Cell-based therapies for lung disease

Abstract

Introduction or background: The adult lung is a complex organ whose large surface area interfaces extensively with both the environment and circulatory system. Yet, in spite of the high potential for exposure to environmental or systemic harm, epithelial cell turnover in adult lung is comparatively slow. Moreover, loss of lung function with advancing age is becoming an increasingly costly healthcare problem. Cell-based therapies stimulating endogenous stem/progenitor cells or supplying exogenous ones have therefore become a prime translational goal. Alternatively when lung repair becomes impossible, replacement with tissue-engineered lung is an attractive emerging alternative using a decellularized matrix or bioengineered scaffold.

Sources of data: Endogenous and exogenous stem cells for lung therapy are being characterized by defining developmental lineages, surface marker expression, functions within the lung and responses to injury and disease. Seeding decellularized lung tissue or bioengineered matrices with various stem and progenitor cells is an approach that has already been used to replace bronchus and trachea in human patients and awaits further development for whole lung tissue.

Areas of agreement: Cellular therapies have clear potential for respiratory disease. However, given the surface size and complexity of lung structure, the probability of a single cellular population sufficing to regenerate the entire organ, as in the bone marrow, remains low. Hence, lung regenerative medicine is currently focused around three aims: (i) to identify and stimulate resident cell populations that respond to injury or disease, (ii) to transplant exogenous cells which can ameliorate disease and (iii) to repopulate decellularized or bioengineered lung matrix creating a new implantable organ.

Areas of controversy: Lack of consensus on specific lineage markers for lung stem and progenitor cells in development and disease constrains transferability of research between laboratories and sources of cellular therapy. Furthermore, effectiveness of individual cellular therapies to correct gas exchange and provide other critical lung functions remains unproven. Finally, feasibility of autologous whole organ replacement has not been confirmed as a durable therapy. Growing points Cellular therapies for lung regeneration would be enhanced by better lineage tracing within the lung, the ability to direct differentiation of exogenous stem or progenitor cells, and the development of functional assays for cellular viability and regenerative properties. Whether endogenous or exogeneous cells will ultimately play a greater therapeutic role remains to be seen. Reducing the need for lung replacement via endogenous cell-mediated repair is a key goal. Thereafter, improving the potential of donor lungs in transplant recipients is a further area where cell-based therapies may be beneficial. Ultimately, lung replacement with autologous tissue-engineered lungs is another goal for cell-based therapy. Areas timely for developing research Defining 'lung stem or progenitor cell' populations in both animal models and human tissue may help. Additionally, standardizing assays for assessing the potential of endogenous or exogenous cells within the lung is important. Understanding cell-matrix interactions in real time and with biomechanical insight will be central for lung engineering. Cautionary note Communicating the real potential for cell-based lung therapy needs to remain realistic, given the keen expectations of patients with end-stage lung disease.

Fig. 1

Illustration of putative stem cell niches in the adult mouse lung. Epithelia of the adult mouse lung can be divided into four major, biologically distinct trophic units (trachea, bronchi, bronchioles and alveoli), each of which encompasses unique types of airway epithelial cells (epithelia relevant to each unit are shown inside circles). Five potential stem cell niches for these various trophic units are shown on the right, with locations of candidate stem cells marked by arrowheads (cells are in red). Stem cells and niches include the following: 1, an unknown cell type in the SMG ducts of the proximal trachea; 2, basal cells in the intercartilaginous zones of the lower trachea and bronchi (these structures may also be associated with innervated NEBs; 3, Clara^v associated with NEBs in bronchioles; 4, Clara cell associated with BADJ and 5, alveolar type II cells of the alveoli. Reprinted with permission from the American Thoracic Society. Copyright © American Thoracic Society. From Liu and Engelhardt. Official Journal of the American Thoracic Society. Diane Gern, Publisher.

Fig. 2

Cellular therapy decision tree.