Advertisement

Lung regeneration and translational implications of the postpneumonectomy model

  • Kristen Thane
    Affiliations
    Department of Clinical Sciences, Regenerative Medicine Laboratory, Tufts University Cummings School of Veterinary Medicine, North Grafton, Mass
    Search for articles by this author
  • Edward P. Ingenito
    Affiliations
    Division of Pulmonary, Critical Care, and Sleep Medicine, Brigham and Women's Hospital, Boston, Mass
    Search for articles by this author
  • Andrew M. Hoffman
    Correspondence
    Reprint requests: Andrew M. Hoffman, DVM, DVSc, Regenerative Medicine Laboratory, Bldg 21, Rm 102, Department of Clinical Sciences, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536
    Affiliations
    Department of Clinical Sciences, Regenerative Medicine Laboratory, Tufts University Cummings School of Veterinary Medicine, North Grafton, Mass
    Search for articles by this author
Published:November 25, 2013DOI:https://doi.org/10.1016/j.trsl.2013.11.010
      Lung regeneration research is yielding data with increasing translational value. The classical models of lung development, postnatal alveolarization, and postpneumonectomy alveolarization have contributed to a broader understanding of the cellular participants including stem-progenitor cells, cell-cell signaling pathways, and the roles of mechanical deformation and other physiologic factors that have the potential to be modulated in human and animal patients. Although recent information is available describing the lineage fate of lung fibroblasts, genetic fate mapping, and clonal studies are lacking in the study of lung regeneration and deserve further examination. In addition to increasing knowledge concerning classical alveolarization (postnatal, postpneumonectomy), there is increasing evidence for remodeling of the adult lung after partial pneumonectomy. Though limited in scope, compelling data have emerged describing restoration of lung tissue mass in the adult human and in large animal models. The basis for this long-term adaptation to pneumonectomy is poorly understood, but investigations into mechanisms of lung regeneration in older animals that have lost their capacity for rapid re-alveolarization are warranted, as there would be great translational value in modulating these mechanisms. In addition, quantitative morphometric analysis has progressed in conjunction with developments in advanced imaging, which allow for longitudinal and nonterminal evaluation of pulmonary regenerative responses in animals and humans. This review focuses on the cellular and molecular events that have been observed in animals and humans after pneumonectomy because this model is closest to classical regeneration in other mammalian systems and has revealed several new fronts of translational research that deserve consideration.

      Abbreviations:

      AECII (alveolar epithelial type II cells), BASCs (bronchoalveolar stem cells), BrdU (bromodeoxyuridine), EGFR (epidermal growth factor receptor), EGR-1 (early growth response protein 1), EpCAM (epithelial cell adhesion molecule), FGFR (fibroblast growth factor receptor), HGF (hepatocyte growth factor), IGF-1 (insulin-like growth factor 1), KGF (keratinocyte growth factor), LR-MSCs (lung-resident mesenchymal stromal cells), PCEC (pulmonary capillary endothelial cells), PDGF (platelet-derived growth factor), PDGFR (platelet-derived growth factor receptor), proSP-C (prosurfactant protein C), Sca-1 (stem cell antigen 1), VEGF (vascular endothelial growth factor)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kawasumi A.
        • Sagawa N.
        • Hayashi S.
        • Yokoyama H.
        • Tamura K.
        Wound healing in mammals and amphibians: toward limb regeneration in mammals.
        Curr Top Microbiol Immunol. 2013; 367: 33-49
        • Voss G.J.
        • Kump D.K.
        • Walker J.A.
        • Voss S.R.
        Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.
        PLoS One. 2013; 8: e67274
        • Li C.
        Histogenetic aspects of deer antler development.
        Front Biosci (Elite Ed). 2013; 5: 479-489
        • Wu Y.
        • Wang K.
        • Karapetyan A.
        • et al.
        Connective tissue fibroblast properties are position-dependent during mouse digit tip regeneration.
        PLoS One. 2013; 8: e54764
        • Duncan A.W.
        • Soto-Gutierrez A.
        Liver repopulation and regeneration: new approaches to old questions.
        Curr Opin Organ Transplant. 2013; 18: 197-202
        • Franquesa M.
        • Flaquer M.
        • Cruzado J.M.
        • Grinyo J.M.
        Kidney regeneration and repair after transplantation.
        Curr Opin Organ Transplant. 2013; 18: 191-196
        • Cagle P.T.
        • Thurlbeck W.M.
        Postpneumonectomy compensatory lung growth.
        Am Rev Respir Dis. 1988; 138: 1314-1326
        • Brown L.M.
        • Rannels S.R.
        • Rannels D.E.
        Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease.
        Respir Res. 2001; 2: 340-347
        • Rawlins E.L.
        • Perl A.K.
        The a“MAZE”ing world of lung-specific transgenic mice.
        Am J Respir Cell Mol Biol. 2012; 46: 269-282
        • Chen L.
        • Acciani T.
        • Le Cras T.
        • Lutzko C.
        • Perl A.K.
        Dynamic regulation of platelet-derived growth factor receptor alpha expression in alveolar fibroblasts during realveolarization.
        Am J Respir Cell Mol Biol. 2012; 47: 517-527
        • Kumar P.A.
        • Hu Y.
        • Yamamoto Y.
        • et al.
        Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection.
        Cell. 2011; 147: 525-538
        • Chapman H.A.
        • Li X.
        • Alexander J.P.
        • et al.
        Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice.
        J Clin Invest. 2011; 121: 2855-2862
        • Massaro D.
        • Massaro G.D.
        • Baras A.
        • Hoffman E.P.
        • Clerch L.B.
        Calorie-related rapid onset of alveolar loss, regeneration, and changes in mouse lung gene expression.
        Am J Physiol Lung Cell Mol Physiol. 2004; 286: L896-L906
        • Mouded M.
        • Egea E.E.
        • Brown M.J.
        • et al.
        Epithelial cell apoptosis causes acute lung injury masquerading as emphysema.
        Am J Respir Cell Mol Biol. 2009; 41: 407-414
        • Maden M.
        • Hind M.
        Retinoic acid in alveolar development, maintenance and regeneration.
        Philos Trans R Soc Lond B Biol Sci. 2004; 359: 799-808
        • Hind M.
        • Maden M.
        Retinoic acid induces alveolar regeneration in the adult mouse lung.
        Eur Respir J. 2004; 23: 20-27
        • Hoffman A.M.
        • Shifren A.
        • Mazan M.R.
        • et al.
        Matrix modulation of compensatory lung regrowth and progenitor cell proliferation in mice.
        Am J Physiol Lung Cell Mol Physiol. 2010; 298: L158-L168
        • Hoffman A.M.
        • Paxson J.A.
        • Mazan M.R.
        • et al.
        Lung derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase injured lung.
        Stem Cells Dev. 2011; 20: 1779-1792
        • Wagner D.E.
        • Bonvillain R.W.
        • Jensen T.
        • et al.
        Can stem cells be used to generate new lungs? Ex vivo lung bioengineering with decellularized whole lung scaffolds.
        Respirology. 2013; 18: 895-911
        • Weiss D.J.
        Stem cells, cell therapies and bioengineering in lung biology and diseases: comprehensive review of the recent literature 2010–2012.
        Ann Am Thorac Soc. 2013; 10: S45-S97
        • Brody J.S.
        Time course of and stimuli to compensatory growth of the lung after pneumonectomy.
        J Clin Invest. 1975; 56: 897-904
        • Rannels D.E.
        • Rannels S.R.
        Compensatory growth of the lung following partial pneumonectomy.
        Exp Lung Res. 1988; 14: 157-182
        • Hsia C.C.
        Lessons from a canine model of compensatory lung growth.
        Curr Top Dev Biol. 2004; 64: 17-32
        • Hsia C.C.
        • Wu E.Y.
        • Wagner E.
        • Weibel E.R.
        Preventing mediastinal shift after pneumonectomy impairs regenerative alveolar tissue growth.
        Am J Physiol Lung Cell Mol Physiol. 2001; 281: L1279-L1287
        • Brody J.S.
        • Burki R.
        • Kaplan N.
        Deoxyribonucleic acid synthesis in lung cells during compensatory lung growth after pneumonectomy.
        Am Rev Respir Dis. 1978; 117: 307-316
        • Jackson S.R.
        • Williams G.N.
        • Lee J.
        • Baer J.F.
        • Warburton D.
        • Driscoll B.
        A modified technique for partial pneumonectomy in the mouse. J Invest Surg.
        . 2011; 24: 81-86
        • Sakurai M.K.
        • Greene A.K.
        • Wilson J.
        • Fauza D.
        • Puder M.
        Pneumonectomy in the mouse: technique and perioperative management.
        J Invest Surg. 2005; 18: 201-205
        • Chen F.
        • Fujinaga T.
        • Shoji T.
        • et al.
        Outcomes and pulmonary function in living lobar lung transplant donors.
        Transplant Int. 2012; 25: 153-157
        • Mizobuchi T.
        • Chen F.
        • Yoshino I.
        • et al.
        Radiologic evaluation for volume and weight of remnant lung in living lung donors.
        J Thorac Cardiovasc Surg. 2013; 146: 1253-1258
        • Butler J.P.
        • Loring S.H.
        • Patz S.
        • Tsuda A.
        • Yablonskiy D.A.
        • Mentzer S.J.
        Evidence for adult lung growth in humans.
        N Engl J Med. 2012; 367: 244-247
        • Deslauriers J.
        • Ugalde P.
        • Miro S.
        • et al.
        Long-term physiological consequences of pneumonectomy.
        Semin Thorac Cardiovasc Surg. 2011; 23: 196-202
        • Rudolph A.M.
        • Neuhauser E.B.
        • Golinko R.J.
        • Auld P.A.
        Effects of pneumonectomy on pulmonary circulation in adult and young animals.
        Circ Res. 1961; 9: 856-861
        • Gilbert K.A.
        • Rannels D.E.
        Increased lung inflation induces gene expression after pneumonectomy.
        Am J Physiol. 1998; 275: L21-L29
        • Landesberg L.J.
        • Ramalingam R.
        • Lee K.
        • Rosengart T.K.
        • Crystal R.G.
        Upregulation of transcription factors in lung in the early phase of postpneumonectomy lung growth.
        Am J Physiol Lung Cell Mol Physiol. 2001; 281: L1138-L1149
        • Zhang Q.
        • Moe O.W.
        • Garcia J.A.
        • Hsia C.C.
        Regulated expression of hypoxia-inducible factors during postnatal and postpneumonectomy lung growth.
        Am J Physiol Lung Cell Mol Physiol. 2006; 290: L880-L889
        • Li D.
        • Fernandez L.G.
        • Dodd-o J.
        • Langer J.
        • Wang D.
        • Laubach V.E.
        Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy.
        Am J Respir Cell Mol Biol. 2005; 32: 185-191
        • Shigemura N.
        • Sawa Y.
        • Mizuno S.
        • et al.
        Induction of compensatory lung growth in pulmonary emphysema improves surgical outcomes in rats.
        Am J Respir Crit Care Med. 2005; 171: 1237-1245
        • Sugahara K.
        • Matsumoto M.
        • Baba T.
        • Nakamura T.
        • Kawamoto T.
        Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during a perioperative period.
        Intensive Care Med. 1998; 24: 434-437
        • Ohmichi H.
        • Koshimizu U.
        • Matsumoto K.
        • Nakamura T.
        Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development.
        Development. 1998; 125: 1315-1324
        • Kaza A.K.
        • Kron I.L.
        • Leuwerke S.M.
        • Tribble C.G.
        • Laubach V.E.
        Keratinocyte growth factor enhances post-pneumonectomy lung growth by alveolar proliferation.
        Circulation. 2002; 106: I120-I124
        • Kaza A.K.
        • Kron I.L.
        • Long S.M.
        • et al.
        Epidermal growth factor receptor upregulation is associated with lung growth after lobectomy.
        Ann Thorac Surg. 2001; 72: 380-385
        • Kaza A.K.
        • Laubach V.E.
        • Kern J.A.
        • et al.
        Epidermal growth factor augments postpneumonectomy lung growth.
        J Thorac Cardiovasc Surg. 2000; 120: 916-921
        • Foster D.J.
        • Yan X.
        • Bellotto D.J.
        • et al.
        Expression of epidermal growth factor and surfactant proteins during postnatal and compensatory lung growth.
        Am J Physiol Lung Cell Mol Physiol. 2002; 283: L981-L990
      1. Mechanisms and limits of induced postnatal lung growth.
        Am J Respir Crit Care Med. 2004; 170: 319-343
        • Tajima A.
        • Kohno M.
        • Watanabe M.
        • et al.
        Occult injury in the residual lung after pneumonectomy in mice.
        Interact Cardiovasc Thorac Surg. 2008; 7: 1114-1120
        • Paxson J.A.
        • Parkin C.D.
        • Iyer L.K.
        • Mazan M.R.
        • Ingenito E.P.
        • Hoffman A.M.
        Global gene expression patterns in the post-pneumonectomy lung of adult mice.
        Respir Res. 2009; 10: 92
        • Gibney B.C.
        • Park M.A.
        • Chamoto K.
        • et al.
        Detection of murine post-pneumonectomy lung regeneration by 18FDG PET imaging.
        EJNMMI Res. 2012; 2: 48
        • Ravikumar P.
        • Yilmaz C.
        • Bellotto D.J.
        • Dane D.M.
        • Estrera A.S.
        • Hsia C.C.
        Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment.
        J Appl Physiol. 2013; 114: 961-970
        • Hsia C.C.W.
        Quantitative morphology of compensatory lung growth.
        Eur Respir Rev. 2006; 15: 148-156
        • Vasilescu D.M.
        • Klinge C.
        • Knudsen L.
        • et al.
        Stereological assessment of mouse lung parenchyma via nondestructive, multiscale micro-CT imaging validated by light microscopic histology.
        J Appl Physiol. 2013; 114: 716-724
        • Wang W.
        • Nguyen N.M.
        • Guo J.
        • Woods J.C.
        Longitudinal, noninvasive monitoring of compensatory lung growth in mice after pneumonectomy via He and H MRI.
        Am J Respir Cell Mol Biol. 2013; 49: 697-703
        • Gibney B.C.
        • Lee G.S.
        • Houdek J.P.
        • et al.
        Dynamic determination of oxygenation and lung compliance in murine pneumonectomy.
        Exp Lung Res. 2011; 37: 301-309
        • Carlin J.I.
        • Hsia C.C.
        • Cassidy S.S.
        • Ramanathan M.
        • Clifford P.S.
        • Johnson Jr., R.L.
        Recruitment of lung diffusing capacity with exercise before and after pneumonectomy in dogs.
        J Appl Physiol. 1991; 70: 135-142
        • Glaab T.
        • Daser A.
        • Braun A.
        • et al.
        Tidal midexpiratory flow as a measure of airway hyper-responsiveness in allergic mice.
        Am J Physiol Lung Cell Mol Physiol. 2001; 280: L565-L573
        • Glaab T.
        • Hoymann H.G.
        • Hohlfeld J.M.
        • et al.
        Noninvasive measurement of midexpiratory flow indicates bronchoconstriction in allergic rats.
        J Appl Physiol. 2002; 93: 1208-1214
        • Bolliger C.T.
        • Jordan P.
        • Soler M.
        • et al.
        Pulmonary function and exercise capacity after lung resection.
        Eur Respir J. 1996; 9: 415-421
        • Ilonen I.K.
        • Rasanen J.V.
        • Sihvo E.I.
        • et al.
        Pneumonectomy: postoperative quality of life and lung function.
        Lung Cancer. 2007; 58: 397-402
        • Konerding M.A.
        • Gibney B.C.
        • Houdek J.P.
        • et al.
        Spatial dependence of alveolar angiogenesis in post-pneumonectomy lung growth.
        Angiogenesis. 2012; 15: 23-32
        • Voswinckel R.
        • Motejl V.
        • Fehrenbach A.
        • et al.
        Characterisation of post-pneumonectomy lung growth in adult mice.
        Eur Respir J. 2004; 24: 524-532
        • Eisenhauer P.
        • Earle B.
        • Loi R.
        • et al.
        Endogenous distal airway progenitor cells, lung mechanics, and disproportionate lobar growth following long-term postpneumonectomy in mice.
        Stem Cells. 2013; 31: 1330-1339
        • Ysasi A.B.
        • Belle J.M.
        • Gibney B.C.
        • et al.
        Effect of unilateral diaphragmatic paralysis on post-pneumonectomy lung growth.
        Am J Physiol Lung Cell Mol Physiol. 2013; 305: L439-L445
        • Hsia C.C.
        • Zhou X.S.
        • Bellotto D.J.
        • Hagler H.K.
        Regenerative growth of respiratory bronchioles in dogs.
        Am J Physiol Lung Cell Mol Physiol. 2000; 279: L136-L142
        • Dane D.M.
        • Johnson Jr., R.L.
        • Hsia C.C.
        Dysanaptic growth of conducting airways after pneumonectomy assessed by CT scan.
        J Appl Physiol. 2002; 93: 1235-1242
        • Ravikumar P.
        • Yilmaz C.
        • Dane D.M.
        • Johnson Jr., R.L.
        • Estrera A.S.
        • Hsia C.C.
        Regional lung growth following pneumonectomy assessed by computed tomography.
        J Appl Physiol. 2004; 97 (discussion 49): 1567-1574
        • Holmes C.
        • Thurlbeck W.M.
        Normal lung growth and response after pneumonectomy in rats at various ages.
        Am Rev Respir Dis. 1979; 120: 1125-1136
        • Wada H.
        • Yoshida S.
        • Suzuki H.
        • et al.
        Transplantation of alveolar type II cells stimulates lung regeneration during compensatory lung growth in adult rats.
        J Thorac Cardiovasc Surg. 2012; 143: 711-719 e2
        • Cagle P.T.
        • Langston C.
        • Thurlbeck W.M.
        The effect of age on postpneumonectomy growth in rabbits.
        Pediatr Pulmonol. 1988; 5: 92-95
        • Langston C.
        • Sachdeva P.
        • Cowan M.J.
        • Haines J.
        • Crystal R.G.
        • Thurlbeck W.M.
        Alveolar multiplication in the contralateral lung after unilateral pneumonectomy in the rabbit.
        Am Rev Respir Dis. 1977; 115: 7-13
        • Paxson J.A.
        • Gruntman A.
        • Parkin C.D.
        • et al.
        Age-dependent decline in mouse lung regeneration with loss of lung fibroblast clonogenicity and increased myofibroblastic differentiation.
        PloS One. 2011; 6: e23232
        • Jackson S.R.
        • Lee J.
        • Reddy R.
        • et al.
        Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response.
        Am J Physiol Lung Cell Mol Physiol. 2011; 300: L898-L909
        • Davies P.
        • McBride J.
        • Murray G.F.
        • Wilcox B.R.
        • Shallal J.A.
        • Reid L.
        Structural changes in the canine lung and pulmonary arteries after pneumonectomy.
        J Appl Physiol. 1982; 53: 859-864
        • Tronc F.
        • Gregoire J.
        • Leblanc P.
        • Deslauriers J.
        Physiologic consequences of pneumonectomy. Consequences on the pulmonary function.
        Chest Surg Clin N Am. 1999; 9 (xii-xiii): 459-473
        • McBride J.T.
        • Kirchner K.K.
        • Russ G.
        • Finkelstein J.
        Role of pulmonary blood flow in postpneumonectomy lung growth.
        J Appl Physiol. 1992; 73: 2448-2451
        • Dane D.M.
        • Yilmaz C.
        • Estrera A.S.
        • Hsia C.C.
        Separating in vivo mechanical stimuli for postpneumonectomy compensation: physiological assessment.
        J Appl Physiol. 2013; 114: 99-106
        • Fernandez L.G.
        • Le Cras T.D.
        • Ruiz M.
        • Glover D.K.
        • Kron I.L.
        • Laubach V.E.
        Differential vascular growth in postpneumonectomy compensatory lung growth.
        J Thorac Cardiovasc Surg. 2007; 133: 309-316
        • Sekhon H.S.
        • Smith C.
        • Thurlbeck W.M.
        Effect of hypoxia and hyperoxia on postpneumonectomy compensatory lung growth.
        Exp Lung Res. 1993; 19: 519-532
        • Sekhon H.S.
        • Thurlbeck W.M.
        A comparative study of postpneumonectomy compensatory lung response in growing male and female rats.
        J Appl Physiol. 1992; 73: 446-451
        • Massaro G.D.
        • Mortola J.P.
        • Massaro D.
        Estrogen modulates the dimensions of the lung's gas-exchange surface area and alveoli in female rats.
        Am J Physiol. 1996; 270: L110-L114
        • Massaro D.
        • Massaro G.D.
        Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice.
        Am J Physiol Lung Cell Mol Physiol. 2004; 287: L1154-L1159
        • Faridy E.E.
        • Sanii M.R.
        • Thliveris J.A.
        Influence of maternal pneumonectomy on fetal lung growth.
        Respir Physiol. 1988; 72: 195-209
        • Nolen-Walston R.D.
        • Kim C.F.
        • Mazan M.R.
        • et al.
        Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration.
        Am J Physiol Lung Cell Mol Physiol. 2008; 294: L1158-L1165
        • Paxson J.A.
        • Gruntman A.M.
        • Davis A.M.
        • Parkin C.D.
        • Ingenito E.
        • Hoffman A.M.
        Age dependence of lung mesenchymal stromal cell dynamics following pneumonectomy.
        Stem Cells Develop. 2013; 22: 3214-3225
        • Chamoto K.
        • Gibney B.C.
        • Ackermann M.
        • et al.
        Alveolar epithelial dynamics in postpneumonectomy lung growth.
        Anat Rec (Hoboken). 2013; 296: 495-503
        • Chamoto K.
        • Gibney B.C.
        • Lee G.S.
        • et al.
        CD34+ Progenitor to Endothelial Cell Transition in Post-Pneumonectomy Angiogenesis.
        Am J Respir Cell Mol Biol. 2012; 46: 283-289
        • Lin M.
        • Chamoto K.
        • Gibney B.C.
        • et al.
        Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth.
        Respir Res. 2011; 12: 98
        • Voswinckel R.
        • Ziegelhoeffer T.
        • Heil M.
        • et al.
        Circulating vascular progenitor cells do not contribute to compensatory lung growth.
        Circ Res. 2003; 93: 372-379
        • Hoffman A.M.
        • Ingenito E.P.
        Alveolar epithelial stem and progenitor cells: emerging evidence for their role in lung regeneration.
        Curr Med Chem. 2012; 19: 6003-6008
        • Rock J.R.
        • Onaitis M.W.
        • Rawlins E.L.
        • et al.
        Basal cells as stem cells of the mouse trachea and human airway epithelium.
        Proc Natl Acad Sci U S A. 2009; 106: 12771-12775
        • Oeztuerk-Winder F.
        • Guinot A.
        • Ochalek A.
        • Ventura J.J.
        Regulation of human lung alveolar multipotent cells by a novel p38alpha MAPK/miR-17-92 axis.
        EMBO J. 2012; 31: 3431-3441
        • Kajstura J.
        • Rota M.
        • Hall S.R.
        • et al.
        Evidence for human lung stem cells.
        N Engl J Med. 2011; 364: 1795-1806
        • Chamoto K.
        • Gibney B.C.
        • Ackermann M.
        • et al.
        Alveolar macrophage dynamics in murine lung regeneration.
        J Cell Physiol. 2012; 227: 3208-3215
        • Chamoto K.
        • Gibney B.C.
        • Lee G.S.
        • et al.
        Migration of CD11b+ accessory cells during murine lung regeneration.
        Stem Cell Res. 2013; 10: 267-277
        • Sakurai M.K.
        • Lee S.
        • Arsenault D.A.
        • et al.
        Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy.
        Am J Physiol Lung Cell Mol Physiol. 2007; 292: L742-L747
        • Shannon J.M.
        Induction of alveolar type II cell differentiation in fetal tracheal epithelium by grafted distal lung mesenchyme.
        Dev Biol. 1994; 166: 600-614
        • Beers M.F.
        • Morrisey E.E.
        The three R's of lung health and disease: repair, remodeling, and regeneration.
        J Clin Invest. 2011; 121: 2065-2073
        • Perl A.K.
        • Gale E.
        FGF signaling is required for myofibroblast differentiation during alveolar regeneration.
        Am J Physiol Lung Cell Mol Physiol. 2009; 297: L299-L308
        • Ninomiya N.
        • Michiue T.
        • Asashima M.
        • Kurisaki A.
        BMP signaling regulates the differentiation of mouse embryonic stem cells into lung epithelial cell lineages.
        In Vitro Cell Dev Biol Anim. 2013; 49: 230-237
        • Park K.S.
        • Wells J.M.
        • Zorn A.M.
        • et al.
        Transdifferentiation of ciliated cells during repair of the respiratory epithelium.
        Am J Respir Cell Mol Biol. 2006; 34: 151-157
        • Takahashi Y.
        • Izumi Y.
        • Kohno M.
        • et al.
        Thyroid transcription factor-1 influences the early phase of compensatory lung growth in adult mice.
        Am J Respir Crit Care Med. 2010; 181: 1397-1406
        • Wolff J.C.
        • Wilhelm J.
        • Fink L.
        • Seeger W.
        • Voswinckel R.
        Comparative gene expression profiling of post-natal and post-pneumonectomy lung growth.
        Eur Respir J. 2010; 35: 655-666
        • Kho A.T.
        • Liu K.
        • Visner G.
        • Martin T.
        • Boudreault F.
        Identification of dedifferentiation and redevelopment phases during postpneumonectomy lung growth.
        Am J Physiol Lung Cell Mol Physiol. 2013; 305: L542-L554
        • McAnulty R.J.
        • Guerreiro D.
        • Cambrey A.D.
        • Laurent G.J.
        Growth factor activity in the lung during compensatory growth after pneumonectomy: evidence of a role for IGF-1.
        Eur Respir J. 1992; 5: 739-747
        • Nobuhara K.K.
        • DiFiore J.W.
        • Ibla J.C.
        • et al.
        Insulin-like growth factor-I gene expression in three models of accelerated lung growth.
        J Pediatr Surg. 1998; 33 (discussion 61): 1057-1060
        • Ricciardi M.
        • Malpeli G.
        • Bifari F.
        • et al.
        Comparison of epithelial differentiation and immune regulatory properties of mesenchymal stromal cells derived from human lung and bone marrow.
        PLoS One. 2012; 7: e35639
        • Ding B.S.
        • Nolan D.J.
        • Guo P.
        • et al.
        Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization.
        Cell. 2011; 147: 539-553
        • Sudo K.
        • Yamada Y.
        • Saito K.
        • et al.
        TNF-alpha and IL-6 signals from the bone marrow derived cells are necessary for normal murine liver regeneration.
        Biochim Biophys Acta. 2008; 1782: 671-679
        • Tiberio G.A.
        • Tiberio L.
        • Benetti A.
        • et al.
        IL-6 Promotes compensatory liver regeneration in cirrhotic rat after partial hepatectomy.
        Cytokine. 2008; 42: 372-378
        • Kaido T.
        • Oe H.
        • Imamura M.
        Interleukin-6 augments hepatocyte growth factor-induced liver regeneration; involvement of STAT3 activation.
        Hepatogastroenterology. 2004; 51: 1667-1670
        • Ingenito E.P.
        • Tsai L.
        • Murthy S.
        • Tyagi S.
        • Mazan M.
        • Hoffman A.
        Autologous lung-derived mesenchymal stem cell transplantation in experimental emphysema.
        Cell Transplant. 2012; 21: 175-189
        • Ingenito E.P.
        • Sen E.
        • Tsai L.W.
        • Murthy S.
        • Hoffman A.
        Design and testing of biological scaffolds for delivering reparative cells to target sites in the lung.
        J Tissue Eng Regen Med. 2010; 4: 259-272
        • Katsha A.M.
        • Ohkouchi S.
        • Xin H.
        • et al.
        Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model.
        Mol Ther. 2011; 19: 196-203
        • Shigemura N.
        • Sawa Y.
        • Mizuno S.
        • et al.
        Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats.
        Circulation. 2005; 111: 1407-1414
        • Sakamaki Y.
        • Matsumoto K.
        • Mizuno S.
        • Miyoshi S.
        • Matsuda H.
        • Nakamura T.
        Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice.
        Am J Respir Cell Mol Biol. 2002; 26: 525-533
        • Lama V.N.
        • Smith L.
        • Badri L.
        • et al.
        Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts.
        J Clin Invest. 2007; 117: 989-996
        • Badri L.
        • Walker N.M.
        • Ohtsuka T.
        • et al.
        Epithelial interactions and local engraftment of lung-resident mesenchymal stem cells.
        Am J Respir Cell Mol Biol. 2011; 45: 809-816
        • Sirianni F.E.
        • Chu F.S.
        • Walker D.C.
        Human alveolar wall fibroblasts directly link epithelial type 2 cells to capillary endothelium.
        Am J Respir Crit Care Med. 2003; 168: 1532-1537
        • Weibel E.R.
        It takes more than cells to make a good lung.
        Am J Respir Crit Care Med. 2013; 187: 342-346
        • Fehrenbach H.
        • Voswinckel R.
        • Michl V.
        • et al.
        Neoalveolarization contributes to compensatory lung growth following pneumonectomy in mice.
        Eur Respir J. 2008; 31: 515-522
        • Zhang Q.
        • Bellotto D.J.
        • Ravikumar P.
        • et al.
        Postpneumonectomy lung expansion elicits hypoxia-inducible factor-1alpha signaling.
        Am J Physiol Lung Cell Mol Physiol. 2007; 293: L497-L504
        • Leuwerke S.M.
        • Kaza A.K.
        • Tribble C.G.
        • Kron I.L.
        • Laubach V.E.
        Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice.
        Am J Physiol Lung Cell Mol Physiol. 2002; 282: L1272-L1278
        • Yuan S.
        • Hannam V.
        • Belcastro R.
        • et al.
        A role for platelet-derived growth factor-BB in rat postpneumonectomy compensatory lung growth.
        Pediatr Res. 2002; 52: 25-33
        • Panigrahy D.
        • Kalish B.T.
        • Huang S.
        • et al.
        Epoxyeicosanoids promote organ and tissue regeneration.
        Proc Natl Acad Sci U S A. 2013; 110: 13528-13533
        • Alvarez D.F.
        • Huang L.
        • King J.A.
        • ElZarrad M.K.
        • Yoder M.C.
        • Stevens T.
        Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity.
        Am J Physiol Lung Cell Mol Physiol. 2008; 294: L419-L430
        • Fehrenbach M.L.
        • Cao G.
        • Williams J.T.
        • Finklestein J.M.
        • Delisser H.M.
        Isolation of murine lung endothelial cells.
        Am J Physiol Lung Cell Mol Physiol. 2009; 296: L1096-L1103
        • Suga A.
        • Ueda K.
        • Takemoto Y.
        • et al.
        Significant role of bone marrow-derived cells in compensatory regenerative lung growth.
        J Surg Res. 2013; 183: 84-90
        • Peng T.
        • Tian Y.
        • Boogerd C.J.
        • et al.
        Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor.
        Nature. 2013; 500: 589-592
        • Calvi C.
        • Podowski M.
        • Lopez-Mercado A.
        • et al.
        Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung.
        PLoS Genet. 2013; 9: e1003228
        • Srisuma S.
        • Bhattacharya S.
        • Simon D.M.
        • et al.
        Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis.
        Am J Respir Crit Care Med. 2010; 181: 838-850
        • Barkauskas C.E.
        • Cronce M.J.
        • Rackley C.R.
        • et al.
        Type 2 alveolar cells are stem cells in adult lung.
        J Clin Invest. 2013; 123: 3025-3036
        • Kim C.F.
        • Jackson E.L.
        • Woolfenden A.E.
        • et al.
        Identification of bronchioalveolar stem cells in normal lung and lung cancer.
        Cell. 2005; 121: 823-835
        • Zheng D.
        • Limmon G.V.
        • Yin L.
        • et al.
        A cellular pathway involved in Clara cell to alveolar type II cell differentiation after severe lung Injury.
        PLoS One. 2013; 8: e71028
        • Xian W.
        • McKeon F.
        Adult stem cells underlying lung regeneration.
        Cell Cycle. 2012; 11: 887-894
        • Mounier R.
        • Theret M.
        • Arnold L.
        • et al.
        AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration.
        Cell Metab. 2013; 18: 251-264
        • Saclier M.
        • Yacoub-Youssef H.
        • Mackey A.L.
        • et al.
        Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration.
        Stem Cells. 2013; 31: 384-396
        • Arnold L.
        • Henry A.
        • Poron F.
        • et al.
        Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.
        J Exp Med. 2007; 204: 1057-1069
        • Godwin J.W.
        • Pinto A.R.
        • Rosenthal N.A.
        Macrophages are required for adult salamander limb regeneration.
        Proc Natl Acad Sci U S A. 2013; 110: 9415-9420
        • Lobov I.B.
        • Rao S.
        • Carroll T.J.
        • et al.
        WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature.
        Nature. 2005; 437: 417-421
        • Miron V.E.
        • Boyd A.
        • Zhao J.W.
        • et al.
        M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination.
        Nat Neurosci. 2013; 16: 1211-1218
        • Perdiguero E.
        • Kharraz Y.
        • Serrano A.L.
        • Munoz-Canoves P.
        MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair.
        Cell Cycle. 2012; 11: 877-886
        • Xiang S.
        • Dong H.H.
        • Liang H.F.
        • et al.
        Oval cell response is attenuated by depletion of liver resident macrophages in the 2-AAF/partial hepatectomy rat.
        PLoS One. 2012; 7: e35180
        • Duffield J.S.
        Macrophages in kidney repair and regeneration.
        J Am Soc Nephrol. 2011; 22: 199-201
        • Kharraz Y.
        • Guerra J.
        • Mann C.J.
        • Serrano A.L.
        • Munoz-Canoves P.
        Macrophage plasticity and the role of inflammation in skeletal muscle repair.
        Mediators Inflamm. 2013;
        • Jones C.V.
        • Williams T.M.
        • Walker K.A.
        • et al.
        M2 macrophage polarisation is associated with alveolar formation during postnatal lung development.
        Respir Res. 2013; 14: 41