 (2008).

  65. 65

    Zeisberg, E.M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).

  66. 66

    Zeisberg, E.M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

  67. 67

    Medici, D. et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat. Med. 16, 1400–1406 (2010).

  68. 68

    Moore, K.A. & Lemischka, I.R. Stem cells and their niches. Science 311, 1880–1885 (2006).

  69. 69

    Bianco, P. Bone and the hematopoietic niche: a tale of two stem cells. Blood 117, 5281–5288 (2011).

  70. 70

    Dimmeler, S. Regulation of bone marrow–derived vascular progenitor cell mobilization and maintenance. Arterioscler. Thromb. Vasc. Biol. 30, 1088–1093 (2010).

  71. 71

    Goldberg, J.S. & Hirschi, K.K. Diverse roles of the vasculature within the neural stem cell niche. Regen. Med. 4, 879–897 (2009).

  72. 72

    Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

  73. 73

    Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289–300 (2008).

  74. 74

    Kokovay, E. et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell 7, 163–173 (2010).

  75. 75

    Gopinath, S.D. & Rando, T.A. Stem Cell Review Series: aging of the skeletal muscle stem cell niche. Aging Cell 7, 590–598 (2008).

  76. 76

    Tilki, D., Hohn, H.-P., Erg¸n, B., Rafii, S. & Ergun, S.l. Emerging biology of vascular wall progenitor cells in health and disease. Trends Mol. Med. 15, 501–509 (2009).

  77. 77

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

  78. 78

    Hu, Y. et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J. Clin. Invest. 113, 1258–1265 (2004).

  79. 79

    Passman, J.N. et al. A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc. Natl. Acad. Sci. USA 105, 9349–9354 (2008).

  80. 80

    Campagnolo, P. et al. Human adult vena saphena contains perivascular progenitor cells endowed with clonogenic and proangiogenic potential. Circulation 121, 1735–1745 (2010).

  81. 81

    Zengin, E. et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133, 1543–1551 (2006).

  82. 82

    Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).

  83. 83

    Hirschi, K.K., Rohovsky, S.A. & D'Amore, P.A. PDGF, TGF-β and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J. Cell Biol. 141, 805–814 (1998).

  84. 84

    Challen, G.A. & Little, M.H. A side order of stem cells: the SP phenotype. Stem Cells 24, 3–12 (2006).

  85. 85

    Xu, Q., Zhang, Z., Davison, F. & Hu, Y. Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice. Circ. Res. 93, e76–e86 (2003).

  86. 86

    Hagensen, M.K., Shim, J., Thim, T., Falk, E. & Bentzon, J.F. Circulating endothelial progenitor cells do not contribute to plaque endothelium in murine atherosclerosis. Circulation 121, 898–905 (2010).

  87. 87

    Daniel, J.-M. et al. Time-course analysis on the differentiation of bone marrow-derived progenitor cells into smooth muscle cells during neointima formation. Arterioscler. Thromb. Vasc. Biol. 30, 1890–1896 (2010).

  88. 88

    Boscolo, E. & Bischoff, J. Vasculogenesis in infantile hemangioma. Angiogenesis 12, 197–207 (2009).

  89. 89

    Chiller, K.G., Passaro, D. & Frieden, I.J. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity and sex. Arch. Dermatol. 138, 1567–1576 (2002).

  90. 90

    Jinnin, M., Ishihara, T., Boye, E. & Olsen, B.R. Recent progress in studies of infantile hemangioma. J. Dermatol. 37, 283–298 (2010).

  91. 91

    Boye, E. et al. Clonality and altered behavior of endothelial cells from hemangiomas. J. Clin. Invest. 107, 745–752 (2001).

  92. 92

    Walter, J.W. et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosom. Cancer 33, 295–303 (2002).

  93. 93

    Khan, Z.A. et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J. Clin. Invest. 118, 2592–2599 (2008).

  94. 94

    Jinnin, M. et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat. Med. 14, 1236–1246 (2008).

  95. 95

    Boscolo, E. et al. JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler. Thromb. Vasc. Biol. 31, 2181–2192 (2011).

  96. 96

    Limaye, N., Boon, L.M. & Vikkula, M. From germline towards somatic mutations in the pathophysiology of vascular anomalies. Hum. Mol. Genet. 18, R65–R74 (2009).

  97. 97

    Limaye, N. et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat. Genet. 41, 118–124 (2009).

  98. 98

    Raaijmakers, M.H.G.P. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010).

  99. 99

    Olive, M. et al. Cardiovascular pathology in hutchinson-gilford progeria: correlation with the vascular pathology of aging. Arterioscler. Thromb. Vasc. Biol. 30, 2301–2309 (2010).

Download references


I apologize to the many colleagues whose work could not be cited due to space constraints. I thank lab members and colleagues for fruitful discussions. I especially thank J. Bischoff, S.-W. Jin, M. Majesky and C. Patterson for thoughtful suggestions and critical comments on an early draft of the manuscript. This work was supported by grants from the US National Institutes of Health (HL43174 and HL86465) and an Innovation Award from the University of North Carolina Lineberger Comprehensive Cancer Center.

Author information

Correspondence to Victoria L Bautch.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading