Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review

Abstract

Recent advances in the fields of microfabrication, biomaterials, and tissue engineering have provided new opportunities for developing biomimetic and functional tissues with potential applications in disease modeling, drug discovery, and replacing damaged tissues. An intact epithelium plays an indispensable role in the functionality of several organs such as the trachea, esophagus, and cornea. Furthermore, the integrity of the epithelial barrier and its degree of differentiation would define the level of success in tissue engineering of other organs such as the bladder and the skin. In this review, we focus on the challenges and requirements associated with engineering of epithelial layers in different tissues. Functional epithelial layers can be achieved by methods such as cell sheets, cell homing, and in situ epithelialization. However, for organs composed of several tissues, other important factors such as (1) in vivo epithelial cell migration, (2) multicell-type differentiation within the epithelium, and (3) epithelial cell interactions with the underlying mesenchymal cells should also be considered. Recent successful clinical trials in tissue engineering of the trachea have highlighted the importance of a functional epithelium for long-term success and survival of tissue replacements. Hence, using the trachea as a model tissue in clinical use, we describe the optimal structure of an artificial epithelium as well as challenges of obtaining a fully functional epithelium in macroscale. One of the possible remedies to address such challenges is the use of bottom-up fabrication methods to obtain a functional epithelium. Modular approaches for the generation of functional epithelial layers are reviewed and other emerging applications of microscale epithelial tissue models for studying epithelial/mesenchymal interactions in healthy and diseased (e.g., cancer) tissues are described. These models can elucidate the epithelial/mesenchymal tissue interactions at the microscale and provide the necessary tools for the next generation of multicellular engineered tissues and organ-on-a-chip systems.

Biocompatible Tissue Scaffold Compliance Promotes Salivary Gland Morphogenesis and Differentiation

“…1,2 While there have been some tissue engineering successes in fairly simple tissues, such as artificial skin grafts and bladders, 3,4 tissue engineering of complex organs will require determination of the environmental cues necessary to establish and maintain proper cellular organization and differentiation in complex environments with multiple cell types.…”

Re-Epithelialization: A Key Element in Tracheal Tissue Engineering

“…However, there are few approaches available for the primary culture of differentiated human tracheal epithelial cells. Available primary culture protocols for tracheal epithelial cells are associated with several issues such as changes in the phenotype of cells during the culture and subsequent loss of specialized cells in the final structure (e.g., lack of basal, goblet or ciliated) [138]. According to Pfenninger, the successful proliferation and differentiation of tracheal epithelial cells in vitro is based on at least three factors: a basal lamina equivalent, consisting of collagen fibers for cellcell interaction and cell polarization; extracellular factors of mesenchymal fibroblasts; and the presence of an air-liquid interface system for the proliferation and differentiation of the epithelial cells (Table 2) [139].…”

“…The ECM is believed to bind to cell surface receptors known as integrins in order to activate intracellular signaling pathways that control gene expression, cytoskeletal organization and cell morphology [147]. Therefore, the utilization of ECM mimicking systems to mimic the physical and biological properties of the epithelial microenvironment is critical to achieve a fully differentiated tracheal epithelium [138,148]. The ECM is a physically complex reticular structure and is principally composed of collagen, laminin, fibronectin, elastin and glycoprotein, which are secreted by the epithelial cells and the underlying mesenchymal cells [149,150].…”

Coming to terms with tissue engineering and regenerative medicine in the lung

“…The field of tissue engineering is geared toward developing clinically viable approaches to recreating or enhancing human organs and tissues that recapitulate both the structure and function of the native organ. For example, engineering of replacement skin tissues is now well recognized (68,187), and there has been substantial progress in other organ systems such as cartilage (45,54,107,159) and bladder (53,104,138,185,212). With regard to the lung, technologies that mimic lung function such as cardiopulmonary bypass and extracorporeal membrane oxygenation are well developed and routinely used in in-hospital settings, but they suffer from being of short-term, nonambula-tory use.…”