Stem cells and cell therapy approaches in lung biology and diseases

Abstract

Cell-based therapies with embryonic or adult stem cells, including induced pluripotent stem cells, have emerged as potential novel approaches for several devastating and otherwise incurable lung diseases, including emphysema, pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. Although initial studies suggested engraftment of exogenously administered stem cells in lung, this is now generally felt to be a rare occurrence of uncertain physiologic significance. However, more recent studies have demonstrated paracrine effects of administered cells, including stimulation of angiogenesis and modulation of local inflammatory and immune responses in mouse lung disease models. Based on these studies and on safety and initial efficacy data from trials of adult stem cells in other diseases, groundbreaking clinical trials of cell-based therapy have been initiated for pulmonary hypertension and for chronic obstructive pulmonary disease. In parallel, the identity and role of endogenous lung progenitor cells in development and in repair from injury and potential contribution as lung cancer stem cells continue to be elucidated. Most recently, novel bioengineering approaches have been applied to develop functional lung tissue ex vivo. Advances in each of these areas will be described in this review with particular reference to animal models.

Fig 1

Schematic showing different cell types in the lung. Figure courtesy of Barry Stripp, PhD, Duke University, North Carolina, USA.

Fig 2

Schematic showing various types of lung endogenous progenitor cells located in different anatomic regions of the lung. CGRP = calcitonin gene-related peptide, Scgb1a1 = secretoglobulin, family 1A (also known as uteroglobulin), SftpC = surfactant protein C, D = dorsal, and V = ventral. Figure reproduced with permission from Rawlins and Hogan. (Color version of figure is available online.)

Fig 3

ESCs can be effectively manipulated in vitro to differentiate into type 2 alveolar epithelial cells using the lung development cell signaling pathway to guide ESCs differentiation. FGF-2 = fibroblast growth factor-2 and pro-Spc = pro-surfactant protein C. Figure courtesy of Christine Finck, MD, University of Connecticut. (Color version of figure is available online.)

Fig 4

Schematic illustrating the range of in vitro immune-modulating effects described for MSCs. DC = dendritic cell; HGF = hepatocyte growth factor; IDO = indoleamine 2,3-dioxygenase; IFN-γ = interferon γ; Ig = immunoglobulin; IL = interleukin; IL-1RA = interleukin-1 receptor antagonist; Mac = macrophage; NK = natural killer; PGE2 = prostaglandin E-2; SDF-1 = stem-cell-derived factor 1; TNF-α = tumor necrosis factor-α; TGF-β1 = transforming growth factor- β1; TLR = toll-like receptor; and VEGF = vascular endothelial growth factor. (Color version of figure is available online.)

Fig 5

CFTR expressed cells can be detected in female CFTR knockout mouse lungs after transplantation with male GFP stromal marrow cells. Donor-derived (Y chromosome, red), CFTR-positive (green), and cytokeratin-positive (blue) cells are indicated by light blue arrows in airway walls of lungs assessed 1 week after transplantation. Inset is a higher power view of the area marked by asterisk. Original magnification: ×1000. Figure reproduced with permission from Loi et al. (Color version of figure is available online.)