Abstract
Recent advances have expanded our understanding of lung endogenous stem cells, and this knowledge provides us with new ideas for future regenerative therapy for lung diseases. In studies using animal models for lung regeneration, compensatory lung growth, and lung repair, promising reagents for lung regeneration have been discovered. Stem or progenitor cells are needed for alveolar regeneration, lung growth, and lung repair after injury. Endogenous progenitor cells mainly participate in alveologenesis. However, human lung endogenous progenitor cells have not yet been clearly defined. Recently discovered human alveolar epithelial progenitor cells may give us a new perspective for understanding the pathogenesis of lung diseases. In parallel with such basic research, projects geared toward clinical application are proceeding. Cell therapy using mesenchymal stem cells to treat acute lung injury is one of the promising areas for this research. The creation of bioartificial lungs, which are based on decellularized lungs, is another interesting approach for future clinical applications. Although lungs are the most challenging organ for regenerative medicine, our cumulative knowledge of lung regeneration and of endogenous progenitor cells makes clear the possibilities and limitations of regenerative medicine for lung diseases.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Wright JL, Cosio M, Churg A. Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 2008;295:L1–L15.
Churg A, Cosio M, Wright JL. Mechanisms of cigarette smoke-induced COPD: insights from animal models. Am J Physiol Lung Cell Mol Physiol 2008;294:L612–L631.
Massaro D, Massaro GD, Baras A, Hoffman EP, Clerch LB. 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.
Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311–1139.
Shapiro SD. Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease. Eur Respir J 2007;29:375–378.
Massaro GD, Massaro D. Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol 1996;270:L305–L310.
Malpel S, Mendelsohn C, Cardoso WV. Regulation of retinoic acid signaling during lung morphogenesis. Development 2000;127:3057–3067.
McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, Snyder JM. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol 2000;23:162–167.
Liu B, Harvey CS, McGowan SE. Retinoic acid increases elastin in neonatal rat lung fibroblast cultures. Am J Physiol 1993;265:L430–L437.
Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 1997;3:675–677.
Kubo H. Lung repair and regeneration: animal models. In: Polak DJ, editor. Cell therapy for lung disease. London: Imperial College Press, UK; 2010. p. 199–235.
Stinchcombe SV, Maden M. Retinoic acid induced alveolar regeneration: critical differences in strain sensitivity. Am J Respir Cell Mol Biol 2008;38:185–191.
Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 1984; 122:1450–1459.
Ohmichi H, Matsumoto K, Nakamura T. In vivo mitogenic action of HGF on lung epithelial cells: pulmotrophic role in lung regeneration. Am J Physiol 1996;270:L1031–L1039.
Ohmichi H, Koshimizu U, Matsumoto K, Nakamura T. Hepatocyte growth factor (HGF) acts as a mesenchymederived morphogenic factor during fetal lung development. Development 1998;125:1315–1324.
Panos RJ, Patel R, Bak PM. Intratracheal administration of hepatocyte growth factor/scatter factor stimulates rat alveolar type II cell proliferation in vivo. Am J Respir Cell Mol Biol 1996;15:574–581.
Mason RJ, Leslie CC, McCormick-Shannon K, Deterding RR, Nakamura T, Rubin JS, et al. Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol 1994;11:561–567.
Ishizawa K, Kubo H, Yamada M, Kobayashi S, Suzuki T, Mizuno S, et al. Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells. Biochem Biophys Res Commun 2004;324: 276–280.
Shigemura N, Sawa Y, Mizuno S, Ono M, Ohta M, Nakamura T, et al. Amelioration of pulmonary emphysema by in vivo gene transfection with hepatocyte growth factor in rats. Circulation 2005;111:1407–1414.
Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y. Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant 2006;6:2592–2600.
Hegab AE, Kubo H, Yamaya M, Asada M, He M, Fujino N, Mizuno S, Nakamura T. Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Ther 2008;16:1417–1426.
Fukuhara S, Tomita S, Nakatani T, Ohtsu Y, Ishida M, Yutani C, et al. G-CSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes. Cell Transplant 2004;13:741–748.
Takagi Y, Omura T, Yoshiyama M, Matsumoto R, Enomoto S, Kusuyama T, et al. Granulocyte-colony stimulating factor augments neovascularization induced by bone marrow transplantation in rat hindlimb ischemia. J Pharmacol Sci 2005;99: 45–51.
Ishizawa K, Kubo H, Yamada M, Kobayashi S, Numasaki M, Ueda S, et al. Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett 2004;556:249–252.
Ulich TR, Yi ES, Longmuir K, Yin S, Biltz R, Morris CF, et al. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest 1994;93:1298–1306.
Fehrenbach H, Kasper M, Tschernig T, Pan T, Schuh D, Shannon JM, et al. Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cells in vivo is resolved by differentiation into type I cells and by apoptosis. Eur Respir J 1999;14:534–544.
Plantier L, Marchand-Adam S, Antico VG, Boyer L, De Coster C, Marchal J, et al. Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 2007;293: L1230–L1239.
Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553–560.
Tokunaga N, Nagaya N, Shirai M, Tanaka E, Ishibashi-Ueda H, Harada-Shiba M, et al. Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin. Circulation 2004;109:526–531.
Martinez A, Miller MJ, Catt KJ, Cuttitta F. Adrenomedullin receptor expression in human lung and in pulmonary tumors. J Histochem Cytochem 1997;45:159–164.
Murakami S, Nagaya N, Itoh T, Iwase T, Fujisato T, Nishioka K, et al. Adrenomedullin regenerates alveoli and vasculature in elastase-induced pulmonary emphysema in mice. Am J Respir Crit Care Med 2005;172:581–589.
Tokunaga T, Ikegami T, Yoshizumi T, Imura S, Morine Y, Shinohara H, et al. Beneficial effects of fluvastatin on liver microcirculation and regeneration after massive hepatectomy in rats. Dig Dis Sci 2008;53:2989–2994.
Takahashi S, Nakamura H, Seki M, Shiraishi Y, Yamamoto M, Furuuchi M, et al. Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol Lung Cell Mol Physiol 2008;294:L882–L890.
Nakajima C, Kijimoto C, Yokoyama Y, Miyakawa T, Tsuchiya Y, Kuroda T, et al. Longitudinal follow-up of pulmonary function after lobectomy in childhood: factors affecting lung growth. Pediatr Surg Int 1998;13:341–345.
Hsia CC, Herazo LF, Fryder-Doffey F, Weibel ER. Compensatory lung growth occurs in adult dogs after right pneumonectomy. J Clin Invest 1994;94:405–412.
Takeda S, Hsia CC, Wagner E, Ramanathan M, Estrera AS, Weibel ER. Compensatory alveolar growth normalizes gasexchange function in immature dogs after pneumonectomy. J Appl Physiol 1999;86:1301–1310.
Sakurai MK, Lee S, Arsenault DA, Nose V, Wilson JM, Heymach JV, et al. Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy. Am J Physiol Lung Cell Mol Physiol 2007;292: L742–L747.
Nijjar MS, Thurlbeck WM. Alterations in enzymes related to adenosine 3′,5′-monophosphate during compensatory growth of rat lung. Eur J Biochem 1980;105:403–407
Cowan MJ, Crystal RG. Lung growth after unilateral pneumonectomy: quantitation of collagen synthesis and content. Am Rev Respir Dis 1975;111:267–277.
Chess PR, Toia L, Finkelstein JN. Mechanical strain-induced proliferation and signaling in pulmonary epithelial h441 cells. Am J Physiol Lung Cell Mol Physiol 2000;279:L43–L51.
Waters CM, Chang JY, Glucksberg MR, DePaola N, Grotberg JB. Mechanical forces alter growth factor release by pleural mesothelial cells. Am J Physiol 1997;272: L552–L557.
Thibeault DW, Haney B. Lung volume, pulmonary vasculature, and factors affecting survival in congenital diaphragmatic hernia. Pediatrics 1998;101:289–295.
Berg JT, Fu Z, Breen EC, Tran HC, Mathieu-Costello O, West JB. High lung inflation increases MRNA levels of ECM components and growth factors in lung parenchyma. J Appl Physiol 1997;83:120–128.
Landesberg LJ, Ramalingam R, Lee K, Rosengart TK, Crystal RG. 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.
Hsia CC, Herazo LF, Ramanathan M, Johnson RL Jr. Cardiopulmonary adaptations to pneumonectomy in dogs. IV. Membrane diffusing capacity and capillary blood volume. J Appl Physiol 1994;77:998–1005.
Haworth SG, McKenzie SA, Fitzpatrick ML. Alveolar development after ligation of left pulmonary artery in newborn pig: clinical relevance to unilateral pulmonary artery. Thorax 1981;36:938–943.
Hsia CC, Zhou XS, Bellotto DJ, Hagler HK. Regenerative growth of respiratory bronchioles in dogs. Am J Physiol Lung Cell Mol Physiol 2000;279:L136–L142.
Kaza AK, Kron IL, Kern JA, Long SM, Fiser SM, Nguyen RP, et al. Retinoic acid enhances lung growth after pneumonectomy. Ann Thorac Surg 2001;71:1645–1650.
Yan X, Bellotto DJ, Foster DJ, Johnson RL Jr, Hagler HK, Estrera AS, et al. Retinoic acid induces nonuniform alveolar septal growth after right pneumonectomy. J Appl Physiol 2004;96:1080–1089.
Dane DM, Yan X, Tamhane RM, Johnson RL Jr, Estrera AS, Hogg DC, et al. Retinoic acid-induced alveolar cellular growth does not improve function after right pneumonectomy. J Appl Physiol 2004;96:1090–1096.
Yan X, Bellotto DJ, Dane DM, Elmore RG, Johnson RL Jr, Estrera AS, et al. Lack of response to all-trans retinoic acid supplementation in adult dogs following left pneumonectomy. J Appl Physiol 2005;99:1681–1688.
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.
Miettinen PJ, Warburton D, Bu D, Zhao JS, Berger JE, Minoo P, et al. Impaired lung branching morphogenesis in the absence of functional EGF receptor. Dev Biol 1997;186: 224–236.
Kaza AK, Laubach VE, Kern JA, Long SM, Fiser SM, Tepper JA, et al. Epidermal growth factor augments postpneumonectomy lung growth. J Thorac Cardiovasc Surg 2000;120:916–921.
Brody JS, Fisher AB, Gocmen A, DuBois AB. Acromegalic pneumonomegaly: lung growth in the adult. J Clin Invest 1970;49:1051–60.
Jain BP, Brody JS, Fisher AB. The small lung of hypopituitarism. Am Rev Respir Dis 1973;108:49–55.
Healy AM, Morgenthau L, Zhu X, Farber HW, Cardoso WV. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung. Dev Dyn 2000;219: 341–352.
Kaner RJ, Crystal RG. Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung. Mol Med 2001;7:240–246.
Leuwerke SM, Kaza AK, Tribble CG, Kron IL, Laubach VE. Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice. Am J Physiol Lung Cell Mol Physiol 2002;282:L1272–L1278.
Li D, Fernandez LG, Dodd-o J, Langer J, Wang D, Laubach VE. Upregulation of hypoxia-induced mitogenic factor in compensatory lung growth after pneumonectomy. Am J Respir Cell Mol Biol 2005;32:185–191.
Kenzaki K, Sakiyama S, Kondo K, Yoshida M, Kawakami Y, Takehisa M, et al. Lung regeneration: implantation of fetal rat lung fragments into adult rat lung parenchyma. J Thorac Cardiovasc Surg 2006;131:1148–1153.
Yamada M, Kubo H, Kobayashi S, Ishizawa K, Numasaki M, Ueda S, et al. Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol 2004;172:1266–1272.
Brass DM, Hollingsworth JW, Cinque M, Li Z, Potts E, Toloza E, et al. Chronic LPS inhalation causes emphysemalike changes in mouse lung that are associated with apoptosis. Am J Respir Cell Mol Biol 2008;39:584–590.
Narasaraju TA, Chen H, Weng T, Bhaskaran M, Jin N, Chen J, et al. Expression profile of IGF system during lung injury and recovery in rats exposed to hyperoxia: a possible role of IGF-1 in alveolar epithelial cell proliferation and differentiation. J Cell Biochem 2006;97:984–998.
Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, McMahon FB, et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010;299:L442–L452.
Yamada M, Kubo H, Ishizawa K, Kobayashi S, Shinkawa M, Sasaki H. Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair. Thorax 2005;60:410–413.
Burnham EL, Taylor WR, Quyyumi AA, Rojas M, Brigham KL, Moss M. Increased circulating endothelial progenitor cells are associated with survival in acute lung injury. Am J Respir Crit Care Med 2005;172:854–860.
Yamada M, Ishizawa K, Kobayashi S, Suzuki T, Kubo H. Bone marrow-derived progenitor cells are not a source of bronchioalveolar stem cells after LPS-induced lung injury. Proc Am Thorac Soc 2006;3:A556.
Voswinckel R, Ziegelhoeffer T, Heil M, Kostin S, Breier G, Mehling T, et al. Circulating vascular progenitor cells do not contribute to compensatory lung growth. Circ Res 2003;93: 372–379.
Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823–835.
McQualter JL, Brouard N, Williams B, Baird BN, Sims-Lucas S, Yuen K, et al. Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the SCA-1 positive cell fraction. Stem Cells 2009;27:623–633.
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.
Hegab AE, Kubo H, Fujino N, Suzuki T, He M, Kato H, et al. Isolation and characterization of murine multipotent lung stem cells. Stem Cells Dev 2010;19:523–535.
Nolen-Walston RD, Kim CF, Mazan MR, Ingenito EP, Gruntman AM, Tsai L, 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.
Fujino N, Kubo H, Suzuki T, Ota C, Hegab AE, He M, et al. Isolation of alveolar epithelial type ii progenitor cells from adult human lungs. Lab Invest. doi: 10.1038/labinvest.2010.187.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells: the International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–317.
Hennrick KT, Keeton AG, Nanua S, Kijek TG, Goldsmith AM, Sajjan US, et al. Lung cells from neonates show a mesenchymal stem cell phenotype. Am J Respir Crit Care Med 2007;175:1158–1164.
Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, 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.
Karoubi G, Cortes-Dericks L, Breyer I, Schmid RA, Dutly AE. Identification of mesenchymal stromal cells in human lung parenchyma capable of differentiating into aquaporin 5-expressing cells. Lab Invest 2009;89:1100–1114.
Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996;166:585–592.
Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, et al. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L131–L141.
Keating A. Mesenchymal stromal cells. Curr Opin Hematol 2006;13:419–425.
Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A 2006;103:1283–1288.
Prockop DJ. “Stemness”: does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 2007;82:241–243.
Wiwanitkit V. CD133 and non-small-cell lung cancer. Eur J Cardiothorac Surg 2010;37:988; reply 988–989.
Moreira AL, Gonen M, Rekhtman N, Downey RJ. Progenitor stem cell marker expression by pulmonary carcinomas. Mod Pathol 2010;23:889–895.
Mao JT, Goldin JG, Dermand J, Ibrahim G, Brown MS, Emerick A, et al. A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 2002;165:718–723.
Roth MD, Connett JE, D’Armiento JM, Foronjy RF, Friedman PJ, Goldin JG, et al. Feasibility of retinoids for the treatment of emphysema study. Chest 2006;130:1334–1345.
Mao JT, Tashkin DP, Belloni PN, Baileyhealy I, Baratelli F, Roth MD. All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema. Chest 2003;124: 1724–1732.
Stolk J, Cooper BG, Stoel B, Rames A, Rutman O, Soliman S, et al. Retinoid treatment of emphysema in patients on the alpha-1 international registry: the repair study-study design, methodology and quality control of study assessments. Ther Adv Respir Dis 2010;4:319–332.
Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890–896.
Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010;28:585–596.
Matthay MA, Thompson BT, Read EJ, McKenna DH, Liu KD, Calfee CS, et al. Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest 2010;138: 965–972.
Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007;292:H1120–H1128.
Weiss DJ, Kolls JK, Ortiz LA, Panoskaltsis-Mortari A, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 2008;5: 637–667.
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005;33: 145–152.
Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxininduced acute lung injury in mice. J Immunol 2007;179: 1855–1863.
Price AP, England KA, Matson AM, Blazar BR, Panoskaltsis-Mortari A. Development of a decellularized lung bioreactor system for bioengineering the lung: the matrix reloaded. Tissue Eng Part A 2010;16:2581–2591.
Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 2010;16:927–933.
Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, et al. Tissue-engineered lungs for in vivo implantation. Science 2010;329:538–541.
Author information
Authors and Affiliations
Corresponding author
Additional information
This review was submitted at the invitation of the editorial committee.
Rights and permissions
About this article
Cite this article
Kubo, H. Molecular basis of lung tissue regeneration. Gen Thorac Cardiovasc Surg 59, 231–244 (2011). https://doi.org/10.1007/s11748-010-0757-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11748-010-0757-x