Mesenchymal Stromal Cell-Based Therapies for Chronic Lung Disease of Prematurity

Abstract

Advances in perinatal care allow the survival of ever more premature infants. By approaching the biological limit of viability, survival free of injury becomes more challenging. As a consequence, bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, remains one of the main complications in infants born before 28 weeks' gestation. Currently, there is no treatment for BPD. Recent progress in understanding the biology of stem cells has opened unprecedented therapeutic options to mitigate lung injury and promote lung growth. Perinatal tissue, such as the umbilical cord and the placenta, represents a rich source of potent repair cells. Thus far, mesenchymal stromal cell (MSC)-based therapies demonstrate the most potential for protecting the developing lung from injury. Preclinical evidence supporting this potential therapeutic role has provided the basis for the initiation of phase I and II clinical trials in preterm neonates. This brief review summarizes the current knowledge accumulated over the past 10 years about MSCs and their repair potential in BPD.

Keywords

newborn - lung injury - inflammation - bronchopulmonary dysplasia - stem cells - regenerative medicine - prematurity

• References

• 1 Blencowe H, Cousens S, Oestergaard MZ. , et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379 (9832): 2162-2172
• 2 Hilgendorff A, Reiss I, Ehrhardt H, Eickelberg O, Alvira CM. Chronic lung disease in the preterm infant. Lessons learned from animal models. Am J Respir Cell Mol Biol 2014; 50 (02) 233-245
• 3 Northway Jr WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967; 276 (07) 357-368
• 4 Van Marter LJ. Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14 (06) 358-366
• 5 Strueby L, Thébaud B. Advances in bronchopulmonary dysplasia. Expert Rev Respir Med 2014; 8 (03) 327-338
• 6 Chang YS, Ahn SY, Yoo HS. , et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr 2014; 164 (05) 966-972.e6
• 7 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 (07) 1723-1729
• 8 Poindexter BB, Feng R, Schmidt B. , et al; Prematurity and Respiratory Outcomes Program. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann Am Thorac Soc 2015; 12 (12) 1822-1830
• 9 Carraro S, Filippone M, Da Dalt L. , et al. Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans. Early Hum Dev 2013; 89 (03) (Suppl. 03) S3-S5
• 10 Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. ; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003; 289 (09) 1124-1129
• 11 Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia. J Pediatr 2014; 165 (06) 1258-1260
• 12 Islam JY, Keller RL, Aschner JL, Hartert TV, Moore PE. Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015; 192 (02) 134-156
• 13 Caskey S, Gough A, Rowan S. , et al. Structural and functional lung impairment in adult survivors of bronchopulmonary dysplasia. Ann Am Thorac Soc 2016; (e-pub ahead of print).
• 14 Dani C, Poggi C. Nutrition and bronchopulmonary dysplasia. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 03) 37-40
• 15 Bose C, Van Marter LJ, Laughon M. , et al; Extremely Low Gestational Age Newborn Study Investigators. Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation. Pediatrics 2009; 124 (03) e450-e458
• 16 Durrmeyer X, Kayem G, Sinico M, Dassieu G, Danan C, Decobert F. Perinatal risk factors for bronchopulmonary dysplasia in extremely low gestational age infants: a pregnancy disorder-based approach. J Pediatr 2012; 160 (04) 578-583.e2
• 17 Bhandari V, Bizzarro MJ, Shetty A. , et al; Neonatal Genetics Study Group. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006; 117 (06) 1901-1906
• 18 Lavoie PM, Pham C, Jang KL. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics 2008; 122 (03) 479-485
• 19 Yu KH, Li J, Snyder M, Shaw GM, O'Brodovich HM. The genetic predisposition to bronchopulmonary dysplasia. Curr Opin Pediatr 2016; 28 (03) 318-323
• 20 Kourembanas S. Stem cell-based therapy for newborn lung and brain injury: feasible, safe, and the next therapeutic breakthrough?. J Pediatr 2014; 164 (05) 954-956
• 21 Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell 2004; 116 (05) 639-648
• 22 Lakshmipathy U, Verfaillie C. Stem cell plasticity. Blood Rev 2005; 19 (01) 29-38
• 23 Dominici M, Le Blanc K, Mueller I. , et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8 (04) 315-317
• 24 Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. ; MSC Committee of the International Society for Cellular Therapy (ISCT). Immunological characterization of multipotent mesenchymal stromal cells—The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 2013; 15 (09) 1054-1061
• 25 Galipeau J, Krampera M, Barrett J. , et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016; 18 (02) 151-159
• 26 Ahn SY, Chang YS, Park WS. Stem cell therapy for bronchopulmonary dysplasia: bench to bedside translation. J Korean Med Sci 2015; 30 (05) 509-513
• 27 Möbius MA, Thébaud B. Stem cells and their mediators - next generation therapy for bronchopulmonary dysplasia. Front Med (Lausanne) 2015; 2: 50
• 28 Herrmann RP, Sturm MJ. Adult human mesenchymal stromal cells and the treatment of graft versus host disease. Stem Cells Cloning 2014; 7: 45-52
• 29 Fernández Vallone VB, Romaniuk MA, Choi H, Labovsky V, Otaegui J, Chasseing NA. Mesenchymal stem cells and their use in therapy: what has been achieved?. Differentiation 2013; 85 (1–2): 1-10
• 30 Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110 (10) 3499-3506
• 31 Barkholt L, Flory E, Jekerle V. , et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies—bridging scientific observations and regulatory viewpoints. Cytotherapy 2013; 15 (07) 753-759
• 32 Lalu MM, McIntyre L, Pugliese C. , et al; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE 2012; 7 (10) e47559
• 33 Hansmann G, Fernandez-Gonzalez A, Aslam M. , et al. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2012; 2 (02) 170-181
• 34 Skalnikova H, Motlik J, Gadher SJ, Kovarova H. Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines. Proteomics 2011; 11 (04) 691-708
• 35 Dowling P, Clynes M. Conditioned media from cell lines: a complementary model to clinical specimens for the discovery of disease-specific biomarkers. Proteomics 2011; 11 (04) 794-804
• 36 Makridakis M, Roubelakis MG, Vlahou A. Stem cells: insights into the secretome. Biochim Biophys Acta 2013; 1834 (11) 2380-2384
• 37 Möbius MA, Rüdiger M. Mesenchymal stromal cells in the development and therapy of bronchopulmonary dysplasia. Mol Cell Pediatr 2016; 3 (01) 18-46
• 38 Amable PR, Teixeira MV, Carias RB, Granjeiro JM, Borojevic R. Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton's jelly. Stem Cell Res Ther 2014; 5 (02) 53
• 39 Kumar ME, Bogard PE, Espinoza FH, Menke DB, Kingsley DM, Krasnow MA. Mesenchymal cells. Defining a mesenchymal progenitor niche at single-cell resolution. Science 2014; 346 (6211): 1258810
• 40 Popova AP, Bentley JK, Cui TX. , et al. Reduced platelet-derived growth factor receptor expression is a primary feature of human bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2014; 307 (03) L231-L239
• 41 van Haaften T, Byrne R, Bonnet S. , et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med 2009; 180 (11) 1131-1142
• 42 Amy RW, Bowes D, Burri PH, Haines J, Thurlbeck WM. Postnatal growth of the mouse lung. J Anat 1977; 124 (Pt 1): 131-151
• 43 Aslam M, Baveja R, Liang OD. , et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med 2009; 180 (11) 1122-1130
• 44 Pierro M, Ionescu L, Montemurro T. , et al. Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax 2013; 68 (05) 475-484
• 45 Fung ME, Thébaud B. Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr Res 2014; 75 (1–1): 2-7
• 46 Chang YS, Choi SJ, Sung DK. , et al. Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats. Cell Transplant 2011; 20 (11–12): 1843-1854
• 47 Chang YS, Choi SJ, Ahn SY. , et al. Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury. PLoS ONE 2013; 8 (01) e52419
• 48 Waszak P, Alphonse R, Vadivel A, Ionescu L, Eaton F, Thébaud B. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev 2012; 21 (15) 2789-2797
• 49 Ohkouchi S, Block GJ, Katsha AM. , et al. Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol Ther 2012; 20 (02) 417-423
• 50 Tang SE, Wu CP, Wu SY. , et al. Stanniocalcin-1 ameliorates lipopolysaccharide-induced pulmonary oxidative stress, inflammation, and apoptosis in mice. Free Radic Biol Med 2014; 71: 321-331
• 51 Ortiz LA, Dutreil M, Fattman C. , et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007; 104 (26) 11002-11007
• 52 Piguet PF, Vesin C, Grau GE, Thompson RC. Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica. Cytokine 1993; 5 (01) 57-61
• 53 Foskett AM, Bazhanov N, Ti X, Tiblow A, Bartosh TJ, Prockop DJ. Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs. Am J Physiol Lung Cell Mol Physiol 2014; 306 (02) L120-L131
• 54 Yun EJ, Lorizio W, Seedorf G, Abman SH, Vu TH. VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development. Am J Physiol Lung Cell Mol Physiol 2016; 310 (04) L287-L298
• 55 Thébaud B, Ladha F, Michelakis ED. , et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation 2005; 112 (16) 2477-2486
• 56 Lee C, Mitsialis SA, Aslam M. , et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 2012; 126 (22) 2601-2611
• 57 Monsel A, Zhu YG, Gudapati V, Lim H, Lee JW. Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases. Expert Opin Biol Ther 2016; 16 (07) 859-871
• 58 Zhu YG, Feng XM, Abbott J. , et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 2014; 32 (01) 116-125
• 59 Liang X, Zhang L, Wang S, Han Q, Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 2016; 129 (11) 2182-2189
• 60 Islam MN, Das SR, Emin MT. , et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18 (05) 759-765
• 61 Phinney DG, Di Giuseppe M, Njah J. , et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 2015; 6: 8472
• 62 Heathman TR, Nienow AW, McCall MJ, Coopman K, Kara B, Hewitt CJ. The translation of cell-based therapies: clinical landscape and manufacturing challenges. Regen Med 2015; 10 (01) 49-64