[Show abstract][Hide abstract] ABSTRACT: The origin of infantile haemangioma (IH) remains enigmatic. A primitive mesodermal phenotype origin of IH with the ability to differentiate down erythropoietic and terminal mesenchymal lineages has recently been demonstrated.
To investigate the expression of human embryonic stem cell (hESC) markers in IH and to determine whether IH-derived cells have the functional capacity to form teratoma in vivo.
Immunohistochemical staining and quantitative reverse transcription PCR were used to investigate the expression of hESC markers in IH biopsies. The ability of cells derived from proliferating IH to form teratomas in a mouse xenograft model was investigated.
The hESC markers, Oct-4, STAT-3 and stage-specific embryonic antigen 4 were collectively expressed on the endothelium of proliferating IH lesions, whereas Nanog was not. Nanog was expressed by cells in the interstitium and these cells did not express Oct-4, stage-specific embryonic antigen 4 or STAT-3. Proliferating IH-derived cells were unable to form teratomas in severely compromised immunodeficient/non-obese diabetic mice.
The novel expression of hESC on two different populations of cells in proliferating IH and their inability to form teratomas in vivo infer the presence of a primitive cellular origin for IH downstream from hESC.
Journal of clinical pathology 03/2012; 65(5):394-8. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors and decoy receptors, including osteoprotegerin (OPG) in infantile haemangioma (IH).
Immunostaining, Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used on IH biopsies and haemangioma explant-derived cells (HaemEDCs). TRAIL and its receptors and decoy receptors, including OPG, are expressed in proliferating IH tissues and in HaemEDCs. Cells forming the endothelium of immature capillaries of proliferating IHs express abundant OPG and show punctate von Willebrand Factor (vWF) staining. As the cells mature and assume the characteristic of endothelial cells they increase expression of vWF, but lose expression of OPG. The endothelium of IH shows minimal expression of receptor activator for nuclear factor кB ligand (RANKL) compared with a small population of RANKL-positive cells located within the interstitium between microvessels. Proliferating HaemEDCs express significantly higher levels of OPG and decoy receptor 2 than the matched tissue samples. Increased OPG expression is detected in the extracellular matrix and in the conditioned medium of HaemEDCs.
Our data suggest that OPG through the TRAIL pathway, but not the RANKL pathway, plays a role in regulating anti-apoptosis during the development of IH.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND; Infantile haemangioma (IH) is a tumour of the microvasculature composed predominantly of proliferating endothelial cells. It expresses markers associated with endothelial, haematopoietic and mesenchymal lineages. We have previously shown that the cells forming the capillary endothelium of proliferating IH express cell surface markers and transcriptions factors consistent with it being a haemogenic endothelium.
We wished to determine whether the expression of transcription factors associated with the erythroid lineage was of physiological relevance and sufficient for IH tissue cultured in vitro to undergo erythropoiesis.
Immunohistochemical staining of paraffin-embedded sections of proliferating IHs was undertaken and expression of the embryonically associated haemoglobin ζ (HBZ) chain and the erythropoietin receptor (EPO-R) was determined. Relative expression of mRNA encoding these proteins was determined by quantitative reverse transcription-polymerase chain reaction using snap-frozen biopsy samples. Differentiation towards erythrocytes was investigated using freshly resected tissue cultured as explants in Matrigel.
The endothelium of the microvessels, but not the pericyte layer, was strongly immunoreactive for the EPO-R and the embryonically associated HBZ chain. Abundant expression of transcripts encoding these proteins was also detected, corroborating the immunohistochemical staining. When tissue was grown in culture the cells emanating from IH explants were able to generate enucleated erythrocytes in vitro. The erythrocytes were immunoreactive for the erythrocyte-specific marker glycophorin A.
The microvessels in IH are a functional haemogenic endothelium that expresses the embryonically associated HBZ chain and is able to form erythrocytes in vitro. IH thus represents a possible extramedullary site for tumour-associated primitive erythropoiesis.
British Journal of Dermatology 05/2011; 164(5):1097-100. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibro-fatty deposition commonly occurs during involution of infantile haemangioma (IH). Mesenchymal stem cells have been identified in this tumour and have been proposed to be recruited from the bone marrow and/or adjacent niches, and then give rise to the fibro-fatty tissue. The authors have recently demonstrated that the capillary endothelium of proliferating IH co-expresses primitive mesodermal, mesenchymal and neural crest markers and proposed that this same endothelium has the ability to give rise to cells of mesenchymal lineage that constitute the fibro-fatty deposition.
Immunohistochemistry and real-time RT-PCR were used to further characterise proliferating IHs and haemangioma explant-derived cells (HaemEDCs).
The authors have further confirmed expression of the mesenchymal-associated proteins including preadipocyte factor-1, a mesenchymal differentiation inhibition-associated cytokine. The HaemEDCs could be differentiated into osteoblasts and adipocytes, indicating their functional potential for terminal differentiation.
The collective expression of neural crest, mesenchymal and mesenchymal differentiation inhibition-associated proteins on the endothelium of proliferating IH suggests that the cells in the capillary endothelium within the lesion possess the ability to undergo terminal mesenchymal differentiation during the proliferating phase, but are inhibited from doing so.
Journal of clinical pathology 03/2011; 64(3):232-6. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: We have recently shown mesenchymal stem cells (MSCs) isolated from haemangioma stained strongly for OPG. Vimentin immunoreactivity (IR) is an established marker for immature cells of mesenchymal origin. This study characterises haemangioma biopsies at different phases of progression to identify the presence of progenitor cells.Methods: Immunohistochemical staining was carried out on formalin-fixed paraffin sections of haemangioma at different phases of progression for vimentin, osteoprotegerin (OPG), von Willebrand factor and glucose transporter-1 (Glut-1).Results: Positive staining for OPG and vimentin was observed on progenitor cells in the proliferating and early involuting phases of haemangioma. Strong Glut-1 staining of mature capillaries of the involuted phase was inversely related to the degree of OPG and vimentin IR. Positive vimentin staining of cells in the interstitium of involuted heamangioma and weak vimentin IR of blood vessels was found suggesting that these vimentin-positive cells may be MSCs that eventually differentiate into adipocytes that characterise involuted lesions. OPG IR diminished as haemangioma involuted, with little staining seen in involuted lesions.Conclusions: OPG and vimentin IR are early progenitor cell markers that stain immature capillaries of proliferating haemangioma. In involuted haemangioma OPG IR is scant whereas vimentin-positive cells are present in the interstitium. This finding supports our hypothesis that OPG IR is a marker for progenitor cells present in immature capillaries of proliferating haemangioma that is lost as the lesions involute.
ANZ Journal of Surgery 01/2009; 79. · 1.50 Impact Factor