Stem cells used to model infant birth defect

Mar 18, 2010

Hemangiomas -- strawberry-like birthmarks that commonly develop in early infancy - are generally harmless, but up to 10 percent cause tissue distortion or destruction and sometimes obstruction of vision or breathing. Since the 1960s, problematic hemangiomas have been treated with corticosteroids such as dexamethasone or prednisone. But steroids have considerable side effects, don't always work, and their mechanism of action in hemangioma has remained a mystery. Researchers at Children's Hospital Boston recently discovered that infantile hemangiomas originate from stem cells, and have used these stem cells to better understand this tumor in the laboratory.

In the March 18 issue of the , they show that steroids target hemangioma stem cells specifically, reveal their mechanism of their action and suggest other possible ways to halt and shrink hemangiomas.

Hemangiomas, affecting 4 to 10 percent of infants, are noncancerous tumors consisting of a tangled mass of blood vessels. Previously, it was assumed that steroids act on endothelial cells, which make up about 30 percent of cells in the tumor. The new research, led by dermatologist Shoshana Greenberger, MD, PhD, working in the lab of Joyce Bischoff, PhD, in Children's Vascular Biology Program, shows that steroids interfere with a much rarer and more primitive cell type - hemangioma stem cells.

Greenberger and Bischoff further showed that steroids work by inhibiting hemangioma stem cells' ability to stimulate , and that they do so by shutting down production of a specific factor called vascular endothelial growth factor (VEGF-A). VEGF is well known as a stimulator of angiogenesis (blood vessel growth) in cancer and age-related macular degeneration.

"We now have more therapies targeting VEGF, so our findings open the way to finding a more specific and safer therapy for hemangioma," says Greenberger.

Steroids usually result only in stabilization of hemangioma growth, and about 30 percent of hemangiomas don't respond to steroid treatment. Steroids also have side effects including facial swelling, hyperactivity, growth retardation and increased blood pressure. Although the effects on appearance may seem minor, research indicates that a baby's physical appearance can interfere with maternal bonding.

"My dream has always been to give a drug to stop hemangioma at its first appearance," says Children's plastic surgeon John Mulliken, MD, co-director of Children's Vascular Anomalies Center and a co-author on the study.

Greenberger, Bischoff and colleagues worked with hemangioma stem cells isolated from patient tissue samples provided by Mulliken, and showed that:

  • When human hemangioma stem cells were pretreated with dexamethasone, then implanted in mice, the tumors that formed had far fewer blood vessels.
  • Dexamethasone suppressed the stem cells' production of VEGF-A, but did not suppress VEGF-A production by from the same hemangioma.
  • When VEGF-A production was suppressed in hemangioma stem cells using shRNA silencing, then implanted in the mice, there was an 89 percent reduction in vessel growth.
  • VEGF-A was detected in actively growing hemangiomas, but not in regressing (involuting) hemangiomas.
Earlier research in Bischoff's lab and that of Bjorn Olsen, MD, PhD, of the Harvard School of Dental Medicine, indicates that hemangiomas may result from an in utero mutation in a stem cell destined to become an endothelial cell, causing a disruption in the normally well-ordered process of blood vessel development. Under a 2008 Translational Research Program grant from Children's, Bischoff's lab has been using hemangioma stem cells to test a library of existing medications that might specifically inhibit the proliferation of the hemangioma , and thereby limit growth of the hemangioma tumor.

"Steroids are inhibiting expression of a central regulator of blood vessel growth: VEGF-A," says Bischoff. "But we'd like to target the stem cell itself - stop its proliferation, prevent it from differentiating into unwanted and, at the same time, eliminate the cellular source of VEGF-A."

Explore further: Artificial sweeteners linked to abnormal glucose metabolism

More information: Citation: Greenberger S, Boscolo E, Adini I, Mulliken J and Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010 Mar 18; 362(11):30-38.

Related Stories

Infants with birthmarks received less oxygen in womb

Jan 07, 2008

A hemangioma is a benign tumor of cells that line blood vessels, appearing during the first few weeks of life as a large birthmark or lesion. A study published in Pediatric Dermatology reveals that a disturbance of oxygen ...

Why do people with Down syndrome have less cancer?

May 20, 2009

Most cancers are rare in people with Down syndrome, whose overall cancer mortality is below 10 percent of that in the general population. Since they have an extra copy of chromosome 21, it's been proposed that people with ...

Precancerous stem cells can form tumor blood vessels

Feb 20, 2008

Tumors require a blood supply to grow, but how they acquire their network of blood vessels is poorly understood. A new study here shows that tumor blood vessels can develop from precancerous stem cells, a recently discovered ...

Recommended for you

Connection found between birth size and brain disorders

15 hours ago

(Medical Xpress)—A trio of researchers has found what appears to be a clear connection between birth size and weight, and the two brain disorders, autism and schizophrenia. In their paper published in Proceedings of ...

A novel therapy for sepsis?

Sep 16, 2014

A University of Tokyo research group has discovered that pentatraxin 3 (PTX3), a protein that helps the innate immune system target invaders such as bacteria and viruses, can reduce mortality of mice suffering ...

User comments : 0