Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation

Doi, Hiroshi; Iso, Tatsuya; Shiba, Yuji; Sato, Hiroko; Yamazaki, Miki; Oyama, Yoshiaki; Akiyama, Hideo; Tanaka, Toru; Tomita, Tomoyuki; Arai, M.; Takahashi, Masafumi; Ikeda, Uichi; Kurabayashi, Masahiko

doi:10.1016/j.bbrc.2009.02.116

Cited by 29 publications

(21 citation statements)

References 29 publications

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“…We previously demonstrated that BM cells contribute to the expansion of the tumor vascular network by migrating to the tumor and differentiating into both endothelial cells and pericytes/vSMCs. 5,16,17,[23][24][25] The tumor blood vessels were surrounded by thick layers of BMderived pericytes/vSMCs. We also previously demonstrated that these BM-derived cells were essential for tumor growth using MEKK3-knockout BM cells, which cannot participate in vessel formation.…”

Section: Discussionmentioning

confidence: 99%

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Stewart

Zhou

Zweidler‐McKay

et al. 2011

Blood

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Delta-like ligand 4 (DLL4) is essential for the formation of mature vasculature. However, the role of DLL4-Notch signaling in pericyte/vascular smooth muscle cell (vSMC) development is poorly understood. We sought to determine whether DLL4-Notch signaling is involved in pericyte/vSMC formation in vitro and during vasculogenesis in vivo using 2 Ewing sarcoma mouse models. Inhibition of DLL4 with the antibody YW152F inhibited pericyte/vSMC marker expression by bone marrow (BM) cells in vitro. Conversely, transfection of 10T1/2 cells with the active domains of Notch receptors led to increased expression of pericyte/vSMC markers. Furthermore, the blood vessels of Ewing sarcoma tumors from mice treated with YW152F had reduced numbers of BM-derived pericytes/vSMCs, fewer open lumens, and were less functional than the vessels in tumors of control-treated mice. Tumor growth was also inhibited. These data demonstrate a specific role for DLL4 in the formation of BM-derived pericytes/vSMCs and indicate that DLL4 may be a novel therapeutic target for the inhibition of vasculogenesis.

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Section: Discussionmentioning

confidence: 99%

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Stewart

Zhou

Zweidler‐McKay

et al. 2011

Blood

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“…26 From in vitro and in vivo studies, it has been demonstrated that Herp2, as downstream of the Notch/Jagged1 signaling, regulates vSMCs differentiation and migration, and induces vascular remodeling in response to stimuli. 10,27 Furthermore, the observation that the hampered proliferation of the Ad-sJag-treated vSMCs could be partially rescued by Herp2 overexpression suggests that Notch-Herp2 signaling is required for vSMCs function, and that sJag1 is an inhibitor for notch signaling both in vivo and in vitro. 22,28 The unique PH-PASMC phenotype is important for the development of PH.…”

Section: Discussionmentioning

confidence: 99%

Soluble Jagged1 Inhibits Pulmonary Hypertension by Attenuating Notch Signaling

Xiao

Gong

Wang

2013

ATVB

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Objective-Notch signaling has been implicated in the development of pulmonary arterial hypertension (PH) as reflected by increased expression of Notch member proteins that induce the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo; however, its capacity to suppress PH remains unknown. Approach and Results-Notch1, Notch3, Jagged1, and Herp2 protein were highly expressed in both the mouse model of hypoxia-induced PH and the rat model of monocrotaline-induced PH. By attenuation and reversal of multiple pathological processes that were associated with PH, adenoviral sJag1 transfection significantly reduced the proliferation and enhanced the apoptosis of PASMCs in PH, whereas vehicle had no effect. The sJag1 inhibitory effect on Notch activation is likely related to its interference with ligand-induced signaling. Importantly, the administration with adenoviral sJag1 improved the survival rate of PH rats. Furthermore, sJag1 can restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state, by giving a positive effect on the physical binding of myocardin to the CC(A/T) n GG (CArG)-containing regions of vascular smooth muscle cells-specific promoters. Conclusions-Our results demonstrated that the potential therapeutic use of the sJag1 may not only inhibit the proliferation of PASMCs but also restore the PH-PASMCs phenotype from the dedifferentiated to the differentiated state through interference with Notch-Herp2 signaling. Because proliferation of PASMCs is a prerequisite for all kinds of PH, we hypothesized that blockage of Notch signaling could inhibit formation and development of PH. Soluble Jagged1 (sJag1) has been shown to inhibit Notch signaling in vitro and in vivo 16,17 ; however, its capacity to suppress PH remains unknown. Here, we showed that 2 kinds of rodent PH models, including the hypoxia-induced mouse and the monocrotaline (MCT)-induced rat, were inhibited by administration of sJag1 treatment. Accordingly, sJag1 was able to reduce the PASMCs proliferation and restore the phenotype by interfering with Notch signaling involving depression of Herp2 expression. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Notch/Jagged1 Signaling Was Highly Activated in PHTo investigate the expression pattern of Notch signaling pathway in normal and PH lungs, we studied 2 kinds of PH rodent models including hypoxia-induced mouse and MTC-induced rat. The Verhoeff-Van Gieson stain sections for lung tissue clearly showed that there was significantly increased vascular medial thickening in the PH models of rat ( Figure 1A) and mouse. Consistent with this observation, our studies showed that the mean pulmonary arterial pressures (mPAP) by day 35 in hypoxia-mouse and by day 42 in MTC-rat were significantly higher than those in normal ( Figure 2B). Collectively, it was suggested that PH has been successfully induced in the hypoxia-treated mouse and MTC-tr...

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“…21 In VSMCs in particular, Notch activity regulates cell differentiation, proliferation, migration, and survival. 20,22,23 Notch3 is the primary receptor that is expressed by VSMCs and its ligand Jagged1 is predominantly expressed by vascular ECs. 19,24,25 Notwithstanding a number of in-vivo-gene-knockout experiments that demonstrate the role of EC-mediated Notch signaling during vascular development and maturity, [26][27][28] it is unknown whether Notch signaling is activated in vitro in 3D cultures to induce the VSMC contractile phenotype.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Vascular Smooth Muscle Cell Phenotype in Three-Dimensional Coculture System by Jagged1-Selective Notch3 Signaling

Bhattacharyya

Lin

Sandig

et al. 2014

Tissue Engineering Part A

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The modulation of vascular smooth muscle cell (VSMC) phenotype is an essential element to fabricate engineered conduits of clinical relevance. In vivo, owing to their close proximity, endothelial cells (ECs) play a role in VSMC phenotype switching. Although considerable progress has been made in vascular tissue engineering, significant knowledge gaps exist on how the contractile VSMC phenotype is induced at the conclusion of the tissue fabrication process. The objectives of this study were as follows: (1) to establish ligand presentation modes on transcriptional activation of VSMC-specific genes, (2) to develop a three-dimensional (3D) coculture model using human coronary artery smooth muscle cells (HCASMCs) and human coronary artery endothelial cells (HCAECs) on porous synthetic scaffolds and, (3) to investigate EC-mediated Notch signaling in 3D cultures and the induction of the HCASMC contractile phenotype. Whereas transcriptional activation of VSMC-specific genes was not induced by presenting soluble Jagged1 and Jagged1 bound to protein G beads, a direct link between HCAEC-bound Jagged1 and HCASMC differentiation genes was observed. Our 3D culture results showed that HCASMCs seeded to scaffolds and cultured for up to 16 days readily attached, infiltrated the scaffold, proliferated, and formed dense confluent layers. HCAECs, seeded on top of an HCASMC layer, formed a distinct, separate monolayer with cell-type partitioning, suggesting that HCAEC growth was contact inhibited. While we observed EC monolayer formation with 200,000 HCAECs/scaffold, seeding 400,000 HCAECs/scaffold revealed the formation of cord-like structures akin to angiogenesis. Western blot analyses showed that 3D coculture induced an upregulation of Notch3 receptor in HCASMCs and its ligand Jagged1 in HCAECs. This was accompanied by a corresponding induction of the contractile HCASMC phenotype as demonstrated by increased expression of smooth muscle-α-actin (SM-α-actin) and calponin. Knockdown of Jagged1 with siRNA showed a reduction in SM-α-actin and calponin in cocultures, identifying a link between Jagged1 and the expression of contractile proteins in 3D cocultures. We therefore conclude that the Notch3 signaling pathway is an important regulator of VSMC phenotype and could be targeted when fabricating engineered vascular tissues.

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Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation

Cited by 29 publications

References 29 publications

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

Soluble Jagged1 Inhibits Pulmonary Hypertension by Attenuating Notch Signaling

Regulation of Vascular Smooth Muscle Cell Phenotype in Three-Dimensional Coculture System by Jagged1-Selective Notch3 Signaling

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