- Open Access
Cell-based therapy in lung regenerative medicine
Regenerative Medicine Researchvolume 2, Article number: 7 (2014)
Chronic lung diseases are becoming a leading cause of death worldwide. There are few effective treatments for those patients and less choices to prevent the exacerbation or even reverse the progress of the diseases. Over the past decade, cell-based therapies using stem cells to regenerate lung tissue have experienced a rapid growth in a variety of animal models for distinct lung diseases. This novel approach offers great promise for the treatment of several devastating and incurable lung diseases, including emphysema, idiopathic pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. In this review, we provide a concise summary of the current knowledge on the attributes of endogenous lung epithelial stem/progenitor cells (EpiSPCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) in both animal models and translational studies. We also describe the promise and challenges of tissue bioengineering in lung regenerative medicine. The therapeutic potential of MSCs is further discussed in IPF and chronic obstructive pulmonary diseases (COPD).
The lung disease has become one of the major public health issues across the world with the increased human activities, environmental changes, air pollution, smoking, and various pathogens like influenza. The World Health Organization ranks lung diseases second in epidemiology, mortality and cost and predicts that about one fifth deaths will be attributed to lung diseases by 2020 . Currently, there are no therapeutic ways to inhibit or reverse the pathobiology of many destructive lung diseases. These include chronic obstructive pulmonary disease (COPD) which is the leading cause of death in pulmonary diseases worldwide, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, pulmonary hypertension (PH) and the acute respiratory distress syndrome (ARDS) . Lung transplantation becomes the only choice for many patients. However, many patients die in the waiting period due to the shortage of available donor lungs. Furthermore, the average of survival time post-transplantation for recipients is around 5–6 years . Long-term graft dysfunction and bronchiolitis obliterans syndrome (BOS) are still the major obstacles to be overcome post transplantation . Thus, new and innovative options are in urgent need for those patients.
Recent progresses in stem cell research allow investigators to study cell-based therapies in the treatment of lung diseases. Stem cells are a population of undifferentiated cells characterized by three main functions: 1) ability to divide asymmetrically (called self-renew); 2) clonality generally arising from a single cell; and 3) potency to differentiate into different type of cells or tissues . Pluripotent stem cells have the ability to generate all lineages of body and include embryonic stem (ES) cells and induced pluripotent stem (iPS) cells . ES cells are first derived from the inner cell mass at the blastocyst-stage embryo. A good example of iPS is the Yamanaka experiment in which mouse and human fibroblasts were transfected with four transcription factors (OCT3/4, SOX2, c-MYC, KLF4) to reprogram the somatic cells into iPS . Lung stem cell research slightly lags behind studies on other organs. There is relatively limited knowledge about the endogenous progenitor cells of human lung tissue until recently. Moodley and colleagues performed a xenograft implantation in which they injected human amnion epithelial cells parenterally into bleomycin-treated severe combined immunodeficiency (SCID) mice as pulmonary fibrosis model and demonstrated reduced inflammation and fibrosis . The injected cells also developed an alveolar epithelial phenotype with lamellar body formation and expression of surfactants A and D. More interesting, Kajstura and coworkers recently identified stem cells from adult human lung tissue using the stem cell antigen marker c-kit . After being administrated into an injured mouse lung, the cells demonstrated pluripotent capability of generating human bronchioles, alveoli, and pulmonary vessels within the damaged organ. Although some disputes exist on tissue-specific adult human lung stem cells in Kajstura study [10, 11], these evidences collectively suggest that isolated adult lung stem cells are potentially of great clinical importance for cell-based therapies in pulmonary diseases.
This review will briefly highlight the recent progresses on mouse lung stem cell research and its applications in some clinical trials for specific lung diseases such as IPF and COPD. We will mainly discuss the endogenous lung stem cells named as epithelial stem/progenitor cells (EpiSPCs) in different anatomic locations, mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs). In addition, we will briefly discuss novel bioengineering approaches to generate implantable lung tissues or organs ex vivo and in vivo. Stem cells from different origins may be repopulated into the decellularized or bioengineered scaffold to create new functional organs.
Lung stem cells: classification, origin, biomarkers, and function
Recent studies mainly in mice have identified several adult stem cell lines in distinct anatomic locations of lung [12–14]. There might be some equivocal terms to define each cell line. In general, these diverse cell lines can be called lung endogenous stem/progenitor cells. According to the ability to differentiate, all stem cells can be categorized into 5 groups: totipotent, pluripotent, multipotent, oligopotent and unipotent . Most lung endogenous stem/progenitor cells belong to multipotent or oligopotent cells. Alveolar epithelial cells (AECs) type II are unipotent since they only differentiate into type I cells . Here we will mainly focus on three extensively studied populations of lung adult stem/progenitor cells in terms of their origin, biomarkers, and function mainly restricted to animal models.
Epithelial stem/progenitor cells (EpiSPCs)
Region-specific endogenous EpiSPCs in the adult lung has been extensively reviewed recently [2, 14, 17, 18]. Briefly, different lineages of EpiSPCs reside in the proximal trachea, bronchi, bronchioles, and alveoli regions to maintain local epithelial homeostasis and repair. Basal cells in tracheobronchial region express transcription factors Trp63, cytokeratin Krt5, and surface receptor Ngfr . Two main types of secretary cells along the proximal-distal axis include the secretoglobin family 1A member 1-positive clara cells (Scgb1a1pos, also known as CCSP or CC10) and mucus/goblet cells Muc5ACpos and Muc5Bpos . Bronchioalveolar stem cells (BASCs) at the bronchioalveolar duct junction of terminal bronchioles, also termed double-positive cells, express CCSP and surfactant protein C . More recently, two independent groups utilized SFTPC-CreER system to track AEC type II and demonstrated that type II cells give rise to AEC type I [22, 23]. The α6β4 positive AECs express little or none of CC10 or pro-SPC. Barkauauskas and colleagues confirmed that SPCpos AECs type II self-renew and maintain differential potential over one year . PDGFRαpos lung stromal cells or lopofibroblasts may contribute to a stem cell niche of Type II cells to facilitate their growth and differentiation, suggesting that direct contact between AECs and mesenchymal cells or a paracrine effect is necessary to activate or initiate cell proliferation and differentiation. One study by McQualter and colleagues supports the idea in which they isolated EpiSPC expressing EpCAM, CD24, CD45, CD31, and Sca-1 from enzymatically digested adult mouse lung tissue [24, 25]. Either co-culture this population with EpCAMneg Sca-1Pos lung mesenchymal cells or directly adding soluble fibroblast growth factor (FGF)-10 and hepatocyte growth factor (HGF) promoted clonal proliferation and self-renewal.
Although there are many endogenous epithelial progenitor cell lineages in the adult lung, bone-marrow derived progenitor cells represent a distinct origin and have been shown to migrate to the airway epithelium and contribute to tissue repair in lung disease models. Wong and colleagues identified a bone-marrow-derived progenitor cells in mice and human that expressed CCSP and hematopoietic marker CD45 and mesenchymal origin (CD73, CD90, CD105) . CSSP+ cells expressed basal cell markers and surfactant protein A-D when cultured at the air-liquid interface ex vivo. These cells homed to injured airway in response to naphthalene-induced lung damage. Moreover, in the sex-mismatched bone marrow transplantation, Y chromosomes were found to be widespread in type II cells in female recipient lung . Taken together, these observations strongly suggest that except lung endogenous epithelial progenitor cells participating in repair, bone marrow-derived progenitor cells may also home to sites of injury and differentiate into epithelial phenotype.
Mesenchymal stem cells (MSCs)
MSCs was first isolated from bone marrow and described by Friedenst in 1968 as a plastic adherent fibrablast-like appearance and distinct from haematopoietic stem cells (HSCs) . Thereafter, MSCs has been isolated from many other tissues, including umbilical cord blood, placenta, adipose tissue, amniotic fluid, Wharton’s jelly [29, 30]. MSCs are multipotent and can differentiate into cells of various tissues like bone, cartilage, muscle, liver, and lung . There is no consistent cell surface markers to isolate MSCs from different tissues, though the Mesenchymal and Tissue Stem Cell International Committee has proposed minimal criteria to define human MSCs . Lineage tracing studies with gene fibroblast growth factor (FGF)-10 have disclosed that at least two distinct populations of MSCs residing at the trachea and branching tip of the epithelium along the airway differentiate into smooth muscle cells . Further studies demonstrated that MSCs can be enriched with cell surface markers CD45neg CD31neg EpCAMneg Sca-1pos and play an important role as the epithelial progenitor cell niche to support their proliferation and differentiation in vitro [24, 33]. More interesting, Chow et al. defines the lung MSCs in the conditional knock-out mice EC-SOD-/- under the control of ABCG2 promoter as multipotent vascular precursors and finds that lung MSCs differentiate into myofibroblast, endothelial and pericytes in vitro . Lama and colleagues successfully isolated MSCs from the bronchoalveolar lavage of adult human lung allografts . These MSCs express common messenchymal markers CD73, CD90, and CD105, but are absent of hematopoietic lineage markers CD14, CD34, and CD45. They are capable of differentiating into adipocytes, chondrocytes, and osteocytes. Although adult lung contains some lineages of MSCs, more studies focus on the BM-derived MSCs in human disease models. Gazdhar and colleagues recently isolated a population of human hepatocyte growth factor (HGF)-expressing stem cells at fibrotic area in usual interstitial pneumonia patients. These HGF-positive cells co-expressed MSC markers CD44, CD29, CD105, CD90 and CXCR4 indicating bone-marrow (BM) derived stem cell characteristic . In order to understand whether they have anti-fibrotic property, they instilled BM-MSCs transfected with HGF into rat lung 7 days after bleomycin treatment and observed an attenuated fibrosis. Although the exact mechanisms of how MSCs contribute to beneficial effects against diseases are not yet fully understood, a growing body of evidences supports a paracrine effect to repair injured cells. Human MSCs condition media facilitates wound repair in human type II cell lines A549 and primary human small airway epithelial cells in vitro by producing secretome containing proteins such as fibronectin, lumican, periostin, and IGFBP7 . Similar studies in cardiac fibrosis shows MSCs condition media inhibited cardiac fibroblast proliferation by up-regulated cell-cycle arresting genes such as elastin, myocardin, DNA-damage inducible transcripts [38, 39]. The above properties make MSCs an attractive therapeutical reagent to treat many chronic diseases in clinical trials as discussed later in this article.
Endothelial progenitor cells (EPCs)
Study on EPCs was first reported by Asahara and colleagues in 1997 by the discovery of HSCs capable of differentiation into an endothelial phenotype . EPCs can be recruited from bone marrow to injured lung tissue. Although the mechanisms are not fully understood, the released cytokines hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) may play a role in the recruitment of EPCs to sites of hypoxia from bone marrow . When EPCs migrated into hypoxic destinations, they have the capacity to differentiate into endothelial cells and generate new blood vessels . The phenotypic identification of EPCs is currently inconsistent because there is a lack of a unique combination of marker proteins to define EPCs. According to the Duda protocol, EPCs can be isolated by FACS through a population of CD31+/CD34bright/CD45dim/CD133+ . A general combination of shared markers for EPCs includes stem cell marker CD133 (also known as AC133), endothelial cell marker VEGFR2, as well as hematopoietic marker CD34 . Ribattihas et al. proposed a way to divide EPCs into two different subpopulations, early (CD34+ CD31+ CD14+) and late (CD31+ CD144+ CD146+ CD105+ CD45- CD14- CD115-) EPCs, with distinct cellular morphology, growth pattern and abilities to secrete angiogenic factors [45, 46]. Currently, it is still unable to discriminate BM or peripheral blood derived EPCs from lung resident EPCs. This may prevent us from further understanding the contribution of endogenous EPCs in lung vascular disease repair and regeneration.
Large numbers of animal and clinical studies have been performed to investigate the beneficial roles of EPCs in lung diseases. Animal studies have shown that BM-derived EPCs can home to site of ischemia, and newly formed vessels were detected at ischemic locations . For example, in animal models of monocrotaline (MCT)-induced pulmonary hypertension (PH), transplantation of BM-derived EPCs prevented PH and restored microvascular architecture and perfusion in rats and dogs [48, 49]. However delayed administration of EPCs at 3 weeks post MCT treatment partially prevented the increase in right ventricular systolic pressure compared to a shorter time point . When the endothelial nitric oxide synthase (eNOS) gene was transfected into EPCs as a vehicle, they found that eNOS gene therapy significantly reversed an established disease in this model. Acute lung injury (ALI) and end stage ARDS are among the most common causes of death in ICU. During the acute exudative stage, endothelial cells can be detached from the pulmonary vessels and thus appear in the peripheral blood circulation. EPCs transplantation represents an innovative treatment option for the de novo formation of blood vessels. Many clinical studies focused on quantification of peripheral EPCs and their correlations with disease outcomes. However, Suratt and colleagues first studied the capacity of EPCs to replenish lung cells indirectly by administration of allogeneic HSCs . They found that lung biopsies from female recipients contain male donor-derived epithelial and endothelial chimerism. Except these promising preclinical and clinical studies, several early phase clinical trials on EPCs transplantation were underway. One pilot trial by Wang and colleagues showed that transplantation of autologous EPCs into patients with idiopathic pulmonary arterial hypertension significantly improved 6-minute walk capacity and hemodynamic function without obvious adverse effects . More recently, a phase I clinical trial (ClinicalTrials.gov Identifier: NCT00469027) of transplantation of autologous EPCs transfected with eNOS gene to patients with severe pulmonary arterial hypertension was completed. Safety concern was not noticed during the trial and patients appeared well tolerated with the genetically engineered EPC . The complete results of the trial will be released soon. Although recent studies indicate that both circulating and lung residential EPCs facilitate tissue repair and regeneration, more knowledge on optimal cell preparation, storage, dosage, administration route and time is strongly needed for future clinical application. Finally, a comprehensive assessment of EPCs can be referred to other reviews [13, 44, 52].
Tissue bioengineering is defined as the generation of functional tissue for replacement of injured or pathological tissue. Adult lung is architecturally complex as a hierarchical model of homoeostasis, and is made up of more than 40 distinct types of cells . It is impractical to directly build a functional whole lung organ with current knowledge and technology. However, it is still feasible to produce part of the upper, lower airway or the alveolar tissue. In fact, significant progress has recently been achieved using decellularized or synthetic scaffolds to generate tracheal cartilage as well as tendon tissue in diaphragm for clinical application [54, 55]. Epithelial cells and MSC-derived chondrocytes were implanted to the decellularized donor trachea and restored the trachea function in the recipient . The generation of lower airway and alveolar tissues is more challenging and restricted to animal studies presently. Seeding somatic lung progenitor cells onto synthetic polymer scaffold in vitro or implanted in vivo promoted cell differentiation . However, the in vivo transplantation caused an inflammatory response which disrupted lung development. A recent pioneer work by Peterson and colleagues demonstrated that a bioengineered lung achieved gas exchange upon reimplantation in rats in vivo . They first decellularized the rat lung with detergents to remove all immunogenic cells. Neonatal epithelial and vascular endothelial cells were seeded into the corresponding anatomic locations in the scaffold cultured in a bioreactor which contained suitable cell growth media. After cultured for several days, the engineered lungs were transplanted into syngeneic rat for 45–120 minutes and recorded gas exchange. Taken together, these preclinical studies indicate a bright future for bioengineered lung tissues in regenerative medicine. However, a number of key challenges still need to be resolved before initiating any clinical trial. These mainly include the optimal origin of progenitor stem cells (EpiSPCs, MSCs, EPCs, and/or other origins), extracellular matrix components, potential immunogenicity, ideal in vitro culture condition, and other implantation-related dosage, order, route, function monitoring system [59, 60].
Lung diseases with cell-based therapies
Idiopathic pulmonary fibrosis (IPF) is a fatal form of pulmonary fibrosis disease characterized by extracellular matrix deposition and scar tissue formation in the interstitial lungs over time. The incidence of IPF is 13 to 20 cases per 100,000 people . Typically the disease is found in old adults and the median survival time is 3–5 years. The clinical presentation includes exertional dyspnea, cough, functional and exercise limitation, impaired quality of life and risk for acute respiratory failure and death. Unfortunately, there is no FDA approved treatment or cure for IPF patients. Pirfenidone is an approved anti-fibrotic and anti-inflammatory drug in Europe and Japan, but still in clinical trials in North America [62, 63]. Although the etiology and pathogenesis of IPF is not fully understood, the accumulation of activated myofibroblasts is thought to be the source of interstitial collagens. There are at least four proposed cellular origins of myofibroblasts including expansion of lung residential fibroblasts, pericytes, recruitment of BM-derived fibrocytes, and alveolar epithelial cells undergoing epithelial-mesenchymal transition (EMT) [64, 65]. The circulating fibrocytes have been proposed as a clinical marker to assess disease progress .
Recently, stem cell therapy has emerged as a critical treatment for many chronic lung diseases. Murine bleomycin model is one of the best characterized animal models for human IPF disease. With this model, several groups have shown that administration of allogeneic BM-MSCs reduced inflammation and collagen deposition [67–69]. Other source of stem cells from placenta and human umbilical cord also demonstrated reduced lung tissue damage in the mouse bleomycin models [70, 71]. More interesting, HSCs and MSCs have been genetically manipulated as vehicles to deliver keratinocyte growth factor (KGF) into the lung injured sites. HSCs provided better protection from bleomycin-induced injury and promoted endogenous type II AECs proliferation while MSCs delivery just reduced collagen 1α1 mRNA . These preclinical studies in animal models strongly suggest that MSCs may be effective to treat human IPF. Furthermore, allogeneic MSCs was safe and well tolerated to treat refractory lupus erythematosus in a recent clinical trial . Considering the potential beneficial role of MSCs in pre-clinical models, a few clinical trials on IPF patients have been approved. One recently completed Phase 1b trial by Tzouvelekis and colleagues that was aimed to determine the safety of endobronchial administration of autologous adipose derived stromal cells-stromal vascular fraction to IPF patients with mild to moderate severity demonstrates an acceptable safety profile . The treatment efficacy will be evaluated in a future trial within a large population of patients. In addition, FDA has approved another clinical trial phase I study of autologous MSCs to treat IPF patients (initiated in March 2013, ClinicalTrials.gov Identifier: NCT01919827). This pilot trial will evaluate the safety and feasibility of the endobronchial administration of autologous BM-MSCs in patients with mild to moderate IPF. This historical step illuminates the great potentiality of cell-based therapy in respiratory regenerative medicine. On the other hand, two separate groups found that MSCs may play a role in the fibrogenic process of the lung. Antoniou and colleagues reported an increased expression of the axis stromal-cell-derived factor-1 (SDF-1)/CXCR4 in BM-MSCs from IPF patients, suggesting the BM-MSCs may probably implicate in the pathogenesis of IPF by recruiting MSCs to lung injury sites . Walker and colleagues recently found that allografted-derived local MSCs contain a profibrotic phenotype by up-regulation of FOXF1, α-SMA, and collagen I in human lung transplant recipients with BOS . Overall, further studies are still necessary to completely understand the exact role of MSCs in the pathophysiology of IPF.
COPD is becoming a major devastating disease worldwide. It is characterized by progressive poor airflow caused by chronic small airway inflammation (known as chronic bronchitis) and destruction of lung tissue (known as emphysema). Cigarette smoke is the major risk factor to induce the chronic inflammation and finally destructs bronchial and alveolar epithelial cells . Repairing the destroyed lung structure with stem cell therapies becomes an extremely attractive choice to treat COPD. MSC is the most extensively studied candidates in clinical trials not only for COPD, but also for other chronic diseases [78–80]. One recently completed placebo-controlled, randomized trial in 62 patients concluded that systemic administration of MSCs was safe in moderate to severe COPD patients . However, they did not observe significant improvement in lung function or quality of life within the 2-year follow-up period after MSCs treatment, except reduced level of C-reactive protein. Further studies with MSCs or other populations of lung endogenous stem cells in more patients are needed to evaluate in depth the efficacy and safety of cell therapies in COPD patients.
Stem cell therapy appears to be a promising strategy to attenuate or even reverse chronic lung diseases. Over the past decade, numerous preclinical studies have demonstrated the capability of EpiSPCs, MSCs, and EPCs from adult lung to facilitate tissue repair and regeneration in a number of pulmonary disease models. Many completed or ongoing clinical trials have supported their safety in the treatment of lung diseases. Another rapid growing field of lung bioengineering offers further promise in lung regenerative medicine. However, there are more unanswered questions in this field than what we currently know. For example, how to achieve stem cell stable growth and differentiation in vitro and in vivo? Can we completely ignore the immune rejection? What about the long-term possibility of tumorigenesis? Overall, stem cell therapy in lung regenerative medicine is still in its infancy and many challenges remain scientists to explore.
Alveolar epithelial cells
Acute respiratory distress syndrome
Bronchioalveolar stem cells
Bronchiolitis obliterans syndrome
cystic fibrosis transmembrane conductance regulator protein
Chronic obstructive pulmonary disease
endothelial nitric oxide synthase
Endothelial progenitor cells
Epithelial stem/progenitor cell
Embryo stem cells
Fibroblast growth factor
Hepatocyte growth factor
Hypoxia inducible factor
Haematopoietic stem cells
Idiopathic pulmonary fibrosis
induced pluripotent stem cells
Models of monocrotaline
Mesenchymal stem cells
Severe combined immunodeficiency
Vascular endothelial growth factor.
Siniscalco D, Sullo N, Maione S, Rossi F, D’Agostino B: Stem cell therapy: the great promise in lung disease. Ther Adv Respir Dis 2008, 2: 173–177. 10.1177/1753465808092340
Sueblinvong V, Weiss DJ: Stem cells and cell therapy approaches in lung biology and diseases. Transl Res 2010, 156: 188–205. 10.1016/j.trsl.2010.06.007
Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI: The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Lung and Heart-Lung Transplant Report–2011. J Heart Lung Transplant 2011, 30: 1104–1122. 10.1016/j.healun.2011.08.004
Weber DJ, Wilkes DS: The role of autoimmunity in obliterative bronchiolitis after lung transplantation. Am J Physiol Lung Cell Mol Physiol 2013, 304: L307-L311. 10.1152/ajplung.00378.2012
Kolios G, Moodley Y: Introduction to stem cells and regenerative medicine. Respiration 2013, 85: 3–10. 10.1159/000345615
Evans MJ, Kaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature 1981, 292: 154–156. 10.1038/292154a0
Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126: 663–676. 10.1016/j.cell.2006.07.024
Moodley Y, Ilancheran S, Samuel C, Vaghjiani V, Atienza D, Williams ED, Jenkin G, Wallace E, Trounson A, Manuelpillai U: Human amnion epithelial cell transplantation abrogates lung fibrosis and augments repair. Am J Respir Crit Care Med 2010, 182: 643–651. 10.1164/rccm.201001-0014OC
Kajstura J, Rota M, Hall SR, Hosoda T, D’Amario D, Sanada F, Zheng H, Ogorek B, Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G, Haley KJ, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella MA, Loscalzo J, Anversa P: Evidence for human lung stem cells. N Engl J Med 2011, 364: 1795–1806. 10.1056/NEJMoa1101324
Anversa P, Kajstura J, Leri A, Loscalzo J: Tissue-specific adult stem cells in the human lung. Nat Med 2011, 17: 1038–1039. 10.1038/nm.2463
Lung stem cells: Looking beyond the hype. Nat Med 2011, 17: 788–789.
Hoffman AM, Ingenito EP: Alveolar epithelial stem and progenitor cells: emerging evidence for their role in lung regeneration. Curr Med Chem 2012, 19: 6003–6008. 10.2174/092986712804485872
Anversa P, Perrella MA, Kourembanas S, Choi AM, Loscalzo J: Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest 2012, 42: 900–913. 10.1111/j.1365-2362.2012.02667.x
Wansleeben C, Barkauskas CE, Rock JR, Hogan BL: Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease. Wiley Interdiscip Rev Dev Biol 2013, 2: 131–148. 10.1002/wdev.58
Austin S: A glossary for stem-cell biology. Nature 2006, 441: 1060. 10.1038/nature04954
Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BL: Type 2 alveolar cells are stem cells in adult lung. J Clin Investig 2013, 123: 3025–3036. 10.1172/JCI68782
Rock JR, Hogan BL: Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol 2011, 27: 493–512. 10.1146/annurev-cellbio-100109-104040
Garcia O, Carraro G, Navarro S, Bertoncello I, McQualter J, Driscoll B, Jesudason E, Warburton D: Cell-based therapies for lung disease. Br Med Bull 2012, 101: 147–161. 10.1093/bmb/ldr051
Rock JR, Onaitis MW, Rawlins EL, Lu Y, Clark CP, Xue Y, Randell SH, Hogan BL: Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A 2009, 106: 12771–12775. 10.1073/pnas.0906850106
Roy MG, Rahmani M, Hernandez JR, Alexander SN, Ehre C, Ho SB, Evans CM: Mucin production during prenatal and postnatal murine lung development. Am J Respir Cell Mol Biol 2011, 44: 755–760. 10.1165/rcmb.2010-0020RC
Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T: Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005, 121: 823–835. 10.1016/j.cell.2005.03.032
Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL: Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 2011, 108: E1475-E1483. 10.1073/pnas.1117988108
Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH: Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Investig 2011, 121: 2855–2862. 10.1172/JCI57673
McQualter JL, Yuen K, Williams B, Bertoncello I: Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung. Proc Natl Acad Sci U S A 2010, 107: 1414–1419. 10.1073/pnas.0909207107
Bertoncello I, McQualter J: Isolation and clonal assay of adult lung epithelial stem/progenitor cells. Curr Protoc Stem Cell Biol 2011, 16: 2G.1.1–2G.1.12.
Wong AP, Keating A, Lu WY, Duchesneau P, Wang X, Sacher A, Hu J, Waddell TK: Identification of a bone marrow-derived epithelial-like population capable of repopulating injured mouse airway epithelium. J Clin Investig 2009, 119: 336–348.
Albera C, Polak JM, Janes S, Griffiths MJ, Alison MR, Wright NA, Navaratnarasah S, Poulsom R, Jeffery R, Fisher C, Burke M, Bishop AE: Repopulation of human pulmonary epithelium by bone marrow cells: a potential means to promote repair. Tissue Eng 2005, 11: 1115–1121. 10.1089/ten.2005.11.1115
Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP: Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968, 6: 230–247. 10.1097/00007890-196803000-00009
Bieback K, Kern S, Kluter H, Eichler H: Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004, 22: 625–634. 10.1634/stemcells.22-4-625
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA: Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006, 24: 2582–2591. 10.1634/stemcells.2006-0228
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8: 315–317. 10.1080/14653240600855905
Mailleux AA, Kelly R, Veltmaat JM, De Langhe SP, Zaffran S, Thiery JP, Bellusci S: Fgf10 expression identifies parabronchial smooth muscle cell progenitors and is required for their entry into the smooth muscle cell lineage. Development 2005, 132: 2157–2166. 10.1242/dev.01795
Hegab AE, Kubo H, Fujino N, Suzuki T, He M, Kato H, Yamaya M: Isolation and characterization of murine multipotent lung stem cells. Stem Cells Dev 2010, 19: 523–536. 10.1089/scd.2009.0287
Chow K, Fessel JP, Kaoriihida S, Schmidt EP, Gaskill C, Alvarez D, Graham B, Harrison DG, Wagner DH Jr, Nozik-Grayck E, West JD, Klemm DJ, Majka SM: Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling. Pulm Circ 2013, 3: 31–49. 10.4103/2045-8932.109912
Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M, Pinsky DJ, Martinez FJ, Thannickal VJ: Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007, 117: 989–996. 10.1172/JCI29713
Gazdhar A, Susuri N, Hostettler K, Gugger M, Knudsen L, Roth M, Ochs M, Geiser T: HGF Expressing Stem Cells in Usual Interstitial Pneumonia Originate from the Bone Marrow and Are Antifibrotic. PLoS One 2013, 8: e65453. 10.1371/journal.pone.0065453
Akram KM, Samad S, Spiteri MA, Forsyth NR: Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. Respir Res 2013, 14: 9. 10.1186/1465-9921-14-9
Li L, Zhang S, Zhang Y, Yu B, Xu Y, Guan Z: Paracrine action mediate the antifibrotic effect of transplanted mesenchymal stem cells in a rat model of global heart failure. Mol Biol Rep 2009, 36: 725–731. 10.1007/s11033-008-9235-2
Ohnishi S, Sumiyoshi H, Kitamura S, Nagaya N: Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. FEBS Lett 2007, 581: 3961–3966. 10.1016/j.febslet.2007.07.028
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM: Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997, 275: 964–967. 10.1126/science.275.5302.964
Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G: HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008, 13: 206–220. 10.1016/j.ccr.2008.01.034
Hristov M, Erl W, Weber PC: Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 2003, 23: 1185–1189. 10.1161/01.ATV.0000073832.49290.B5
Duda DG, Cohen KS, Scadden DT, Jain RK: A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood. Nat Protoc 2007, 2: 805–810. 10.1038/nprot.2007.111
Resch T, Pircher A, Kahler CM, Pratschke J, Hilbe W: Endothelial progenitor cells: current issues on characterization and challenging clinical applications. Stem Cell Rev 2012, 8: 926–939. 10.1007/s12015-011-9332-9
Ribatti D: The discovery of endothelial progenitor cells. An historical review, Leuk Res 2007, 31: 439–444.
Ardhanareeswaran K, Mirotsou M: Lung stem and progenitor cells. Respiration 2013, 85: 89–95. 10.1159/000346500
Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T: Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000, 97: 3422–3427. 10.1073/pnas.97.7.3422
Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ: Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005, 96: 442–450. 10.1161/01.RES.0000157672.70560.7b
Takahashi M, Nakamura T, Toba T, Kajiwara N, Kato H, Shimizu Y: Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng 2004, 10: 771–779. 10.1089/1076327041348563
Suratt BT, Cool CD, Serls AE, Chen L, Varella-Garcia M, Shpall EJ, Brown KK, Worthen GS: Human pulmonary chimerism after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003, 168: 318–322. 10.1164/rccm.200301-145OC
Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, Chen JZ: Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007, 49: 1566–1571. 10.1016/j.jacc.2006.12.037
Rafat N, Tonshoff B, Bierhaus A, Beck GC: Endothelial progenitor cells in regeneration after acute lung injury: do they play a role? Am J Respir Cell Mol Biol 2013, 48: 399–405. 10.1165/rcmb.2011-0132TR
McQualter JL, Bertoncello I: Concise review: Deconstructing the lung to reveal its regenerative potential. Stem Cells 2012, 30: 811–816. 10.1002/stem.1055
Fishman JM, De Coppi P, Elliott MJ, Atala A, Birchall MA, Macchiarini P: Airway tissue engineering. Expert Opin Biol Ther 2011, 11: 1623–1635. 10.1517/14712598.2011.623696
Badylak SF, Weiss DJ, Caplan A, Macchiarini P: Engineered whole organs and complex tissues. Lancet 2012, 379: 943–952. 10.1016/S0140-6736(12)60073-7
Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S, Conconi MT, Birchall MA: Clinical transplantation of a tissue-engineered airway. Lancet 2008, 372: 2023–2030. 10.1016/S0140-6736(08)61598-6
Cortiella J, Nichols JE, Kojima K, Bonassar LJ, Dargon P, Roy AK, Vacant MP, Niles JA, Vacanti CA: Tissue-engineered lung: an in vivo and in vitro comparison of polyglycolic acid and pluronic F-127 hydrogel/somatic lung progenitor cell constructs to support tissue growth. Tissue Eng 2006, 12: 1213–1225. 10.1089/ten.2006.12.1213
Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE: Tissue-engineered lungs for in vivo implantation. Science 2010, 329: 538–541. 10.1126/science.1189345
Weiss DJ: Current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells 2014,32(1):16–25. 10.1002/stem.1506
Nichols JE, Niles JA, Cortiella J: Production and utilization of acellular lung scaffolds in tissue engineering. J Cell Biochem 2012, 113: 2185–2192. 10.1002/jcb.24112
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G: Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006, 174: 810–816. 10.1164/rccm.200602-163OC
Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T: Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010, 35: 821–829.
Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM: Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011, 377: 1760–1769. 10.1016/S0140-6736(11)60405-4
Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA, Gharib SA, Schnapp LM, Duffield JS: Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2013, 188: 820–830. 10.1164/rccm.201212-2297OC
Yang J, Wheeler SE, Velikoff M, Kleaveland KR, Lafemina MJ, Frank JA, Chapman HA, Christensen PJ, Kim KK: Activated Alveolar Epithelial Cells Initiate Fibrosis through Secretion of Mesenchymal Proteins. Am J Pathol 2013, 183: 1559–1570. 10.1016/j.ajpath.2013.07.016
Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, O’Byrne PM, Strieter RM, Kolb M: Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009, 179: 588–594. 10.1164/rccm.200810-1534OC
Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 2003, 100: 8407–8411. 10.1073/pnas.1432929100
Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104: 11002–11007. 10.1073/pnas.0704421104
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005, 33: 145–152. 10.1165/rcmb.2004-0330OC
Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, Lombardi G, Albertini A, Wengler GS, Parolini O: Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 2009, 18: 405–422. 10.3727/096368909788809857
Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A: Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol 2009, 175: 303–313. 10.2353/ajpath.2009.080629
Aguilar S, Scotton CJ, McNulty K, Nye E, Stamp G, Laurent G, Bonnet D, Janes SM: Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis. PLoS One 2009, 4: e8013. 10.1371/journal.pone.0008013
Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L: Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010, 69: 1423–1429. 10.1136/ard.2009.123463
Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E, Oikonomou A, Zissimopoulos A, Boussios N, Dardzinski B, Gritzalis D, Antoniadis A, Froudarakis M, Kolios G, Bouros D: A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med 2013, 11: 171. 10.1186/1479-5876-11-171
Antoniou KM, Papadaki HA, Soufla G, Kastrinaki MC, Damianaki A, Koutala H, Spandidos DA, Siafakas NM: Investigation of bone marrow mesenchymal stem cells (BM MSCs) involvement in Idiopathic Pulmonary Fibrosis (IPF). Respir Med 2010, 104: 1535–1542. 10.1016/j.rmed.2010.04.015
Walker N, Badri L, Wettlaufer S, Flint A, Sajjan U, Krebsbach PH, Keshamouni VG, Peters-Golden M, Lama VN: Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts. Am J Pathol 2011, 178: 2461–2469. 10.1016/j.ajpath.2011.01.058
Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC: Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001, 164: 469–473. 10.1164/ajrccm.164.3.2007149
Elnakish MT, Kuppusamy P, Khan M: Stem cell transplantation as a therapy for cardiac fibrosis. J Pathol 2013, 229: 347–354. 10.1002/path.4111
Le Blanc K, Fibbe W: A new cell therapy registry coordinated by the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2008, 41: 319. 10.1038/sj.bmt.1705920
D’Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F: Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther 2010, 10: 681–687. 10.1517/14712591003610614
Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP: A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest 2013, 143: 1590–1598. 10.1378/chest.12-2094
This work was supported by grants from National Center for Complementary and Alternative Medicine in the National Institutes of Health (1R15AT005372).
The authors declare that they have no competing interests.
JY and ZJ drafted the manuscript. JY and ZJ revised the manuscript and both contributed equally for writing this review article. Both authors read and approved the final manuscript.
About this article
- Lung regenerative medicine
- Stem cells
- Lung injury
- Lung epithelial stem/progenitor cells
- Mesenchymal stem cells
- Endothelial progenitor cells