The study of stem cell and neuro-vascular development

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

1) Development of functional neuro-vascular networks. We have developed a novel in vivo Ca2+ imaging system of embryonic forelimb skin using sensory neuron-specific Ca2+ indicator mice: a knock-in mouse line in which the expression of GCaMP3, a calcium indicator whose green fluorescent intensity is driven by a sensory neuron-specific phosphoinositide-binding protein (Pirt) promoter. The limb skin is dissected from Pirt-GCaMP3 embryos, and sensory neurons are stimulated by capsaicin. We have successfully demonstrated GCaMP3 fluorescence in response to the capsaicin stimuli. We are currently attempting 1) to carry out the time course analysis to study the relationship between sensory activity and the processes of neurovascular co-patterning and 2) to examine what happens to sensory activity in the mutants having neuro-vascular mis-patterning. 2) Neuro-vascular networks in pathological situations including obesity-related nerve disorders. We have developed a high-resolution whole-mount imaging method to analyze neuro-vascular branching in the entire ear skin of adult mice. This method enabled us to visualize branching morphogenesis and patterning of peripheral nerves and blood vessels in the animal models of obesity and type 2 diabetes, with comprehensive quantification measurements (Yamazaki et al. 2018 Sci Rep). We are currently investigating the functional consequence of defective neuro-vascular branching using an in vivo Ca2+ imaging system of adult ear skin of sensory neuron-specific Pirt-GCaMP3 mice. 3) CXCL12-CXCR4 signaling controls organ-specific blood vessel patterning. We and others have previously discovered the essential role of chemokine CXCL12-CXCR4 signaling in organ-specific patterns of arterial branching: in the developing skin vasculature, sensory nerve-derived CXCL12 recruits its receptor CXCR4+ endothelial cells to form arteries to align with the nerves (Li et al. 2013 Dev Cell). Our recent studies have revealed that endothelial cell-specific gain- and loss-of-function Cxcr4 mutations lead to impaired blood vessel patterning in the developing skin and coronary vasculature, suggesting that appropriate CXCR4 expression in the appropriate endothelial cell type is required for organ-specific vessel patterning (Li et al. 2021 Dev Biol). We are currently investigating what controls endothelial CXCR4 expression in vascular development: given that pre-specified CXCR4-expressing arterial cells are thought to migrate against flow direction and coalesce into a developing coronary artery, we are interested in examining how CXCL12-CXCR4 signaling and blood flow-de