Project Summary
Damage to salivary glands is a devastating condition – identification of therapies to
promote regeneration of these important organs is imperative. Great progress is being made in
engineering and transplantation of salivary gland epithelium. A major remaining hurdle in
gland engineering is the need to establish a functional vasculature, which is essential for survival
of any replacement tissue in vivo. In addition to essential support, therapeutic angiogenesis also
stimulates healing of non-vascular tissue. This study will characterize methods of promoting
vascularization in regenerating salivary gland tissues. Using mice as a pre-clinical model system,
we will evaluate two distinct therapeutic approaches – individually and in combination – to
promote vascularization and regeneration of damaged glands. One therapeutic approach
involves implantation of an exogenous vascular cell milieu as a method to enhance formation of
functional blood vessel networks. The other approach, which may be effective when used in
conjunction with implanted cells, or on its own, will involve systemic delivery of a drug with
potential to stimulate angiogenesis. The therapeutic potentials of the of the two approaches will
be evaluated separately and in combination in vivo in mice in a biopsy wound healing model.
Cellular and molecular events of vascular assembly associated with each therapy will be defined
using cell culture assays in vitro. For implantation of vascular cells, we will use a cell milieu of
stromal vascular fraction derived from adipose (AdSVF). The AdSVF cell milieu has real
advantages as a cell source. It includes many cell types needed to form functional blood vessel
networks (endothelial, pericytes, vascular smooth muscle, fibroblasts) it reduces inflammation
to promote regeneration of parenchymal tissue, it is readily available for self-donation, and,
importantly, has proven safe for clinical use. As an adjunct to implanted AdSVF, or as a
stand-alone vascularizing therapeutic, we will also test the ability of a systemic pharmacologic
agent Tazarotene to stimulate formation of functional vascular networks. Tazarotene is a
synthetic retinoid. Its vascular promoting activity is consistent with the action of natural
retinoids, including vitamin A and its derivative retinoic acid, which are essential for vascular
assembly in vivo. This project will identify methods to promote functional vasculature in
regenerating salivary glands. Resulting knowledge can be used to enhance success of therapies
aimed at repairing salivary epithelium, thereby advancing the field toward developing effective
therapies for patients suffering from salivary gland damage.