Volume 9 Issue 3
Mar.  2018
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Qiwang Ma, Yu Ma, Xiaotian Dai, Tao Ren, Yingjie Fu, Wenbin Liu, Yufei Han, Yingchuan Wu, Yu Cheng, Ting Zhang, Wei Zuo. Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation[J]. Protein&Cell, 2018, 9(3): 267-282. doi: 10.1007/s13238-018-0506-y
Citation: Qiwang Ma, Yu Ma, Xiaotian Dai, Tao Ren, Yingjie Fu, Wenbin Liu, Yufei Han, Yingchuan Wu, Yu Cheng, Ting Zhang, Wei Zuo. Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation[J]. Protein&Cell, 2018, 9(3): 267-282. doi: 10.1007/s13238-018-0506-y

Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation

doi: 10.1007/s13238-018-0506-y

This work was funded by The National Key Research and Development Program of China (2017YFA0104600), Youth 1000 Talent Plan of China to W. Zuo, Tongji University (Basic Scientific Research-Interdisciplinary Fund and 985 Grant to W. Zuo), Shanghai Pulmonary Hospital (Annual Grant to W. Zuo), National Science Fund Committee of China (81570091 and 81770073 to W. Zuo), Academic Leadership Fund of Shanghai (16XD1403100 to T. Ren), Postdoc Grant of China (2016M601651 to Y. Ma and 2016M591716 to Q. Ma) and Kiangnan Stem Cell Institute.

  • Received Date: 2017-12-08
  • Rev Recd Date: 2017-12-24
  • Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient's lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3-12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.
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  • [1]
    Asano S, Takemura T, Katoh K, Taneda M, Kitagawa M (2011) Epithelial regeneration after diffuse alveolar damage in relation to underlying disease and DAD stage:an autopsy study. Journal of medical and dental sciences 58:113-121
    Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BL (2013) Type 2 alveolar cells are stem cells in adult lung. The Journal of clinical investigation 123:3025-3036. https://doi.org/10.1172/JCI68782
    Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL (1997) Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124:4867-4878
    Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH (2011) Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. The Journal of clinical investigation 121:2855-2862. https://doi.org/10.1172/JCI57673
    Cheng Y, Samia CA, Meyers JD, Panagopoulos I, Fei B, Burda C (2008) Highly efficient drug delivery with gold nanoparticle vectors for in vivo photodynamic therapy of cancer. Journal of the American Chemical Society 130:10643-10647. https://doi.org/10.1021/ja801631c
    Chilosi M, Poletti V, Murer B, Lestani M, Cancellieri A, Montagna L, Piccoli P, Cangi G, Semenzato G, Doglioni C (2002) Abnormal reepithelialization and lung remodeling in idiopathic pulmonary fibrosis:the role of deltaN-p63. Laboratory investigation; a journal of technical methods and pathology 82:1335-1345
    Clevers H (2013) The intestinal crypt, a prototype stem cell compartment. Cell 154:274-284. https://doi.org/10.1016/j.cell.2013.07.004
    Copelan EA (2006) Hematopoietic stem-cell transplantation. The New England journal of medicine 354:1813-1826. https://doi.org/10.1056/NEJMra052638
    Desai TJ, Brownfield DG, Krasnow MA (2014) Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507:190-194. https://doi.org/10.1038/nature12930
    Gallico GG 3rd, O'Connor NE, Compton CC, Kehinde O, Green H (1984) Permanent coverage of large burn wounds with autologous cultured human epithelium. The New England journal of medicine 311:448-451. https://doi.org/10.1056/NEJM198408163110706
    Hackett NR, Shaykhiev R, Walters MS, Wang R, Zwick RK, Ferris B, Witover B, Salit J, Crystal RG (2011) The human airway epithelial basal cell transcriptome. PloS one 6:e18378. https://doi.org/10.1371/journal.pone.0018378
    Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, Niklason L, Calle E, Le A, Randell SH, Rock J, Snitow M, Krummel M, Stripp BR, Vu T, White ES, Whitsett JA, Morrisey EE (2014) Repair and regeneration of the respiratory system:complexity, plasticity, and mechanisms of lung stem cell function. Cell stem cell 15:123-138. https://doi.org/10.1016/j.stem.2014.07.012
    Huang SX, Islam MN, O'Neill J, Hu Z, Yang YG, Chen YW, Mumau M, Green MD, Vunjak-Novakovic G, Bhattacharya J, Snoeck HW (2014) Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nature biotechnology 32:84-91.https://doi.org/10.1038/nbt.2754
    Ke MT, Fujimoto S, Imai T (2013) SeeDB:a simple and morphologypreserving optical clearing agent for neuronal circuit reconstruction. Nature neuroscience 16:1154-1161. https://doi.org/10.1038/nn.3447
    Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823-835. https://doi.org/10.1016/j.cell.2005.03.032
    King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW, Group AS (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England journal of medicine 370:2083-2092. https://doi.org/10.1056/nejmoa1402582
    Kotton DN, Morrisey EE (2014) Lung regeneration:mechanisms, applications and emerging stem cell populations. Nature medicine 20:822-832. https://doi.org/10.1038/nm.3642
    Mannino DM (2002) COPD:epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest 121:121S-126S Meirelles Lda S, Fontes AM, Covas DT, Caplan AI (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & growth factor reviews 20:419-427. https://doi.org/10.1016/j.cytogfr.2009
    Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J (2016) Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell stem cell 19:217-231. https://doi.org/10.1016/j.stem.2016.05.012
    Moulton BC, Barker AF (2012) Pathogenesis of bronchiectasis. Clinics in chest medicine 33:211-217. https://doi.org/10.1016/j.ccm.2012.02.004
    Nichane M, Javed A, Sivakamasundari V, Ganesan M, Ang LT, Kraus P, Lufkin T, Loh KM, Lim B (2017) Isolation and 3D expansion of multipotent Sox9(+) mouse lung progenitors. Nature methods 14:1205-1212. https://doi.org/10.1038/nmeth.4498
    Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP (2010) Regeneration and orthotopic transplantation of a bioartificial lung. Nature medicine 16:927-933. https://doi.org/10.1038/nm.2193
    Perl AK, Kist R, Shan Z, Scherer G, Whitsett JA (2005) Normal lung development and function after Sox9 inactivation in the respiratory epithelium. Genesis 41:23-32. https://doi.org/10.1002/gene.20093
    Phan SH (2012) Genesis of the myofibroblast in lung injury and fibrosis. Proceedings of the American Thoracic Society 9:148-152. https://doi.org/10.1513/pats.201201-011AW
    Rajagopal J, Carroll TJ, Guseh JS, Bores SA, Blank LJ, Anderson WJ, Yu J, Zhou Q, McMahon AP, Melton DA (2008) Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development 135:1625-1634. https://doi.org/10.1242/dev.015495
    Rama P, Bonini S, Lambiase A, Golisano O, Paterna P, De Luca M, Pellegrini G (2001) Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation 72:1478-1485
    Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G (2010) Limbal stem-cell therapy and long-term corneal regeneration. The New England journal of medicine 363:147-155. https://doi.org/10.1056/NEJMoa0905955
    Rockich BE, Hrycaj SM, Shih HP, Nagy MS, Ferguson MA, Kopp JL, Sander M, Wellik DM, Spence JR (2013) Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 110:E4456-4464. https://doi.org/10.1073/pnas.1311847110
    Rosen C, Shezen E, Aronovich A, Klionsky YZ, Yaakov Y, Assayag M, Biton IE, Tal O, Shakhar G, Ben-Hur H, Shneider D, Vaknin Z, Sadan O, Evron S, Freud E, Shoseyov D, Wilschanski M, Berkman N, Fibbe WE, Hagin D, Hillel-Karniel C, Krentsis IM, Bachar-Lustig E, Reisner Y (2015) Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice. Nature medicine 21:869-879. https://doi.org/10.1038/nm.3889
    Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd (2004) Idiopathic pulmonary fibrosis:pathogenesis and therapeutic approaches. Drugs 64:405-430
    Smirnova NF, Schamberger AC, Nayakanti S, Hatz R, Behr J, Eickelberg O (2016) Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs.
    Respiratory research 17:83. https://doi.org/10.1186/s12931-016-0404-x
    ten Hacken NH, Wijkstra PJ, Kerstjens HA (2007) Treatment of bronchiectasis in adults. Bmj 335:1089-1093. https://doi.org/10.1136/bmj.39384.657118.80
    Tsao PN, Chen F, Izvolsky KI, Walker J, Kukuruzinska MA, Lu J, Cardoso WV (2008) Gamma-secretase activation of notch signaling regulates the balance of proximal and distal fates in progenitor cells of the developing lung. The Journal of biological chemistry 283:29532-29544. https://doi.org/10.1074/jbc.M801565200
    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 (2013) 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. Journal of translational medicine 11:171. https://doi.org/10.1186/1479-5876-11-171
    Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517:621-625. https://doi.org/10.1038/nature14112
    Wang X, Yamamoto Y, Wilson LH, Zhang T, Howitt BE, Farrow MA, Kern F, Ning G, Hong Y, Khor CC, Chevalier B, Bertrand D, Wu L, Nagarajan N, Sylvester FA, Hyams JS, Devers T, Bronson R, Lacy DB, Ho KY, Crum CP, McKeon F, Xian W (2015) Cloning and variation of ground state intestinal stem cells. Nature 522:173-178. https://doi.org/10.1038/nature14484
    Wimberley NW, Bass JB Jr, Boyd BW, Kirkpatrick MB, Serio RA, Pollock HM (1982) Use of a bronchoscopic protected catheter brush for the diagnosis of pulmonary infections. Chest 81:556-562
    Zhang HY, Gharaee-Kermani M, Zhang K, Karmiol S, Phan SH (1996) Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis.The American journal of pathology 148:527-537
    Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, Wang X, Lim SJ, Vincent M, Lessard M, Crum CP, Xian W, McKeon F (2015) p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature 517:616-620. https://doi.org/10.1038/nature13903
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