JAGGED1 Signaling Regulates Hemangioma Stem Cell–to–Pericyte/Vascular Smooth Muscle Cell Differentiation

Abstract

OBJECTIVE The aim of our study is to determine the cellular and molecular origin for the pericytes in infantile hemangioma (IH) and their functional role in the formation of pathological blood vessels. METHODS AND RESULTS Here we show that IH-derived stem cells (HemSCs) form pericyte-like cells. With in vitro studies, we demonstrate that HemSC-to-pericyte differentiation depends on direct contact with endothelial cells. JAGGED1 expressed ectopically in fibroblasts was sufficient to induce HemSCs to acquire a pericyte-like phenotype, indicating a critical role for JAGGED1. In vivo, we blocked pericyte differentiation with recombinant JAGGED1, and observed reduced formation of blood vessels, with an evident lack of pericytes. Silencing JAGGED1 in the endothelial cells reduced blood vessel formation and resulted in a paucity of pericytes. CONCLUSIONS Our data show that endothelial JAGGED1 controls HemSC-to-pericyte differentiation in a murine model of IH and suggests that pericytes have a fundamental role in formation of blood vessels in IH.

NOTCH3 regulates stem-to–mural cell differentiation in infantile hemangioma

“…Thus, NOTCH3 may function to regulate HemSC differentiation into perivascular mural cells in IH. Consistent with this model, knockdown of endothelial JAG1 disrupted IH development in a xenograft model that was associated with an absence of mural cell coverage (10).…”

“…In this assay, HemSC-ECFC cell contact induces mural cell differentiation (10). When GFP + HemSCs were cocultured with ECFCs for 9 days, there was an increase in αSMA expression ( Figure 3 …”

“…NOTCH1 and the Notch effectors, HEY1 and HEY2, which are also expressed by HemSCs (9), were not significantly changed (Supplemental Figure 6A). Pericytes isolated from IH specimens have been suggested to promote angiogenesis (10). Therefore, we determined if N3KD altered the expression of the proangiogenic factors, VEGFA, ANG1 (angiopoietin 1), and ANG2 (angiopoietin 2).…”

“…(10), and we have shown that HemSCs are located in perivascular space and express mural cell markers such as αSMA, PDGFRβ, neuroglial proteoglycan 2 (NG2), and calponin (9,10). However, the mechanisms and signaling pathways regulating HemSC differentiation into mural cells in IHs has yet to be elucidated.…”

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

“…These characteristics likely result from the genetic instability of HemECs as somatic missense mutations in the kinase insert of the VEGFR-2 gene have been found in IHs [41]. In addition, imbalances in gene expression have been reported in mesenchymal compartments compared to normal tissues, suggesting a possible reciprocal interaction between HemECs and the surrounding cells [42][43][44]. Alternatively, HemECs may originate from progenitor/stem-like cells, which are known to display robust proliferative and clonogenic capabilities and to express high levels of VEGF-A [15,21].…”