VE-Cadherin and Anastomosis of Blood Vessels Formed by Dental Stem Cells

Abstract

It is known that dental pulp stem cells (DPSCs) can be induced to differentiate into vasculogenic endothelial (VE) cells. However, the process that results in sprouting and anastomosis of DPSC-derived vessels remains unclear. Here, we performed studies to understand the mechanisms underpinning the anastomosis of the host vasculature with blood vessels generated by DPSCs (a model for mesenchymal stem cells). VE-cadherin–silenced primary human DPSCs seeded in tooth slice/scaffolds and transplanted into the subcutaneous space of immunodeficient mice generated fewer functional blood vessels (i.e., anastomosed with the host vasculature) than control DPSCs transduced with scrambled sequences. Both VE-cadherin–silenced and mitogen-activated protein kinase kinase 1 (MEK1)–silenced cells showed a decrease in the number of capillary sprouts in vitro. Interestingly, DPSC stably transduced with a VE-cadherin reporter demonstrated that vascular endothelial growth factor (VEGF) induces VE-cadherin expression in sprouting DPSCs undergoing anastomosis, but not in quiescent DPSCs. To begin to understand the mechanisms regulating VE-cadherin, we stably silenced MEK1 and observed that VEGF was no longer able to induce VE-cadherin expression and capillary sprout formation. Notably ERG, a transcriptional factor downstream from MEK/ERK, binds to the promoter region of VE-cadherin (chip assay) and is induced by VEGF in DPSCs. Collectively, these data defined a signaling pathway triggered by VEGF that results in phosphorylation of MEK1/ERK and activation of ERG leading to expression of VE-cadherin, which is required for anastomosis of DPSC-derived blood vessels. In conclusion, these results unveiled a signaling pathway that enables the generation of functional blood vessels upon vasculogenic differentiation of DPSCs.

VEGFR1 primes a unique cohort of dental pulp stem cells for vasculogenic differentiation

“…5c,d), despite the fact that the anti-Factor VIII antibody used cross-reacted with both human and mouse endothelial cells. These findings confirmed previous reports according to which transplantation of human endothelial cells or human DPSCs results in the engineering of human blood vessels in murine hosts (Bento et al, 2013;Nör et al, 2001;Sakai et al, 2010;Sasaki et al, 2020).…”

“…and anastomosis of these stemcell-derived blood vessels with the host vasculature through VE-cadherin (Sasaki et al, 2020). 3 to 5 d after induction with VEGF, DPSCs acquire VEGFR2 expression (Sasaki et al, 2020), which then drives vessel maturation and functional angiogenesis (Janebodin et al, 2013;Monache et al, 2019;Xu et al, 2019).…”

“…and anastomosis of these stemcell-derived blood vessels with the host vasculature through VE-cadherin (Sasaki et al, 2020). 3 to 5 d after induction with VEGF, DPSCs acquire VEGFR2 expression (Sasaki et al, 2020), which then drives vessel maturation and functional angiogenesis (Janebodin et al, 2013;Monache et al, 2019;Xu et al, 2019). These pulp stem cells are considered to be good candidates for bone tissue engineering, as they are able to differentiate into both vasculogenic endothelial cells and bone-forming osteoblasts when implanted in environments conducive to bone formation (D'Aquino et al, 2007;D'Aquino et al, 2009;Giuliani et al, 2013;Paino et al, 2017;Yusof et al, 2018).…”

Pseudoginsenoside F11 Enhances the Viability of Random-Pattern Skin Flaps by Promoting TFEB Nuclear Translocation Through AMPK-mTOR Signal Pathway

“…MMP9 stimulates the migration of endothelial cells and angiogenesis ( Xu et al, 2001 ). Cadherin 5, on the other hand, promotes the formation during angiogenesis ( Sasaki et al, 2020 ). The results showed that VEGF, MMP9, and Cadherin 5 protein levels were higher in PF11 group compared with control group.…”

Regenerative Potential of DPSCs and Revascularization: Direct, Paracrine or Autocrine Effect?

“…In conclusion, these results unveiled a signaling pathway that enables the generation of functional blood vessels upon vasculogenic stimulus of DPSCs. [56] DPSCs Regenerative Mechanism: Paracrine or Direct Differentiation As described in this review, depending on the microenvironment, the MSCs/pericytes have several key roles. Firstly, they inspect the damage, isolate foreign components, stabilize the injured tissue, provide antibiotics and then start the sequence of events to regenerate the damaged tissue [75].…”