Joan E. Nichols, Ph.D., associate professor in the departments of internal medicine and microbiology and immunology at the University of Texas Medical Branch (UTMB), discussed her lab’s work on the use of whole acellular (AC) lung as a matrix to support development of engineered lung tissue from murine embryonic stem cells (mESCs).
Dr. Nichols explained that the design of biomaterials that can guide stem cell behavior and facilitate lung lineage choice, as well as allow seamless integration of the engineered lung tissue into living lung tissue, will require both the development of decellularized matrices, as well as an understanding of the impact of the unique lung ECM on cell behavior and function.
Thus far, she said, attempts to develop lung tissue equivalents have used relatively simple matrices not designed to meet requirements for lung in terms of matrix composition, elasticity, or porosity. Dr. Nichols and her research partner, Joaquin Cortiella, M.D., professor in the department of anesthesiology at UTMB, have used ACM populated with mESCs to build a potentially more robust lung tissue equivalent.
Dr. Nichols explained that the ECM of any tissue supports the architecture and structure of the tissue and plays a role in development, growth, physiology, and response to injury. For matrix selection for lung tissue development, she noted that the biocompatibility, elasticity, and the adsorption kinetics of the material used are particularly important.
“Biomaterials designed for use as a matrix for regenerative medicine purposes fail to replicate the complexity of the ECM that is found in the natural lung. So the best overall choice for a matrix to support growth of lung tissue may be the natural decellularized lung itself. In our studies, we found that AC lung promoted better ESC survival, attachment to the matrix, and lung-specific differentiation.”
AC natural lung allowed, she added, for better retention of cells with more differentiation of mESCs into epithelial and endothelial lineages than was seen for synthetic matrices evaluated. “In constructs formed from mESCs and whole AC lung we saw indications of differentiating ESC organized into 3-D structures reminiscent of complex lung tissue.”
In the initial part of their study, the scientists compared growth and differentiation of mESCs to growth on AC rat lung, Matrigel, Gelfoam, and a type I collagen matrix. In the AC-cultured mESCs, the investigators saw that significantly more of the cells were viable and had differentiated into cells found in the lung.
The investigators also reported evidence of site-specific differentiation in the trachea and distal lung. “For example, type II pneumocytes found in the distal lung formed hollow alveolar–like cysts lined by a monolayer of epithelial cells, which produced both pro-SPC, the nonsecreted form of surfactant protein C, as well as production of surfactant protein A.”
With respect to immunogenicity, Dr. Nichols said that preliminary in vitro data suggests that the matrix is nonimmunogenic and that little activation of immune cells cultured in contact with AC lung/trachea matrix derived from normal tissues occurs. “Little to no response in these types of studies suggests that rejection may not be a problem.”
“We are just beginning to understand how we can use this novel matrix material. I think that clinical applications of the matrix itself could be developed for clinical use in five to seven years. AC trachea has already been used in a clinical application in Italy, which is a good first step.”