Which types of cells are involved in the development of infantile hemangiomas?

Updated: Nov 09, 2020
  • Author: Richard J Antaya, MD; Chief Editor: William D James, MD  more...
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Hemangiomas fail to stain for numerous trophoblastic markers, somewhat discounting the placental embolism theory. [19] Some reports suggest that infants born to mothers who have undergone chorionic villus sampling may be at an increased risk of developing hemangiomas, but this has not been uniformly observed. [20] One model suggests that infantile hemangiomas result from aberrantly displaced or embolized placental chorionic villous mesenchymal core cells into the fetus. These cells give rise to a primitive mesoderm-derived hemogenic endothelium that has a neural crest phenotype, which is regulated by the renin-angiotensin system. This hemogenic endothelium differentiates into neuroglial, mesenchymal, and hematopoietic stems cells as well as endothelial progenitor cells (EPC). During infantile hemangioma proliferation and stimulated by angiotensin II (ATII), the mesenchymal stem cells (MSC) produce VEGF, which stimulates the EPCs to grow, and osteoprotegerin (OPG), which prevents the apoptosis of the hemogenic endothelium, MSC, and EPC, creating an excitatory pathway from endothelial cell proliferation. [21] See Pathophysiology.

An in utero local tissue environment of hypoxia appears to influence the subsequent vasculature. [22] This microenvironmental condition is a potent inducer of angiogenesis, leading to increased production of hypoxia-inducible factor-1α (HIF-1α), which, in turn, causes VEGF gene transcription in association with cytokine-stromal cell-derived factor 1 (SDF-1). This appears to stimulate endothelial progenitor cells to proliferate and differentiate into endothelial cells. [23] The production of HIF-1α is stimulated by ATII, helping explain the effect of beta-blocker and angiotensin-converting enzyme inhibitor therapy in the accelerated involution of infantile hemangiomas, as both decrease ATII.

Several VEGF receptors (VEGFRs) may play a role in the development of hemangiomas. VEGFR1 on endothelial cells acts as a decoy receptor such that the binding of VEGF to this receptor does not effect a change in the endothelial cell. However, the binding of VEGF to VEGFR2 elicits robust endothelial cell proliferation and migration. Hemangioma endothelial cells exhibit low levels of VEGFR1, with marked constitutive activation of VEGFR2. Gene transcription for VEGFR1 in hemangioma cells is dependent on nuclear factor of activated T cells (NFAT). This, in turn, is dependent on a pathway involving beta1 integrin, VEGFR2, and integrinlike receptor tumor endothelial marker-8 (TEM8).

Missense mutations in genes encoding for VEGFR2 and TEM8 have been identified in a subset of infantile hemangiomas. These mutations are likely responsible for the constitutive activation of VEGFR2 and resultant hemangioma endothelial cell proliferation. Soluble VEGFR1 or anti-VEGF antibodies normalize the constitutive VEGFR2 signaling. Consequently, these or other similar molecules may be exploited in future hemangioma therapy. [24]

It is believed that infantile hemangiomas may be derived from endothelial progenitor cells (EPCs). EPCs are bone marrow-derived CD133 (or AC133)–positive, CD34-positive, and KDR (VEGFR-2)-positive pluripotent cells that demonstrate the ability to develop into Glut-1–positive endothelial cells. [25] A hemangioma model using these cells exhibits growth characteristics typical of an infantile hemangioma, with both proliferating and involuting phases and the development of fibrofatty residua during involution. The endothelial cells in an infantile hemangioma are thought to be primitive endothelial clonal cells that exhibit abnormal behavior. [26] Infantile hemangiomas express elevated levels of the embryonic stem cell reprogramming factors Oct4, Nanog, Sox2, and Klf4, similar to malignant tumors, suggesting that at least a subpopulation of cells with stem-cell properties exists within these lesions. [27]

Two possibly interrelated theories exist regarding the pathogenesis of hemangiomas with regard to the EPCs, intrinsic and extrinsic. The intrinsic theory proposes that EPCs are monoclonal and behave differently from normal endothelial progenitor cells. The extrinsic theory postulates that the EPCs are polyclonal and behave normally and proliferate in response to the surrounding tissue angiogenic and angiostatic factors. [28]

Mesenchymal stem cells may also play a role in the formation of infantile hemangiomas. These cells have been identified in hemangioma tissue. [29] Mesenchymal stem cells retain the capacity to differentiate into numerous mesodermal cells, including adipocytes, suggesting that these cells may be the source of the resultant adipose tissue found in involuted hemangiomas.

Evidence to support a hereditary/genetic component in the development of most infantile hemangiomas is minimal; most appear to be sporadic. However, at least one report described a kindred in which infantile hemangiomas may be the result of an autosomal dominant trait. [30] These infantile hemangiomas were seen in association with an increased incidence of vascular malformations (mostly capillary malformations) in various members of the same family.

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