Comparative biology of decellularized lung matrix: Implications of species mismatch in regenerative medicine

Abstract

Lung engineering is a promising technology, relying on re-seeding of either human or xenographic decellularized matrices with patient-derived pulmonary cells. Little is known about the species-specificity of decellularization in various models of lung regeneration, or if species dependent cell-matrix interactions exist within these systems. Therefore decellularized scaffolds were produced from rat, pig, primate and human lungs, and assessed by measuring residual DNA, mechanical properties, and key matrix proteins (collagen, elastin, glycosaminoglycans). To study intrinsic matrix biologic cues, human endothelial cells were seeded onto acellular slices and analyzed for markers of cell health and inflammation. Despite similar levels of collagen after decellularization, human and primate lungs were stiffer, contained more elastin, and retained fewer glycosaminoglycans than pig or rat lung scaffolds. Human endothelial cells seeded onto human and primate lung tissue demonstrated less expression of vascular cell adhesion molecule and activation of nuclear factor-κB compared to those seeded onto rodent or porcine tissue. Adhesion of endothelial cells was markedly enhanced on human and primate tissues. Our work suggests that species-dependent biologic cues intrinsic to lung extracellular matrix could have profound effects on attempts at lung regeneration.

Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung

“…We next evaluated the potential of human PC to respond to the IPF lung microenvironment using 3-dimensional decellularized lung tissue, used to simulate the biochemical and biophysical properties of native lung tissue (18). Decellularization strategies have the advantage of removing cellular content of human lung (healthy and IPF) in its entirety, while maintaining presentation of major structural proteins (19,20). However, small molecules and glycosaminoglycans are sacrificed in the stringent process of cell removal (21).…”

Developmental pathways in lung regeneration

“…An additional in vitro bioengineered lung model is the decellularized tissue system, where cells are removed using a combination of detergents leaving behind a rigid extracellular matrix that can be subsequently used for reseeding with pulmonary derived cells (Balestrini, Gard et al 2016). Using this technique, the unique architecture of the lungs, with bifurcating networks of airways and blood vessels, can be maintained following the removal of the living cellular component (Gilpin and Ott 2015).…”

Regenerative potential of human airway stem cells in lung epithelial engineering

“…In order to reduce the amount of starting donor tissue required, additional experimental factors including longer ex vivo culture time and optimized microenvironment (biomechanics, growth factors) may be developed to enhance the recellularization process. In addition to cell origin, the source of biologic scaffold may also play an important role in regeneration capacity, both in terms of cell distribution and survival in the construct (49). …”