A Novel Three-Dimensional Skin Disease Model to Assess Macrophage Function in
Authors Smith A, Watkins T, Theocharidis G, Lang I, Leschinsky M, Maione A, Kashpur O,
Raimondo T, Rahmani S, Baskin J, Mooney D, Veves A, Garlick J
Submitted By Jonathan Garlick on 5/5/2021
Status Published
Journal Tissue engineering. Part C, Methods
Year 2021
Date Published 2/1/2021
Volume : Pages 27 : 49 - 58
PubMed Reference 33280487
Abstract A major challenge in the management of patients suffering from diabetes is the
risk of developing nonhealing foot ulcers. Most in vitro methods to screen drugs
for wound healing therapies rely on conventional 2D cell cultures that do not
closely mimic the complexity of the diabetic wound environment. In addition,
while three-dimensional (3D) skin tissue models of human skin exist, they have
not previously been adapted to incorporate patient-derived macrophages to model
inflammation from these wounds. In this study, we present a 3D human skin
equivalent (HSE) model incorporating blood-derived monocytes and primary
fibroblasts isolated from patients with diabetic foot ulcers (DFUs). We
demonstrate that the monocytes differentiate into macrophages when incorporated
into HSEs and secrete a cytokine profile indicative of the proinflammatory M1
phenotype seen in DFUs. We also show how the interaction between fibroblasts and
macrophages in the HSE can guide macrophage polarization. Our findings take us a
step closer to creating a human, 3D skin-like tissue model that can be applied
to evaluate the response of candidate compounds needed for potential new foot
ulcer therapies in a more complex tissue environment that contributes to
diabetic wounds. Impact statement This study is the first to incorporate
disease-specific, diabetic macrophages into a three-dimensional (3D) model of
human skin. We show how to fabricate skin that incorporates macrophages with
disease-specific fibroblasts to guide macrophage polarization. We also show that
monocytes from diabetic patients can differentiate into macrophages directly in
this skin disease model, and that they secrete a cytokine profile mimicking the
proinflammatory M1 phenotype seen in diabetic foot ulcers. The data presented
here indicate that this 3D skin disease model can be used to study
macrophage-related inflammation in diabetes and as a drug testing tool to
evaluate new treatments for the disease.