Stem cells and regenerative medicine in lung biology and diseases

Abstract

A number of novel approaches for repair and regeneration of injured lung have developed over the past several years. These include a better understanding of endogenous stem and progenitor cells in the lung that can function in reparative capacity as well as extensive exploration of the potential efficacy of administering exogenous stem or progenitor cells to function in lung repair. Recent advances in ex vivo lung engineering have also been increasingly applied to the lung. The current status of these approaches as well as initial clinical trials of cell therapies for lung diseases are reviewed below.

Figure 1

Endogenous lung progenitor cells. (a) A graphic representation of putative lung stem/progenitor cells in the mouse lung. 1) Basal cells in the tracheobronchial region; 2) variant Clara cells associated with pulmonary neuroendocrine cell (PNEC) bodies; 3) variant Clara cells/BASCs present at the bronchiolar–alveolar duct junction; 4) alveolar type II cells present in the alveolar space. See text for further explanation. Modified with permission of the American Thoracic Society. Copyright © American Thoracic Society from Randell, SH (2006). Airway epithelial stem cells and the pathophysiology of chronic obstructive pulmonary disease. Proc Am Thorac Soc 3: 718–725. (b) Endogenous regenerative microenvironments in the bronchiolar epithelium of the mouse. In situ hybridization for CCSP mRNA (white autoradiographic grains) was used to identify regions of regenerating epithelium following naphthalene-mediated progenitor cell depletion. Regenerative zones of neuroepithelial bodies were identified located at branch points in the airways (red ovals) and at the bronchoalveolar duct junction (green ovals). Adapted with permission from Stripp, BR, Maxson, K, Mera, R and Singh, G (1995). Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol 269(6 Pt 1): L791–L799. BASC, bronchioalveolar stem cell; CCSP, Clara cell secretory protein; mRNA, messenger RNA.

Figure 2

Systemic administration of different populations of bone marrow-derived cells results in rare epithelial engraftment but can stimulate pulmonary vascular growth. (a) Detection of Cftr expression in female Cftr KO mouse lungs following transplantation with male GFP bone marrow-derived stromal cells. Rare donor derived (Y chromosome, red), Cftr positive (green), and cytokeratin positive (blue) cells are found in airway walls of lungs assessed 1 week after transplantation. Only ~0.01% of the total airway epithelial cells appeared to be of donor marrow origin and expressed Cftr. Original magnification ×1,000. Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society from Loi, R, Beckett, T, Goncz, KK, Suratt, BT and Weiss, DJ (2006). Am J Resp Crit Care Med 173: 171–179. (b) Representative confocal projection images of lung sections (a) perfused with fluorescent microspheres (green) suspended in agarose (i.e.,fluorescent microangiography) and immunostained for α-smooth muscle actin (red). Normal filling of the microvasculature was observed in control rats (a), whereas rats treated with monocrotaline (MCT) showed a marked loss of microvascular perfusion and widespread precapillary occlusion 21 (b) and 35 (d) days after MCT injection. In the prevention model, animals receiving bone marrow-derived endothelial-like progenitor cells (ELPC) displayed improved microvascular perfusion and preserved continuity of the distal vasculature (c). In the reversal model, eNOS-transduced ELPCs dramatically improved the appearance of the pulmonary microvasculature (f),whereas progenitor cells alone resulted in more modest increases in perfusion and little noticeable reduction in arteriolar muscularization (e, calibration bars = 100 µm). Figure reprinted with permission from Zhao, YD, Courtman, DW, Deng, Y, Kugathasan, L, Zhang, Q and Stewart, DJ (2005). Circ Res 96: 442–450. eNOS, endothelial nitric oxide synthase; GFP, green fluorescence protein.

Figure 3

Schematic representation illustrating the range of in vitro immune-modulating effects described for mesenchymal stem cells (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; NO, nitric oxide; PDL-1, programmed cell death ligand-1; 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; VEGF, vascular endothelial growth factor. Reprinted with permission from Sueblinvong, V and Weiss, DJ (2010). Stem cells and cell therapy approaches in lung biology and diseases. Transl Res 156: 188–205.

Figure 4

Systemic administration of syngeneic and allogeneic BMSCs during sensitization to ovalbumin-alum inhibits airways hyperresponsiveness and allergic airways inflammation. (a) Airways hyperresponsiveness following allogeneic administration of bone marrow-derived MSCs, (Ova + MSC), MSCs treated with the cross-linking agent EDCI to inhibit secretion of soluble mediators (Ova + EDCI-MSC), PBS-treated ova immunized mice (Ova), or MSCs administration to sham-treated mice (MSC, sham ova) as determined by peak airways resistance responses at each methacholine dose as a function of % change from resting baseline. (b) Tissue inflammation demonstrating a decrease in ova-stimulated perobronchial infilatrates in mice receiving MSCs but not EDCI-treated MSCs. Reprinted with permission from Goodwin, M, Sueblinvong, V, Eisenhauer, P, Ziats, NP, LeClair, L, Poynter, ME et al. (2011). Bone marrow derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells 29: 1137–1148. *P < 0.05 compared to naive. EDCI, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; MSC, mesenchymal stromal cell; OVA, ovalbumin; PBS, phosphate-buffered saline.

Figure 5

Use of decellularized lung scaffolds for ex vivo lung bioengineering. (a) Massome's trichrome and pentachrome staining of extracellular matrix proteins collagen and elastin in native and decellularized mouse lung. Reprinted with permission from Price, AP, England, KA, Matson, AM, Blazar, BR and Panoskaltsis-Mortari, A (2010). Development of a decellularized lung bioreactor system for bioengineering the lung: the matrix reloaded. Tissue Eng Part A 16: 2581–2591. (b) (A) Tissue-engineered left lung was implanted into adult Fischer 344 rat recipient and photographed ~30 minutes later. (B) X-ray image of rat showing the implanted engineered left lung (white arrow) and the right native lung. (C) H and E stain of explanted lung. Red blood cells perfusing septa are evident, and some red blood cells are present in airspaces. Bar 50 µm. Reprinted with permission from Petersen, TH, Calle, EA, Zhao, L, Lee, EJ, Gui, L, Raredon, MB et al. (2010). Tissue-engineered lungs for in vivo implantation. Science 329: 538–541. H&E, hematoxylin and eosin.