Endothelial progenitor cells in infantile hemangioma

Yu, Ying; Flint, Alan; Mulliken, John B.; Wu, June K.; Bischoff, Joyce

doi:10.1182/blood-2003-08-2859

Cited by 191 publications

(131 citation statements)

References 16 publications

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“…The presence of EPCs in proliferating hemangiomas 8 and increased circulating EPC levels in hemangioma patients, 7 in combination with the appearance of endothelial-lined vascular channels in the involuting phase, support our hypothesis that HemECs arise from HemEPCs. We used the ES response to compare the HemEPCs to HemECs and normal cbEPCs.…”

Section: Discussionsupporting

confidence: 70%

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Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Khan

Melero‐Martin

et al. 2006

Blood

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111

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Infantile hemangiomas are composed of endothelial cells (ECs), endothelial progenitor cells (EPCs), as well as perivascular and hematopoietic cells. Our hypothesis is that hemangioma-derived EPCs (HemEPCs) differentiate into the mature ECs that comprise the major compartment of the tumor. To test this, we isolated EPCs (CD133 ؉ /Ulex europeus-I ؉ ) and mature ECs (CD133 ؊ /Ulex europeus-I ؉ ) from proliferating hemangiomas and used a previously described property of hemangioma-derived ECs (HemECs), enhanced migratory activity in response to the angiogenesis inhibitor endostatin, to determine if HemEPCs share this abnormal behavior. Umbilical cord bloodderived EPCs (cbEPCs) were analyzed in parallel as a normal control. Our results show that HemEPCs, HemECs, and cbEPCs exhibit increased adhesion, migration, and proliferation in response to endostatin. This angiogenic response to endostatin was consistently expressed by HemEPCs over several weeks in culture, whereas HemECs and cbEPCs shifted toward the mature endothelial response to endostatin. Similar mRNAexpression patterns among HemEPCs, HemECs, and cbEPCs, revealed by microarray analyses, provided further indication of an EPC phenotype. This is the first demonstration that human EPCs, isolated from blood or from a proliferating hemangioma, are stimulated by an angiogenesis inhibitor. These findings suggest that EPCs respond differently from mature ECs when exposed to angiogenic or antiangiogenic signals. IntroductionInfantile hemangioma, the most common tumor of infancy, is characterized by rapid proliferation of the endothelial cells followed by slow spontaneous involution. 1 This transition from the proliferating phase to the involuting phase represents a gradient of cellular activity from unregulated proliferation to apoptosis. The molecular events that control the evolution of hemangioma remain obscure. Both intrinsic and extrinsic anomalies have been suggested to underlie the primary defect. [2][3][4][5][6] Recent studies showing that hemangioma-derived endothelial cells (HemECs) are clonal provide support for an intrinsic defect. 4,6 We and others have identified endothelial progenitor cells (EPCs) in hemangioma tissue and circulating blood of patients with hemangiomas, respectively. 7,8 These findings suggest that a hemangioma may arise from the clonal expansion of an EPC.An angioblastic origin for hemangiomas has been envisioned for over a century. In 1863, Virchow 9 questioned whether hemangiomas represented sequestered embryonic mesoderm. Pack and Miller 10 suggested that hemangiomas arise from the localized growth of angioblastic cells. Similarly, Malan 11 imagined hemangiomas as an activation of dormant angioblasts. Histologic examination of hemangioma ECs reveals an immature phenotype with large nuclei and scant cytoplasm. 12 During the rapid growth phase of hemangiomas, syncytial EC hyperplasia, with and without lumens, is seen. In the involuting phase, hyperplasia diminishes and mature vascular channels with defined lumens become prominent. 1 C...

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Section: Discussionsupporting

confidence: 70%

“…4,6 We and others have identified endothelial progenitor cells (EPCs) in hemangioma tissue and circulating blood of patients with hemangiomas, respectively. 7,8 These findings suggest that a hemangioma may arise from the clonal expansion of an EPC.…”

Section: Introductionmentioning

confidence: 93%

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Khan

Melero‐Martin

et al. 2006

Blood

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111

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“…2 Mast cells have been proposed to have a role in hemangioma progression 3 as have endothelial progenitor cells. 4 Hemangioma endothelial cells were shown to express the lymphatic endothelial marker LYVE-1, suggesting that these cells are arrested in an early vascular differentiation state. 5 The nonrandom distribution of facial hemangiomas has raised ideas relating to developmental patterning and the deposition of precursor cells.…”

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confidence: 99%

Myeloid Cells in Infantile Hemangioma

Ritter

Reinisch

Friedlander

et al. 2006

The American Journal of Pathology

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Little is known about the pathogenesis of infantile hemangiomas despite the fact that they are relatively common tumors. These benign neoplasms occur in as many as 1 in 10 births, and although rarely life threatening, hemangiomas can pose serious concerns to the cosmetic and psychosocial development of the afflicted child. Ulceration, scarring, and disfigurement are significant problems as are encroachment of the ear and eye, which can threaten hearing and vision. The precise mechanisms controlling the rapid growth observed in the first months of life and the spontaneous involution that follows throughout the course of years remain unknown. In this report we demonstrate the presence of large numbers of hematopoietic cells of the myeloid lineage in proliferating hemangiomas and propose a mechanism for the observed evolution of these lesions that is triggered by hypoxia and involves the participation of myeloid cells. We report the results of experiments using myeloid markers (CD83, CD32, CD14, CD15) that unexpectedly colabeled hemangioma endothelial cells, providing new evidence that these cells are distinct from normal endothelium.

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“…Early proliferating hemangiomas contain endothelial cells that express CD133 and CD34, markers for endothelial precursor cells, suggesting that the endothelial cells in proliferating hemangiomas may be arrested at an immature stage of vascular development. 10,11 Third, some aspects of hemangioma resemble that seen in the placenta. An unexpected set of tissue-specific markers co-expressed by both infantile hemangiomas at all stages of their evolution and placental vessels has suggested that the vasculature of the placenta and hemangioma may share a common cellular origin.…”

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confidence: 99%

Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling

Calicchio

Collins

Kozakewich

2009

The American Journal of Pathology

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Infantile hemangiomas are characterized by rapid capillary growth during the first year of life followed by involution during early childhood. The natural history of these lesions creates a unique opportunity to study the changes in gene expression that occur in the vessels of these tumors as they proliferate and regress. Here we use laser capture microdissection and genome-wide transcriptional profiling of vessels from proliferating and involuting hemangiomas to identify differentially expressed genes. Relative to normal placental vessels, proliferating hemangiomas were characterized by increased expression of genes involved in endothelial-pericyte interactions, such as angiopoietin-2 (ANGPT2), jagged-1 (JAG1), and notch-4 (NOTCH4), as well as genes involved in neural and vascular patterning, such as neuropilin-2 (NETO2), a plexin domain containing receptor (plexinC1), and an ephrin receptor (EPHB3). Insulin-like growth factor binding protein-3 (IGFBP3) was down-regulated in proliferating hemangiomas. Involuting hemangiomas were characterized by the expression of chronic inflammatory mediators, such as the chemokine, stromal cellderived factor-1 (SDF-1), and factors that may attenuate the angiogenic response, such as a member of the Down syndrome critical region (DSCR) family. The identification of genes differentially expressed in proliferating and involuting hemangiomas in vivo will contribute to our understanding of this vascular lesion, which remains a leading cause of morbidity in newborn children.

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Endothelial progenitor cells in infantile hemangioma

Abstract: Infantile hemangioma is an endothelial tumor that grows rapidly after birth but slowly regresses during early childhood.

Cited by 191 publications

References 16 publications

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Myeloid Cells in Infantile Hemangioma

Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling

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