Concise review: current status of stem cells and regenerative medicine in lung biology and diseases

Abstract

Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases.

Keywords: Bioengineering; Cell therapy; Embryonic stem cell; Endogenous progenitor cell; Endothelial progenitor cell; Induced pluripotent stem cell; Lung; Lung diseases; Lung regeneration; Mesenchymal stem cell.

Figure 1. Schematic illustrating various stem cell, cell therapy and ex vivo bioengineering approaches for lung diseases

Abbreviations: AFSC amniotic fluid stem cell; BM-MNC bone marrow-derived mononuclear cells; EPC endothelial progenitor cell; ESC embryonic stem cell; iPSC induced pluripotent stem cell; MSC mesenchymal stem (stromal) cell;.

Figure 2. Lung epithelial stem and progenitor cell candidates

Shown is a schematic of proposed lung epithelial candidate stem or progenitor cells and their niches in the proximal conducting airways and distal alveoli. Cells whose localization or existence is not yet clear or accepted are indicated with dashed boxes and/or question marks. AEC2 = type 2 alveolar epithelial cell; BADJ = bronchoalveolar duct junction; Gland = submucosal gland duct; NEB = neuroepithelial body.Marker abbreviations used for each cell subtype include the following: CCSP = Clara cell secretory protein; CGFP = calcitonin gene– related peptide; Itg = integrin; K = cytokeratin; SPC = surfactant protein C. Modified with permission from Kotton D. Next Generation Research: The hope and hype of lung stem cell research. Am J. Resp Crit Care Med, 198:125501260, 2012 (116).

Figure 3. Schematic illustrating the range of in vitro immune-modulating effects described for mesenchymal stromal (stem) cells (MSCs)

Ang 1 angiopoietin 1;EGF epidermal growth factor; eNOS endothelial nitric oxide synthase; FGF2 fibroblast growth factor 2; HGF = hepatocyte growth factor; IGF1 insulin-like growth factor; (s)IL -1RA = (soluble) interleukin-1 receptor antagonist; IL-10 interleukin 10; KGF keratinocyte growth factor; soluble TNFR1 = soluble tumor necrosis factor-α receptor antagonist; stanniocalcin 1; TGF-β1 = transforming growth factor- β1; TSG-6 Tumor necrosis factor-inducible gene 6 protein; VEGF = vascular endothelial growth factor. Adapted with permission from Weiss DJ and Rojas M. MSCs in Chronic Lung Diseases: COPD and Lung Fibrosis. In Stem Cell-Dependent Therapies (2013), Copyright DeGruyter Publisher GmbH Berlin, G. Gross G, T. Häupl, editors (117).