Skip to main content
Top
Published in: Brain Tumor Pathology 4/2018

01-10-2018 | Original Article

Stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties

Authors: Shigeki Takada, Masato Hojo, Noriyoshi Takebe, Kenji Tanigaki, Susumu Miyamoto

Published in: Brain Tumor Pathology | Issue 4/2018

Login to get access

Abstract

Hemangioblastoma is composed of neoplastic stromal cells and a prominent capillary network. To date, the identity of stromal cells remains unclear. Mesenchymal stem cells can give rise to committed vascular progenitor cells, and ephrin-B2/EphB4 and Notch signaling have crucial roles in these steps. The aim of our study was to elucidate that stromal cells of central nervous system hemangioblastomas have mesenchymal stem cell-derived vascular progenitor cell properties. Ten hemangioblastomas were investigated immunohistochemically. CD44, a mesenchymal stem cell marker, was detected in stromal cells of all cases, suggesting that stromal cells have mesenchymal stem cell-like properties. Neither CD31 nor α-SMA was expressed in stromal cells, suggesting that stromal cells have not acquired differentiated vascular cell properties. Both ephrin-B2 and EphB4, immature vascular cell markers, were detected in stromal cells of all cases. Jagged1, Notch1, and Hesr2/Hey2, which are known to be detected in both immature endothelial cells and mural cells, were expressed in stromal cells of all cases. Notch3, which is known to be detected in differentiating mural cells, was also expressed in all cases. These results suggest that stromal cells also have vascular progenitor cell properties. In conclusion, stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties.
Literature
1.
go back to reference Rachinger J, Buslei R, Prell J et al (2009) Solid haemangioblastomas of the CNS: a review of 17 consecutive cases. Neurosurg Rev 32:37–47 (discussion 47–48) CrossRefPubMed Rachinger J, Buslei R, Prell J et al (2009) Solid haemangioblastomas of the CNS: a review of 17 consecutive cases. Neurosurg Rev 32:37–47 (discussion 47–48) CrossRefPubMed
2.
go back to reference Merrill MJ, Edwards NA, Lonser RR (2011) Notch receptor and effector expression in von Hippel-Lindau disease-associated central nervous system hemangioblastomas. J Neurosurg 115:512–517CrossRefPubMedPubMedCentral Merrill MJ, Edwards NA, Lonser RR (2011) Notch receptor and effector expression in von Hippel-Lindau disease-associated central nervous system hemangioblastomas. J Neurosurg 115:512–517CrossRefPubMedPubMedCentral
4.
go back to reference Bamps S, Calenbergh FV, Vleeschouwer SD et al (2013) What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: a literature review. Surg Neurol Int 4:145CrossRefPubMedPubMedCentral Bamps S, Calenbergh FV, Vleeschouwer SD et al (2013) What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: a literature review. Surg Neurol Int 4:145CrossRefPubMedPubMedCentral
5.
go back to reference Hojo M, Arakawa Y, Funaki T et al (2014) Usefulness of tumor blood flow imaging by intraoperative indocyanine green videoangiography in hemangioblastoma surgery. World Neurosurg 82:e495–e501CrossRefPubMed Hojo M, Arakawa Y, Funaki T et al (2014) Usefulness of tumor blood flow imaging by intraoperative indocyanine green videoangiography in hemangioblastoma surgery. World Neurosurg 82:e495–e501CrossRefPubMed
6.
go back to reference Spence AM, Rubinstein LJ (1975) Cerebellar capillary hemangioblastoma: its histogenesis studied by organ culture and electron microscopy. Cancer 35:326–341CrossRefPubMed Spence AM, Rubinstein LJ (1975) Cerebellar capillary hemangioblastoma: its histogenesis studied by organ culture and electron microscopy. Cancer 35:326–341CrossRefPubMed
7.
go back to reference Ding XH, Zhou LF, Tan YZ et al (2007) Histologic and histogenetic investigations of intracranial hemangioblastomas. Surg Neurol 67:239–245 (discussion 245) CrossRefPubMed Ding XH, Zhou LF, Tan YZ et al (2007) Histologic and histogenetic investigations of intracranial hemangioblastomas. Surg Neurol 67:239–245 (discussion 245) CrossRefPubMed
8.
go back to reference Lach B, Gregor A, Rippstein P et al (1999) Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol 23:299–310CrossRefPubMed Lach B, Gregor A, Rippstein P et al (1999) Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol 23:299–310CrossRefPubMed
9.
go back to reference Ishizawa K, Komori T, Hirose T (2005) Stromal cells in hemangioblastoma: neuroectodermal differentiation and morphological similarities to ependymoma. Pathol Int 55:377–385CrossRefPubMed Ishizawa K, Komori T, Hirose T (2005) Stromal cells in hemangioblastoma: neuroectodermal differentiation and morphological similarities to ependymoma. Pathol Int 55:377–385CrossRefPubMed
10.
go back to reference Ma D, Zhang M, Chen L et al (2011) Hemangioblastomas might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche. Carcinogenesis 32:102–109CrossRefPubMed Ma D, Zhang M, Chen L et al (2011) Hemangioblastomas might derive from neoplastic transformation of neural stem cells/progenitors in the specific niche. Carcinogenesis 32:102–109CrossRefPubMed
11.
go back to reference Ma D, Zhu W, Zhang M et al (2011) Identification of tumorigenic cells and implication of their aberrant differentiation in human hemangioblastomas. Cancer Biol Ther 12:727–736CrossRefPubMed Ma D, Zhu W, Zhang M et al (2011) Identification of tumorigenic cells and implication of their aberrant differentiation in human hemangioblastomas. Cancer Biol Ther 12:727–736CrossRefPubMed
12.
go back to reference Park DM, Zhuang Z, Chen L et al (2007) von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med 4:e60CrossRefPubMedPubMedCentral Park DM, Zhuang Z, Chen L et al (2007) von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med 4:e60CrossRefPubMedPubMedCentral
13.
go back to reference Epari S, Bhatkar R, Moyaidi A et al (2014) Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: an entity of unclear histogenesis. Indian J Pathol Microbiol 57:542–548CrossRefPubMed Epari S, Bhatkar R, Moyaidi A et al (2014) Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: an entity of unclear histogenesis. Indian J Pathol Microbiol 57:542–548CrossRefPubMed
14.
go back to reference Shively SB, Beltaifa S, Gehrs B et al (2008) Protracted haemangioblastic proliferation and differentiation in von Hippel-Lindau disease. J Pathol 216:514–520CrossRefPubMedPubMedCentral Shively SB, Beltaifa S, Gehrs B et al (2008) Protracted haemangioblastic proliferation and differentiation in von Hippel-Lindau disease. J Pathol 216:514–520CrossRefPubMedPubMedCentral
15.
go back to reference Stein AA, Schilp AO, Whitfield RD (1960) The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–761CrossRefPubMed Stein AA, Schilp AO, Whitfield RD (1960) The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–761CrossRefPubMed
16.
go back to reference Welten CM, Keats EC, Ang LC et al (2012) Hemangioblastoma stromal cells show committed stem cell phenotype. Can J Neurol Sci 39:821–827CrossRefPubMed Welten CM, Keats EC, Ang LC et al (2012) Hemangioblastoma stromal cells show committed stem cell phenotype. Can J Neurol Sci 39:821–827CrossRefPubMed
17.
go back to reference Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147CrossRefPubMed Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147CrossRefPubMed
18.
go back to reference Reyes M, Dudek A, Jahagirdar B et al (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Investig 109:337–346CrossRefPubMed Reyes M, Dudek A, Jahagirdar B et al (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Investig 109:337–346CrossRefPubMed
19.
go back to reference Zhang G, Zhou J, Fan Q et al (2008) Arterial-venous endothelial cell fate is related to vascular endothelial growth factor and Notch status during human bone mesenchymal stem cell differentiation. FEBS Lett 582:2957–2964CrossRefPubMed Zhang G, Zhou J, Fan Q et al (2008) Arterial-venous endothelial cell fate is related to vascular endothelial growth factor and Notch status during human bone mesenchymal stem cell differentiation. FEBS Lett 582:2957–2964CrossRefPubMed
20.
go back to reference Liu Y, Deng B, Zhao Y et al (2013) Differentiated markers in undifferentiated cells: expression of smooth muscle contractile proteins in multipotent bone marrow mesenchymal stem cells. Dev Growth Differ 55:591–605CrossRefPubMed Liu Y, Deng B, Zhao Y et al (2013) Differentiated markers in undifferentiated cells: expression of smooth muscle contractile proteins in multipotent bone marrow mesenchymal stem cells. Dev Growth Differ 55:591–605CrossRefPubMed
22.
go back to reference Duffy GP, D’Arcy S, Ahsan T et al (2010) Mesenchymal stem cells overexpressing ephrin-b2 rapidly adopt an early endothelial phenotype with simultaneous reduction of osteogenic potential. Tissue Eng Part A 16:2755–2768CrossRefPubMed Duffy GP, D’Arcy S, Ahsan T et al (2010) Mesenchymal stem cells overexpressing ephrin-b2 rapidly adopt an early endothelial phenotype with simultaneous reduction of osteogenic potential. Tissue Eng Part A 16:2755–2768CrossRefPubMed
23.
go back to reference Kurpinski K, Lam H, Chu J et al (2010) Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 28:734–742CrossRefPubMed Kurpinski K, Lam H, Chu J et al (2010) Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 28:734–742CrossRefPubMed
24.
go back to reference Foo SS, Turner CJ, Adams S et al (2006) Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124:161–173CrossRefPubMed Foo SS, Turner CJ, Adams S et al (2006) Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124:161–173CrossRefPubMed
25.
go back to reference Wang HU, Chen ZF, Anderson DJ (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:741–753CrossRefPubMed Wang HU, Chen ZF, Anderson DJ (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:741–753CrossRefPubMed
26.
go back to reference Adams RH, Wilkinson GA, Weiss C et al (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13:295–306CrossRefPubMedPubMedCentral Adams RH, Wilkinson GA, Weiss C et al (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13:295–306CrossRefPubMedPubMedCentral
27.
28.
go back to reference Fischer A, Schumacher N, Maier M et al (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18:901–911CrossRefPubMedPubMedCentral Fischer A, Schumacher N, Maier M et al (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18:901–911CrossRefPubMedPubMedCentral
29.
go back to reference Fischer A, Gessler M (2003) Hey genes in cardiovascular development. Trends Cardiovasc Med 13:221–226CrossRefPubMed Fischer A, Gessler M (2003) Hey genes in cardiovascular development. Trends Cardiovasc Med 13:221–226CrossRefPubMed
30.
go back to reference Kageyama R, Ohtsuka T, Shimojo H et al (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11:1247–1251CrossRefPubMed Kageyama R, Ohtsuka T, Shimojo H et al (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11:1247–1251CrossRefPubMed
31.
go back to reference Lawson ND, Scheer N, Pham VN et al (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683PubMed Lawson ND, Scheer N, Pham VN et al (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683PubMed
32.
go back to reference Hofmann JJ, Iruela-Arispe ML (2007) Notch signaling in blood vessels: who is talking to whom about what? Circ Res 100:1556–1568CrossRefPubMed Hofmann JJ, Iruela-Arispe ML (2007) Notch signaling in blood vessels: who is talking to whom about what? Circ Res 100:1556–1568CrossRefPubMed
33.
go back to reference Villa N, Walker L, Lindsell CE et al (2001) Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108:161–164CrossRefPubMed Villa N, Walker L, Lindsell CE et al (2001) Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108:161–164CrossRefPubMed
34.
go back to reference Roca C, Adams RH (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21:2511–2524CrossRefPubMed Roca C, Adams RH (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21:2511–2524CrossRefPubMed
35.
go back to reference Swift MR, Weinstein BM (2009) Arterial-venous specification during development. Circ Res 104:576–588CrossRefPubMed Swift MR, Weinstein BM (2009) Arterial-venous specification during development. Circ Res 104:576–588CrossRefPubMed
36.
go back to reference Lonser RR, Glenn GM, Walther M et al (2003) von Hippel-Lindau disease. The Lancet 361:2059–2067CrossRef Lonser RR, Glenn GM, Walther M et al (2003) von Hippel-Lindau disease. The Lancet 361:2059–2067CrossRef
37.
go back to reference Takada S, Hojo M, Tanigaki K et al (2017) Contribution of endothelial-to-mesenchymal transition to the pathogenesis of human cerebral and orbital cavernous malformations. Neurosurgery 81:176–183CrossRefPubMed Takada S, Hojo M, Tanigaki K et al (2017) Contribution of endothelial-to-mesenchymal transition to the pathogenesis of human cerebral and orbital cavernous malformations. Neurosurgery 81:176–183CrossRefPubMed
39.
go back to reference Aruffo A, Stamenkovic I, Melnick M et al (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–1313CrossRefPubMed Aruffo A, Stamenkovic I, Melnick M et al (1990) CD44 is the principal cell surface receptor for hyaluronate. Cell 61:1303–1313CrossRefPubMed
40.
go back to reference Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45CrossRefPubMed Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45CrossRefPubMed
41.
go back to reference Oswald J, Boxberger S, Jrgensen B et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384CrossRefPubMed Oswald J, Boxberger S, Jrgensen B et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384CrossRefPubMed
43.
go back to reference Böhling T, Mäenpää A, Timonen T et al (1996) Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma. Acta Neuropathol 92:461–466CrossRefPubMed Böhling T, Mäenpää A, Timonen T et al (1996) Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma. Acta Neuropathol 92:461–466CrossRefPubMed
44.
go back to reference Bai J, Wang YJ, Liu L et al (2014) Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res 42:405–415CrossRefPubMed Bai J, Wang YJ, Liu L et al (2014) Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res 42:405–415CrossRefPubMed
45.
46.
48.
go back to reference Li S, Wang R, Wang Y et al (2014) Receptors of the Notch signaling pathway are associated with hemorrhage of brain arteriovenous malformations. Mol Med Rep 9:2233–2238CrossRefPubMed Li S, Wang R, Wang Y et al (2014) Receptors of the Notch signaling pathway are associated with hemorrhage of brain arteriovenous malformations. Mol Med Rep 9:2233–2238CrossRefPubMed
49.
go back to reference Yamashita J, Itoh H, Hirashima M et al (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96CrossRefPubMed Yamashita J, Itoh H, Hirashima M et al (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96CrossRefPubMed
50.
go back to reference Boscolo E, Stewart CL, Greenberger S et al (2011) JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler Thromb Vasc Biol 31:2181–2192CrossRefPubMedPubMedCentral Boscolo E, Stewart CL, Greenberger S et al (2011) JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler Thromb Vasc Biol 31:2181–2192CrossRefPubMedPubMedCentral
51.
go back to reference Alles JU, Bosslet K, Schachenmayr W (1986) Hemangioblastoma of the cerebellum—an immunocytochemical study. Clin Neuropathol 5:238–241PubMed Alles JU, Bosslet K, Schachenmayr W (1986) Hemangioblastoma of the cerebellum—an immunocytochemical study. Clin Neuropathol 5:238–241PubMed
52.
go back to reference Jurco SR, Nadji M, Harvey DG et al (1982) Hemangioblastomas: histogenesis of the stromal cell studied by immunocytochemistry. Hum Pathol 13:13–18CrossRefPubMed Jurco SR, Nadji M, Harvey DG et al (1982) Hemangioblastomas: histogenesis of the stromal cell studied by immunocytochemistry. Hum Pathol 13:13–18CrossRefPubMed
53.
go back to reference Mizuno J, Iwata K, Takei Y (1993) Immunohistochemical study of hemangioblastoma with special reference to its cytogenesis. Neurol Med Chir (Tokyo) 33:420–424CrossRef Mizuno J, Iwata K, Takei Y (1993) Immunohistochemical study of hemangioblastoma with special reference to its cytogenesis. Neurol Med Chir (Tokyo) 33:420–424CrossRef
54.
go back to reference Bleistein M, Geiger K, Franz K et al (2000) Transthyretin and transferrin in hemangioblastoma stromal cells. Pathol Res Pract 196:675–681CrossRefPubMed Bleistein M, Geiger K, Franz K et al (2000) Transthyretin and transferrin in hemangioblastoma stromal cells. Pathol Res Pract 196:675–681CrossRefPubMed
55.
go back to reference Becker I, Paulus W, Roggendorf W (1989) Histogenesis of stromal cells in cerebellar hemangioblastomas. An immunohistochemical study. Am J Pathol 134:271–275PubMedPubMedCentral Becker I, Paulus W, Roggendorf W (1989) Histogenesis of stromal cells in cerebellar hemangioblastomas. An immunohistochemical study. Am J Pathol 134:271–275PubMedPubMedCentral
56.
go back to reference Nemes Z (1992) Fibrohistiocytic differentiation in capillary hemangioblastoma. Hum Pathol 23:805–810CrossRefPubMed Nemes Z (1992) Fibrohistiocytic differentiation in capillary hemangioblastoma. Hum Pathol 23:805–810CrossRefPubMed
57.
go back to reference Adams SA, Hilton DA (2002) Recurrent haemangioblastoma with glial differentiation. Neuropathol Appl Neurobiol 28:142–146CrossRefPubMed Adams SA, Hilton DA (2002) Recurrent haemangioblastoma with glial differentiation. Neuropathol Appl Neurobiol 28:142–146CrossRefPubMed
58.
go back to reference Tanimura A, Nakamura Y, Hachisuka H et al (1984) Hemangioblastoma of the central nervous system: nature of the stromal cells as studied by the immunoperoxidase technique. Hum Pathol 15:866–869CrossRefPubMed Tanimura A, Nakamura Y, Hachisuka H et al (1984) Hemangioblastoma of the central nervous system: nature of the stromal cells as studied by the immunoperoxidase technique. Hum Pathol 15:866–869CrossRefPubMed
59.
go back to reference Gläsker S, Li J, Xia JB et al (2006) Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res 66:4167–4172CrossRefPubMed Gläsker S, Li J, Xia JB et al (2006) Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res 66:4167–4172CrossRefPubMed
60.
go back to reference Shively SB, Falke EA, Li J et al (2011) Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease. Mod Pathol 24:1023–1030CrossRefPubMedPubMedCentral Shively SB, Falke EA, Li J et al (2011) Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease. Mod Pathol 24:1023–1030CrossRefPubMedPubMedCentral
61.
go back to reference Vortmeyer AO, Frank S, Jeong SY et al (2003) Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 63:7051–7055PubMed Vortmeyer AO, Frank S, Jeong SY et al (2003) Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 63:7051–7055PubMed
Metadata
Title
Stromal cells of hemangioblastomas exhibit mesenchymal stem cell-derived vascular progenitor cell properties
Authors
Shigeki Takada
Masato Hojo
Noriyoshi Takebe
Kenji Tanigaki
Susumu Miyamoto
Publication date
01-10-2018
Publisher
Springer Singapore
Published in
Brain Tumor Pathology / Issue 4/2018
Print ISSN: 1433-7398
Electronic ISSN: 1861-387X
DOI
https://doi.org/10.1007/s10014-018-0323-2