Project Summary
Even without comorbidities associated with aging, wound healing in healthy elderly people (>65)
is delayed, posing a high risk of infection. However, mechanisms for the age-related decline in
wound healing are largely unknown. Integrin adhesion receptors on epidermal keratinocytes bind
to extracellular matrix (ECM) and have critical roles in controlling the wound microenvironment
and critical parameters of wound healing. Age-dependent changes in adhesion receptors may
contribute to reduced wound healing in aged skin, but these have not been explored. This is an
important knowledge gap, as integrins are cell surface receptors that can be readily targetable
therapeutically. Integrin α3β1 is an excellent candidate for mediating epidermal wound functions
that diminish with age. Indeed, our preliminary data show that α3β1 expression decreases in
aging murine skin. Furthermore, our new genetic model of inducible, epidermis-specific α3KO
(iα3eKO) has begun to elucidate α3β1-dependent wound functions in adult skin, free from
compensation and/or basement membrane defects caused by embryonic and sustained deletion
of epidermal α3β1 in the widely used constitutive α3KO mice. Our preliminary data indicate that
acute loss of α3β1 in epidermis of young adult mice (1) slows wound reepithelialization and (2)
impairs epidermal factors that mediate immune cell infiltration. Indeed, reepithelialization and
immune cell infiltration are compromised in aging skin of humans and rodents, and contribute to
impaired wound healing in the elderly. The proposed work will use an aging model in combination
with our iα3eKO model to test our hypothesis that α3β1 in epidermis promotes wound healing
by regulating two distinct processes: (1) epidermal migration over the provisional wound
ECM, and (2) induction of epidermal factors that mediate immune cell infiltration, and that
these α3β1-dependent functions are diminished during intrinsic (chronological) aging,
impeding the ability to heal wounds. We propose two Specific Aims to test our hypothesis and
answer the question: Does waning epidermal integrin α3β1 function in aging skin contribute to
wound healing deficiencies in the elderly? We will determine, in vivo and in vitro, the ability of
young, middle, and aged keratinocytes which express or lack α3β1 to (Aim 1) proliferate and
migrate during re-epithelialization, and to (Aim 2) secrete soluble immune cell-stimulating factors
that promote immune cell recruitment during wound healing. Aim 2 is a particularly innovative
aspect, as it extends our studies beyond traditional roles for integrins in adhesion/motility to further
explore keratinocyte-driven paracrine crosstalk. This work will enhance understanding of how
age-related changes in the functions of epidermal integrins contribute to reduced wound healing.
