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Hemangiomas are Stem Cell Tumors Derived From Pericytes
Laura K. Tom, B.S.1, Chris Spock, MD, MSc2, Cheryl Maier, PhD1, Raj Sawh-Martinez, BS1, Brent Schultz, MD3, Milton Waner, MD4, Deepak Narayan, MD1.
1Yale University School of Medicine, New Haven, CT, USA, 2University of Miami, Miami, FL, USA, 3University of Washington, Seattle, WA, USA, 4Vascular Birth Institute, New York City, NY, USA.
Hemangiomas are the most common benign tumors of infancy predominantly affecting the head and neck area of female infants. They are clinically well-described vascular tumor with a period of rapid growth (including endothelial proliferation) shortly after birth followed by complete involution to a fibrofatty residuum. However, very little is known about their pathogenesis. It is postulated that the head and neck distribution is nonrandom and along lines of mesenchymal embryonic fusion. Given the evolution of the lesion, the cell-type involved is likely to have angiogenic and adipogenic properties. Recently, Tang et al. provided substantial support for the pericyte, a perivascular cell, as a precursor for adipocytes (preadipocyte). Etchevers et al. have shown that pericytes and a significant component of the soft tissue of the head and neck region are derived from the neural crest. With this information, neural crest derived pluripotent pericytes may be the cells of origin for hemangiomas.
Transcription factors of “stemness” Oct -4, C-myc, Sox-2 and Nanog in 16 hemangiomas (representing proliferative, quiescent, and involuting stages) were compared to normal adult human dermal endothelial cells (n=2) and neonatal dermal endothelial cells (n=2) by qRT-PCR. Additional qRT-PCR was conducted to examine expression of neural crest markers: Sox 10, Nestin and NG2 as well as pericyte/adipocyte markers: dlk and PPARgamma. All specimens were immunohistochemically stained for GLUT-1, a known marker of pericytes. Hemangioma tumor cells were cultured and a FACS analysis (n=3, placental pericytes, HUVEC controls) was performed for CD31, CD34, NG2, and CD90. MicroRNA microarray was performed, results were compared with t-tests and significant microRNAs were analyzed using INGINUITY.
All hemangiomas expressed stem cell factors, Oct-4, C-myc, Sox-2, and Nanog, at a significantly higher level with values increased (fold increase, p-value): Oct-4(11x,p=0.013); C-myc(7.2x,p=0.035); Sox-2(7.6x,p=0.01); Nanog(65,p=0.01). Neural crest markers Sox10 and NG2 were both significantly increased. Nestin levels were variable. PPARgamma levels were found to be increased 8-fold and dlk was increased by 7x10^6-fold, (p=0.001). All specimens stained positive for GLUT. FACS analysis revealed that the cultured hemangioma cells had a profile matching pericytes but not endothelial cells. INGINUITY pathway results of significant microRNAs demonstrated unsuspected links between various growth regulatory genes including IGF2 axis, dlk (from the notch pathway), the TGFβ superfamily.
This suggests that hemangiomas are stem cell tumors derived from the neural crest and have pericyte associated markers. This provides an explanation for location, pathogenesis and fibrofatty involution of hemangiomas.
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