Regenerative Therapies in Neonatology: Clinical Perspectives

Abstract

Regenerative therapy based on stem cells is applied as standard therapy in pediatric oncology. Furthermore, they are frequently used to treat immunodeficiency disorders of infants. For severe neonatal diseases, e. g. hypoxic-ischemic encephalopathy in term neonates or bronchopulmonary dysplasia in preterm infants, animal models have been established. According to some first preclinical results stem cell administration appears as a promising tool to improve the clinical outcome in high-risk infants. Provided the benefit of regenerative therapies can further be evaluated in appropriate preclinical neonate models, carefully controlled clinical trials to assess the significance of regenerative therapies, such as autologous stem cell administration, are indicated.

Zusammenfassung

Regenerative Therapien sind Standard bei onkologischen pädiatrischen Erkrankungen sowie Immundefekten, wobei sowohl Stammzellen als auch Wachstumsfaktoren eingesetzt werden. In der Neonatologie wurden bislang nur tierexperimentell bei hypoxisch-ischämischer Enzephalopathie und bei der bronchopulmonalen Dysplasie Stammzellen mit Erfolg appliziert. Diese Ergebnisse legen nahe, dass bei Bestätigung dieser Befunde in weiteren experimentellen Studien kontrollierte Studien an Hochrisikokindern notwendig sind. Der Einsatz von autologen Stammzellpräparaten ist hierbei ein erster Schritt, um die Bedeutung der regenerativen Therapie in der Neonatologie zu evaluieren.

Key words

regenerative therapy - neonate - perinatal brain injury - bronchopulmonary dysplasia - cellular therapy

Schlüsselwörter

regenerative Therapie - Neugeborenes - perinatale Hirnschädigung - bronchopulmonale Dysplasie - Zelltherapie

• References

• 1 Arpino C, Compagnone E, Montanaro ML et al. Preterm birth and neurodevelopmental outcome: a review. Childs Nerv Syst 2010; 26: 1139-1149
• 2 Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967
• 3 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: 1122-1130
• 4 Baker CD, Balasubramaniam V, Mourani PM et al. Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J [Published online April 10, 2012]
• 5 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 2010; 298: L315-L323
• 6 Baron F, Storb R. Mensenchymal Stromal Cells: A New Tool against Graft-versus-Host Disease?. Biol Blood Marrow Transplant 2012; 18: 822-840
• 7 Bassler D, Stoll BJ, Schmidt B et al. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics 2009; 123: 313-318
• 8 Beck Jr L, D’Amore PA. Vascular development: cellular and molecular regulation. FASEB J 1997; 11: 365-373
• 9 Beckett T, Loi R, Prenovitz R et al. Acute lung injury with endotoxin or NO2 does not enhance development of airway epithelium from bone marrow. Mol Ther 2005; 12: 680-686
• 10 Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008; 2: 313-319
• 11 Bieback K. Basic Biology of Mesenchymal Stem Cells. Transfus Med Hemother 2008; 35: 151-152
• 12 Bieback K, Brinkmann I. Mesenchymal stromal cells from human perinatal tissues: From biology to cell therapy. World J Stem Cells 2010; 2: 81-92
• 13 Bieback K, Kern S, Kluter H et al. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22: 625-634
• 14 Bieback K, Kinzebach S, Karagianni M. Translating research into clinical scale manufacturing of mesenchymal stromal cells. Stem Cells Int [Published online January 20, 2011]
• 15 Bieback K, Kluter H. Non-hematopoietic stem and progenitor cells derived from human umbilical cord blood. In: Bhattacharya N, Stubblefield P. (eds.). Frontiers of Cord Blood Science. Springer-Verlag London Limited; 2009: 123-157
• 16 Bieback K, Schallmoser K, Kluter H et al. Clinical Protocols for the Isolation and Expansion of Mesenchymal Stromal Cells. Transfus Med Hemother 2008; 35: 286-294
• 17 Borghesi A, Massa M, Campanelli R et al. Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2009; 180: 540-546
• 18 Borte S, Lanig H, Borte M et al. Therapeutic implications of the IL-21: IL-4 receptor system in children with common variable immunodeficiency syndrome. Klin Padiatr 2010; 222: 362-367
• 19 Brown NC, Inder TE, Bear MJ et al. Neurobehavior at term and white and gray matter abnormalities in very preterm infants. J Pediatr 2009; 155: 32-38
• 20 Bruder D, Westendorf AM, Geffers R et al. CD4 T Lymphocyte-mediated lung disease: steady state between pathological and tolerogenic immune reactions. Am J Respir Crit Care Med 2004; 170: 1145-1152
• 21 Buchmann EJ, Pattinson RC, Nyathikazi N. Intrapartum-related birth asphyxia in South Africa – lessons from the first national perinatal care survey. S Afr Med J 2002; 92: 897-901
• 22 Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011; 9: 11-15
• 23 Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98: 1076-1084
• 24 Chouaib S, Messai Y, Couve S et al. Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol 2012; 3: 21
• 25 Critser PJ, Voytik-Harbin SL, Yoder MC. Isolating and defining cells to engineer human blood vessels. Cell Prolif 2011; 44 (Suppl. 01) 15-21
• 26 Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 2009; 30: 626-635
• 27 De Paepe ME, Mao Q, Ghanta S et al. Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. Am J Pathol 2011; 178: 1329-1339
• 28 Domagala-Kulawik J, Hoser G, Dabrowska M et al. CD4+/CD25+ cells in systemic inflammation in COPD. Scand J Immunol 2011; 73: 59-65
• 29 Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone Treatment in the First Week of Life for Preventing Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review. Neonatology 2010; 98 217-224
• 30 Ferriero DM. Neonatal brain injury. N Engl J Med 2004; 351: 1985-1995
• 31 Fujinaga H, Baker CD, Ryan SL et al. Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants. Am J Physiol 2009; 297: L1160-L1169
• 32 Giebel B, Punzel M. Lineage development of hematopoietic stem and progenitor cells. Biol Chem 2008; 389: 813-824
• 33 Girard S, Kadhim H, Roy M et al. Role of perinatal inflammation in cerebral palsy. Pediatr Neurol 2009; 40: 168-174
• 34 Gluckman E, Broxmeyer HA, Auerbach AD et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989; 321: 1174-1178
• 35 Gluckman E, Wagner J, Hows J et al. Cord blood banking for hematopoietic stem cell transplantation: an international cord blood transplant registry. Bone Marrow Transplant 1993; 11: 199-200
• 36 Gluckman PD, Wyatt JS, Azzopardi D et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663-670
• 37 Gonzalez FF, Ferriero DM. Therapeutics for neonatal brain injury. Pharmacol Ther 2008; 120: 43-53
• 38 Gortner L, Misselwitz B, Milligan D et al. Rates of bronchopulmonary dysplasia in very preterm neonates in Europe: results from the MOSAIC cohort. Neonatology 2011; 99: 112-117
• 39 Greenough A. Long-term pulmonary outcome in the preterm infant. Neonatology 2008; 93: 324-327
• 40 Grunewald M, Avraham I, Dor Y et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006; 124: 175-189
• 41 Gupta N, Su X, Popov B et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007; 179: 1855-1863
• 42 Hack M, Taylor HG, Klein N et al. School-age outcomes in children with birth weights under 750 g. N Engl J Med 1994; 331: 753-759
• 43 Haller MJ, Viener HL, Wasserfall C et al. Autologous umbilical cord blood infusion for type 1 diabetes. Exp Hematol 2008; 36: 710-715
• 44 Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 1983; 97: 329-339
• 45 Honig M, Schulz A, Friedrich W. Hematopoietic stem cell transplantation for severe combined immunodeficiency. Klin Padiatr 2011; 223: 320-325
• 46 Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood 2005; 106: 1525-1531
• 47 Jeong JO, Han JW, Kim JM et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res 2011; 108: 1340-1347
• 48 Jin K, Minami M, Lan JQ et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 2001; 98: 4710-4715
• 49 Johnstone RM, Adam M, Hammond JR et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262: 9412-9420
• 50 Jones CP, Pitchford SC, Lloyd CM et al. CXCR2 mediates the recruitment of endothelial progenitor cells during allergic airways remodeling. Stem Cells 2009; 27: 3074-3081
• 51 Kern S, Eichler H, Stoeve J et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24: 1294-1301
• 52 Kirton JP, Xu Q. Endothelial precursors in vascular repair. Microvasc Res 2010; 79: 193-199
• 53 Klopp AH, Gupta A, Spaeth E et al. Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth?. Stem Cells 2011; 29: 11-19
• 54 Kribs A, Hartel C, Kattner E et al. Surfactant without intubation in preterm infants with respiratory distress: first multi-center data. Klin Padiatr 2010; 222: 13-17
• 55 Kurtzberg J. Update on umbilical cord blood transplantation. Curr Opin Pediatr 2009; 21: 22-29
• 56 Lai RC, Arslan F, Lee MM et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4: 214-222
• 57 Le BK, Rasmusson I, Sundberg B et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439-1441
• 58 Lee JA, Kim BI, Jo CH et al. Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res 2010; 67: 42-46
• 59 Lenssen J, Stolk J. Pulmonary stem cells and the induction of tissue regeneration in the treatment of emphysema. Int J Chron Obstruct Pulmon Dis 2007; 2: 131-139
• 60 Liu F, Liu J, Weng D et al. CD4+CD25+Foxp3+ regulatory T cells depletion may attenuate the development of silica-induced lung fibrosis in mice. PLoS One 2010; 5: e15404
• 61 Ludwig AK, Giebel B. Exosomes: Small vesicles participating in intercellular communication. Int J Biochem Cell Biol 2011;
• 62 Majhail NS, Brunstein CG, Wagner JE. Double umbilical cord blood transplantation. Curr Opin Immunol 2006; 18: 571-575
• 63 Majka S, Alvarez DF. Neovascular capacity of endothelial progenitor cells in the adult pulmonary circulation. Am J Physiol 2009; 296: L868-L869
• 64 Mao M, Wang SN, Lv XJ et al. Intravenous delivery of bone marrow-derived endothelial progenitor cells improves survival and attenuates lipopolysaccharide-induced lung injury in rats. Shock 2010; 34: 196-204
• 65 Martin JA, Hamilton BE, Sutton PD et al. Births: final data for 2005. Natl Vital Stat Rep 2007; 56: 1-103
• 66 Mello RR, Silva KS, Rodrigues MC et al. Predictive factors for neuromotor abnormalities at the corrected age of 12 months in very low birth weight premature infants. Arq Neuropsiquiatr 2009; 67: 235-241
• 67 Mercier JC, Hummler H, Durrmeyer X et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 2010; 376: 346-354
• 68 Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147
• 69 Popova AP, Bozyk PD, Bentley JK et al. Isolation of tracheal aspirate mesenchymal stromal cells predicts bronchopulmonary dysplasia. Pediatrics 2010; 126: e1127-e1133
• 70 Raposo G, Nijman HW, Stoorvogel W et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996; 183: 1161-1172
• 71 Reid SM, Carlin JB, Reddihough DS. Rates of cerebral palsy in Victoria, Australia, 1970 to 2004: has there been a change?. Dev Med Child Neurol 2011; 53: 907-912
• 72 Reith W. White matter lesions in neonates. Klin Padiatr 2010; 222: 427-429
• 73 Richter E, Eichler H, Leveringhaus A et al. The Mannheim Cord Blood Project: Data on volume reduction by buffy coat preparation of 209 cb samples. Bone Marrow Transplant 1998; 21: S22
• 74 Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345-352
• 75 Sala E, Villena C, Balaguer C et al. Abnormal levels of circulating endothelial progenitor cells during exacerbations of COPD. Lung 2010; 188: 331-338
• 76 Samuel GN, Kerridge IH, O’Brien TA. Umbilical cord blood banking: public good or private benefit?. Med J Aust 2008; 188: 533-535
• 77 Schoemans H, Theunissen K, Maertens J et al. Adult umbilical cord blood transplantation: a comprehensive review. Bone Marrow Transplant 2006; 38: 83-93
• 78 Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2009; CD007836
• 79 Shankaran S, Pappas A, Laptook AR et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2008; 122: e791-e798
• 80 Sokolova V, Ludwig AK, Hornung S et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces 2011; 87: 146-150
• 81 Thomas W, Speer CP. Nonventilatory strategies for prevention and treatment of bronchopulmonary dysplasia – what is the evidence?. Neonatology 2008; 94: 150-159
• 82 Thornberg E, Thiringer K, Odeback A et al. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Paediatr 1995; 84: 927-932
• 83 Timmers L, Lim SK, Arslan F et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 2007; 1: 129-137
• 84 Tolar J, Hippen KL, Blazar BR. Immune regulatory cells in umbilical cord blood: T regulatory cells and mesenchymal stromal cells. Br J Haematol 2009; 147: 200-206
• 85 Tolar J, Le BK, Keating A et al. Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 2010; 28: 1446-1455
• 86 Urban C, Lackner H, Muller E et al. Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome. Klin Padiatr 2011; 223: 332-334
• 87 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: 1131-1142
• 88 Van Marter LJ, Kuban KC, Allred E et al. Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation?. Arch Dis Child Fetal Neonatal Ed 2011; 96: F20-F29
• 89 van Velthoven CT, Kavelaars A, van BF et al. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun March 2010; 24: 387-393
• 90 van Velthoven CT, Kavelaars A, van BF et al. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci 2010; 30: 9603-9611
• 91 Vrijlandt EJ, Gerritsen J, Boezen HM et al. Lung function and exercise capacity in young adults born prematurely. Am J Respir Crit Care Med 2006; 173: 890-896
• 92 Wahid FS, Nasaruddin MZ, Idris MR et al. Effects of preeclampsia on the yield of hematopoietic stem cells obtained from umbilical cord blood at delivery. J Obstet Gynaecol Res 2012; 38: 490-497
• 93 Weiss DJ, Kolls JK, Ortiz LA et al. Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 2008; 5: 637-667
• 94 Wood NS, Costeloe K, Gibson AT et al. The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed 2005; 90: F134-F140
• 95 Yasuhara T, Hara K, Maki M et al. Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab 2008; 28: 1804-1810
• 96 Yasuhara T, Matsukawa N, Yu G et al. Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury. Cell Transplant 2006; 15: 231-238
• 97 Yoder MC, Ingram DA. The definition of EPCs and other bone marrow cells contributing to neoangiogenesis and tumor growth: is there common ground for understanding the roles of numerous marrow-derived cells in the neoangiogenic process?. Biochim Biophys Acta 2009; 1796: 50-54
• 98 Zhang RL, Zhang ZG, Zhang L et al. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 2001; 105: 33-41
• 99 Zhang X, Wang H, Shi Y et al. The Role Of Bone Marrow-Derived Mesenchymal Stem Cells in the Prevention of Hyperoxia-Induced Lung Injury in Newborn Mice. Cell Biol Int 2012; 36: 589-594
• 100 Zhu JH, Wang XX, Zhang FR et al. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transplant 2008; 12: 650-655