Lung bioengineering: physical stimuli and stem/progenitor cell biology interplay towards biofabricating a functional organ

Abstract

A current approach to obtain bioengineered lungs as a future alternative for transplantation is based on seeding stem cells on decellularized lung scaffolds. A fundamental question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes. Whereas the use of soluble factors as agents to modulate the fate of stem cells was established from an early stage of the research with this type of cells, it took longer to recognize that the physical microenvironment locally sensed by stem cells (e.g. substrate stiffness, 3D architecture, cyclic stretch, shear stress, air-liquid interface, oxygenation gradient) also contributes to their differentiation. The potential role played by physical stimuli would be particularly relevant in lung bioengineering since cells within the organ are physiologically subjected to two main stimuli required to facilitate efficient gas exchange: air ventilation and blood perfusion across the organ. The present review focuses on describing how the cell mechanical microenvironment can modulate stem cell differentiation and how these stimuli could be incorporated into lung bioreactors for optimizing organ bioengineering.

Artificial lungs––Where are we going with the lung replacement therapy?

“…Bioengineering the lung based on its natural extracellular matrix offers novel opportunities to overcome the shortage of donors, reduce chronic allograft rejections, and improve the median survival rate of transplant patients. Lung tissue engineering has advanced to combine scaffolds, cells, and biologically active molecules into functional tissues 23‐26,103 . The additional cell layer increases the diffusion barrier of the blood‐gas interface, and thus, alters gas transfer, increasing the overall gas exchange 104,105 …”

“…A main question to be solved in this approach is how to drive stem cell differentiation onto the different lung cell phenotypes 23 . Several types of local progenitor cells that contribute to cell repair have been described at different levels of the respiratory tract.…”

“…The potential role played by physical stimuli would be particularly relevant in lung bioengineering since cells within the organ are physiologically subjected to two main stimuli required to facilitate efficient gas exchange: air ventilation and blood perfusion across the organ 23,104 . A promising option to increase the donor organ pool is to use allogeneic or xenogeneic decellularized lungs as a scaffold to engineer functional lung tissue ex vivo.…”

“…Tissue engineering and cell‐based technologies have provided the concept of bioartificial lungs with properties similar to the native organ 23‐26 . “Bioartifical” is a broad term, and describes systems composed of both living and manufactured components, typically a collection of cells held within a scaffold or membrane.…”

Acellular human lung scaffolds to model lung disease and tissue regeneration

“…proximal versus distal lung epithelium) or be delivered in a progenitor state and targeted to specifically differentiate once in the lung scaffold. The microenvironment, including growth factors, local oxygen tension, cell-cell interactions and dynamic tissue mechanics, can be manipulated to direct higher-level tissue organisation [56,57]. This process will require the design of specific bioreactors to provide the optimal regenerative environment for ex vivo tissue maturation.…”