Am J Perinatol 2019; 36(S 02): S68-S73
DOI: 10.1055/s-0039-1691774
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Stem Cells for Extreme Prematurity

Bernard Thébaud
1   Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
2   Department of Molecular Medicine, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
3   Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
4   Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
25. Juni 2019 (online)

Abstract

Regenerative medicine is a bourgeoning field promising to repair damaged organs and thus has created high hopes in neonatology to curb some of the complications due to extreme preterm birth. Extensive laboratory investigations over the past 15 years have tried to harness the regenerative potential of a variety of (stem) cell-based therapies. Most preclinical studies have focused on experimental neonatal lung and brain injury. These promising results lead to the initiation of phase I clinical trials for chronic lung disease of prematurity and severe intraventricular hemorrhage, two of the most devastating complications of extreme preterm birth. Despite this relative rapid clinical translation, major gaps persist in our understanding of the biology of these putative repair cells and our ability to predict the quality and thus the efficacy of the cell product. This review will provide a brief overview of the various cell-based therapies that have been investigated in experimental neonatal lung injury and the remaining challenges in utilizing these new, disruptive therapies to their full extend to realize the promise of regenerative medicine in neonatology.

 
  • References

  • 1 Stoll BJ, Hansen NI, Bell EF. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015; 314 (10) 1039-1051
  • 2 Owen LS, Manley BJ, Davis PG, Doyle LW. The evolution of modern respiratory care for preterm infants. Lancet 2017; 389 (10079): 1649-1659
  • 3 Thebaud B. Chronic lung disease in the neonate: past, present, and future. Neoreviews 2013; 14 (05) e252-e258
  • 4 Collaco JM, McGrath-Morrow SA. Respiratory phenotypes for preterm infants, children, and adults: bronchopulmonary dysplasia and more. Ann Am Thorac Soc 2018; 15 (05) 530-538
  • 5 Goss KN, Beshish AG, Barton GP. , et al. Early Pulmonary Vascular Disease in Young Adults Born Preterm. American Journal of Respiratory and Critical Care Medicine 2018; 198 (12) 1549-1558
  • 6 Heinonen K, Eriksson JG, Lahti J. , et al. Late preterm birth and neurocognitive performance in late adulthood: a birth cohort study. Pediatrics 2015; 135 (04) e818-e825
  • 7 Fischbach MA, Bluestone JA, Lim WA. Cell-based therapeutics: the next pillar of medicine. Sci Transl Med 2013; 5 (179) 179ps7
  • 8 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
  • 9 Willis GR, Fernandez-Gonzalez A, Anastas J. , et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med 2018; 197 (01) 104-116
  • 10 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
  • 11 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976; 4 (05) 267-274
  • 12 Crisan M, Yap S, Casteilla L. , et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3 (03) 301-313
  • 13 Popova AP, Bozyk PD, Bentley JK. , et al. Isolation of tracheal aspirate mesenchymal stromal cells predicts bronchopulmonary dysplasia. Pediatrics 2010; 126 (05) e1127-e1133
  • 14 Möbius MA, Freund D, Vadivel A. , et al. Oxygen disrupts human fetal lung mesenchymal cells. Implications for bronchopulmonary dysplasia. Am J Respir Cell Mol Biol 2019; 60 (05) 592-600
  • 15 Collins JJP, Lithopoulos MA, Dos Santos CC. , et al. Impaired angiogenic supportive capacity and altered gene expression profile of resident CD146+ mesenchymal stromal cells isolated from hyperoxia-injured neonatal rat lungs. Stem Cells Dev 2018; 27 (16) 1109-1124
  • 16 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
  • 17 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
  • 18 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
  • 19 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
  • 20 Augustine S, Avey MT, Harrison B. , et al. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cells Transl Med 2017; 6 (12) 2079-2093
  • 21 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.e6-972.e6
  • 22 Ahn SY, Chang YS, Kim JH, Sung SI, Park WS. Two-year follow-up outcomes of premature infants enrolled in the phase I trial of mesenchymal stem cells transplantation for bronchopulmonary dysplasia. J Pediatr 2017; 185: 49-54.e2
  • 23 Álvarez-Fuente M, Arruza L, Lopez-Ortego P. , et al. Off-label mesenchymal stromal cell treatment in two infants with severe bronchopulmonary dysplasia: clinical course and biomarkers profile. Cytotherapy 2018; 20 (11) 1337-1344
  • 24 Pierro M, Thébaud B, Soll R. Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2017; 11: CD011932
  • 25 Ilancheran S, Michalska A, Peh G, Wallace EM, Pera M, Manuelpillai U. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol Reprod 2007; 77 (03) 577-588
  • 26 Vosdoganes P, Hodges RJ, Lim R. , et al. Human amnion epithelial cells as a treatment for inflammation-induced fetal lung injury in sheep. Am J Obstet Gynecol 2011; 205 (02) 156.e26-156.e33
  • 27 Vosdoganes P, Lim R, Koulaeva E. , et al. Human amnion epithelial cells modulate hyperoxia-induced neonatal lung injury in mice. Cytotherapy 2013; 15 (08) 1021-1029
  • 28 Vosdoganes P, Wallace EM, Chan ST, Acharya R, Moss TJ, Lim R. Human amnion epithelial cells repair established lung injury. Cell Transplant 2013; 22 (08) 1337-1349
  • 29 Lim R, Malhotra A, Tan J. , et al. First-in-human administration of allogeneic amnion cells in premature infants with bronchopulmonary dysplasia: a safety study. Stem Cells Transl Med 2018; 7 (09) 628-635
  • 30 Baker EK, Malhotra A, Lim R. , et al. Human amnion cells for the prevention of bronchopulmonary dysplasia: a protocol for a phase I dose escalation study. BMJ Open 2019; 9 (02) e026265
  • 31 Medina RJ, Barber CL, Sabatier F. , et al. Endothelial progenitors: a consensus statement on nomenclature. Stem Cells Transl Med 2017; 6 (05) 1316-1320
  • 32 Ingram DA, Mead LE, Tanaka H. , et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104 (09) 2752-2760
  • 33 Thébaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007; 175 (10) 978-985
  • 34 Alphonse RS, Vadivel A, Zhong S. , et al. The isolation and culture of endothelial colony-forming cells from human and rat lungs. Nat Protoc 2015; 10 (11) 1697-1708
  • 35 Alphonse RS, Vadivel A, Fung M. , et al. Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 2014; 129 (21) 2144-2157
  • 36 Bertagnolli M, Nuyt AM, Thébaud B, Luu TM. Endothelial progenitor cells as prognostic markers of preterm birth-associated complications. Stem Cells Transl Med 2017; 6 (01) 7-13
  • 37 Balasubramaniam V, Ryan SL, Seedorf GJ. , et al. Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol 2010; 298 (03) L315-L323
  • 38 Firsova AB, Bird AD, Abebe D, Ng J, Mollard R, Cole TJ. Fresh noncultured endothelial progenitor cells improve neonatal lung hyperoxia-induced alveolar injury. Stem Cells Transl Med 2017; 6 (12) 2094-2105
  • 39 Baker CD, Seedorf GJ, Wisniewski BL. , et al. Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2013; 305 (01) L73-L81
  • 40 Krause DS, Theise ND, Collector MI. , et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105 (03) 369-377
  • 41 Kotton DN, Fabian AJ, Mulligan RC. Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 2005; 33 (04) 328-334
  • 42 Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014; 507 (7491): 190-194
  • 43 Reddy R, Buckley S, Doerken M. , et al. Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 2004; 286 (04) L658-L667
  • 44 Chapman HA, Li X, Alexander JP. , et al. Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest 2011; 121 (07) 2855-2862
  • 45 Lin SE, Barrette AM, Chapin C. , et al. Expression of human carcinoembryonic antigen-related cell adhesion molecule 6 and alveolar progenitor cells in normal and injured lungs of transgenic mice. Physiol Rep 2015; 3 (12) e12657
  • 46 Monz D, Tutdibi E, Mildau C. , et al. Human umbilical cord blood mononuclear cells in a double-hit model of bronchopulmonary dysplasia in neonatal mice. PLoS One 2013; 8 (09) e74740
  • 47 Ahn SY, Chang YS, Sung DK. , et al. Cell type-dependent variation in paracrine potency determines therapeutic efficacy against neonatal hyperoxic lung injury. Cytotherapy 2015; 17 (08) 1025-1035
  • 48 Moorefield EC, McKee EE, Solchaga L. , et al. Cloned, CD117 selected human amniotic fluid stem cells are capable of modulating the immune response. PLoS One 2011; 6 (10) e26535
  • 49 Carraro G, Perin L, Sedrakyan S. , et al. Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells 2008; 26 (11) 2902-2911
  • 50 Grisafi D, Pozzobon M, Dedja A. , et al. Human amniotic fluid stem cells protect rat lungs exposed to moderate hyperoxia. Pediatr Pulmonol 2013; 48 (11) 1070-1080
  • 51 Takahashi K, Tanabe K, Ohnuki M. , et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131 (05) 861-872
  • 52 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126 (04) 663-676
  • 53 Jacob A, Morley M, Hawkins F. , et al. Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell 2017; 21 (04) 472.e10-488.e10
  • 54 Shafa M, Ionescu LI, Vadivel A. , et al. Human induced pluripotent stem cell-derived lung progenitor and alveolar epithelial cells attenuate hyperoxia-induced lung injury. Cytotherapy 2018; 20 (01) 108-125
  • 55 Liang Q, Monetti C, Shutova MV. , et al. Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature 2018; 563 (7733): 701-704
  • 56 Martin I, De Boer J, Sensebe L. ; MSC Committee of the International Society for Cellular Therapy. A relativity concept in mesenchymal stromal cell manufacturing. Cytotherapy 2016; 18 (05) 613-620
  • 57 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
  • 58 Sammour I, Somashekar S, Huang J. , et al. The effect of gender on mesenchymal stem cell (MSC) efficacy in neonatal hyperoxia-induced lung injury. PLoS One 2016; 11 (10) e0164269
  • 59 Chen CM, Chou HC, Lin W, Tseng C. Surfactant effects on the viability and function of human mesenchymal stem cells: in vitro and in vivo assessment. Stem Cell Res Ther 2017; 8 (01) 180
  • 60 Chinnadurai R, Copland IB, Garcia MA. , et al. Cryopreserved mesenchymal stromal cells are susceptible to t-cell mediated apoptosis which is partly rescued by IFNγ licensing. Stem Cells 2016; 34 (09) 2429-2442
  • 61 Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 2015; 77: 13-27
  • 62 Bryan C, Sammour I, Guerra K. , et al. TNFα-stimulated protein 6 (TSG-6) reduces lung inflammation in an experimental model of bronchopulmonary dysplasia. Pediatr Res 2019; 85 (03) 390-397
  • 63 Lal CV, Olave N, Travers C. , et al. Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants. JCI Insight 2018; 3 (05) 93994
  • 64 Porzionato A, Zaramella P, Dedja A. , et al. Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2019; 316 (01) L6-L19
  • 65 Lesage F, Thébaud B. Nanotherapies for micropreemies: stem cells and the secretome in bronchopulmonary dysplasia. Semin Perinatol 2018; 42 (07) 453-458
  • 66 Sucre JMS, Jetter CS, Loomans H. , et al. Successful establishment of primary type II alveolar epithelium with 3D organotypic coculture. Am J Respir Cell Mol Biol 2018; 59 (02) 158-166
  • 67 Boregowda SV, Krishnappa V, Haga CL, Ortiz LA, Phinney DG. A clinical indications prediction scale based on TWIST1 for human mesenchymal stem cells. EBioMedicine 2015; 4: 62-73