MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

Current Stem Cell Reports

Volumn 2, Issue 2, 2016, Pages 158-167

  Pierro, M ^a   Thebaud B ^b,c,d  

^a UNIVERSITY OF MILAN   (Italy)

^b CHILDREN S HOSPITAL OF EASTERN ONTARIO   (Canada)

^c OTTAWA HOSPITAL RESEARCH INSTITUTE   (Canada)

^d UNIVERSITY OF OTTAWA   (Canada)

Author keywords

Immune system; Inflammation; Mesenchymal stromal cells; Newborn

Indexed keywords

GAMMA INTERFERON; HEME OXYGENASE; INDOLEAMINE 2,3 DIOXYGENASE; INTERLEUKIN 10; INTERLEUKIN 17; INTERLEUKIN 6; NITRIC OXIDE; PROSTAGLANDIN E2; SCATTER FACTOR; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR;

ADAPTIVE IMMUNITY; APOPTOSIS; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; HOMEOSTASIS; HUMAN; HYPOXIC ISCHEMIC ENCEPHALOPATHY; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOMODULATION; INFECTION; INFLAMMATION; LUNG DYSPLASIA; LYMPHOCYTE PROLIFERATION; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMA CELL; NECROTIZING ENTEROCOLITIS; NERVE CELL DIFFERENTIATION; NEUTROPHIL; NEWBORN; NEWBORN DISEASE; NEWBORN MORTALITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW;

EID: 85033485345     PISSN: None     EISSN: 21987866     Source Type: Journal    
DOI: 10.1007/s40778-016-0045-5     Document Type: Review

References (107)

1. Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29:617–25.
2. Schultz C, Temming P, Bucsky P, Göpel W, Strunk T, Härtel C. Immature anti-inflammatory response in neonates. Clin Exp Immunol. 2004;135:130–6.
3. Getahun D, Strickland D, Zeiger RS, et al. Effect of chorioamnionitis on early childhood asthma. Arch Pediatr Adolesc Med. 2010;164:187–92.
4. Sobko T, Schiött J, Ehlin A, Lundberg J, Montgomery S, Norman M. Neonatal sepsis, antibiotic therapy and later risk of asthma and allergy. Paediatr Perinat Epidemiol. 2010;24:88–92.
5. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292:2357–65.
6. Pappas A, Kendrick DE, Shankaran S, et al. Chorioamnionitis and early childhood outcomes among extremely low-gestational-age neonates. JAMA Pediatr. 2014;168:137–47.
7. Murphy J, Sellers S, MacKenzie ZI, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet. 1995;346:1449–54.
8. Brown AS. The environment and susceptibility to schizophrenia. Prog Neurobiol. 2010;93:23–8.
9. Meyer U, Feldon J, Dammann O. Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr Res. 2011;69:26–33R.
10. Soleymaninejadian E, Pramanik K, Samadian E. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Am J Reprod Immunol. 2012;67:1–8.
11. 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;8:315–7.
12. da Silva ML, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.
13. Bieback K, Brinkmann I. Mesenchymal stromal cells from human perinatal tissues: from biology to cell therapy. World J Stem Cells. 2010;2:81–92.
14. Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–77.
15. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45, e54.
16. Kim CJ, Romero R, Chaemsaithong P, et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol. 2015;213:S29–52.
17. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998;179:194–202.
18. Rogers BB, Alexander JM, Head J, McIntire D, Leveno KJ. Umbilical vein interleukin-6 levels correlate with the severity of placental inflammation and gestational age. Hum Pathol. 2002;33:335–40.
19. Nishimaki S, Shima Y, Sato M, An H, Kadota K, Yokota S. Postnatal changes of cytokines in premature infants with or without funisitis. J Matern Fetal Neonatal Med. 2014;27:1545–9.
20. Melville JM, Moss TJ. The immune consequences of preterm birth. Front Neurosci. 2013;7:79.
21. Zhao J, Kim KD, Yang X, Auh S, Fu YX, Tang H. Hyper innate responses in neonates lead to increased morbidity and mortality after infection. Proc Natl Acad Sci U S A. 2008;105:7528–33.
22. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229:176–85.
23. Nguyen CN, Schnulle PM, Chegini N, Luo X, Koenig JM. Neonatal neutrophils with prolonged survival secrete mediators associated with chronic inflammation. Neonatology. 2010;98:341–7.
24. Gille C, Dreschers S, Leiber A, et al. The CD95/CD95L pathway is involved in phagocytosis-induced cell death of monocytes and may account for sustained inflammation in neonates. Pediatr Res. 2013;73:402–8.
25. Caron JE, La Pine TR, Augustine NH, Martins TB, Hill HR. Multiplex analysis of toll-like receptor-stimulated neonatal cytokine response. Neonatology. 2010;97:266–73.
26. Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014;10:1171–84.
27. Maddux AB, Douglas IS. Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance? Immunology. 2015;145:1–10.
28. Smith NL, Wissink E, Wang J, Pinello JF, Davenport MP, Grimson A, et al. Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J Immunol. 2014;193:177–84.
29. Dirix V, Vermeulen F, Mascart F. Maturation of CD4+ regulatory T lymphocytes and of cytokine secretions in infants born prematurely. J Clin Immunol. 2013;33:1126–33.
30. Xu L, Tanaka S, Bonno M, Ido M, Kawai M, Yamamoto H, et al. Cell Cord blood CD4(+)CD25(+) regulatory T cells fail to inhibit cord blood NK cell functions due to insufficient production and expression of TGF-beta1. Immunol. 2014;290:89–95.
31. Rueda CM, Moreno-Fernandez ME, Jackson CM, Kallapur SG, Jobe AH, Chougnet CA. Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function. Eur J Immunol. 2015;45:2582–92.
32. Rueda CM, Wells CB, Gisslen T, Jobe AH, Kallapur SG, Chougnet CA. Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates. Hum Immunol. 2015;76:65–73.
33. Sykes L, MacIntyre D, Yap XJ, Teoh TG, Bennett PR. The Th1:th2 dichotomy of pregnancy and preterm labour. Mediators Inflamm. 2012;2012:967629.
34. Albertsson AM, Bi D, Duan L, et al. The immune response after hypoxia-ischemia in a mouse model of preterm brain injury. J Neuroinflammation. 2014;11:153.
35. Weitkamp JH, Koyama T, Rock MT, et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut. 2013;62:73–82.
36. + T cells in bronchopulmonary dysplasia. Hum Immunol. 2015;76:329–38.
37. Bonestroo HJ, Nijboer CH, van Velthoven CT, et al. Cerebral and hepatic inflammatory response after neonatal hypoxia-ischemia in newborn rats. Dev Neurosci. 2013;35:197–211.
38. Syed MA, Bhandari V. Hyperoxia exacerbates postnatal inflammation-induced lung injury in neonatal BRP-39 null mutant mice promoting the M1 macrophage phenotype. Mediators Inflamm. 2013;2013:457189.
39. De Paepe ME, Hanley LC, Lacourse Z, Pasquariello T, Mao Q. Pulmonary dendritic cells in lungs of preterm infants: neglected participants in bronchopulmonary dysplasia? Pediatr Dev Pathol. 2011;14:20–7.
40. Nold MF, Mangan NE, Rudloff I, et al. Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Proc Natl Acad Sci U S A. 2013;110:14384–9.
41. Turunen R, Vaarala O, Nupponen I, et al. Activation of T cells in preterm infants with respiratory distress syndrome. Neonatology. 2009;96:248–58.
42. Wei J, Besner GE. M1 to M2 macrophage polarization in heparin-binding epidermal growth factor-like growth factor therapy for necrotizing enterocolitis. J Surg Res. 2015;197:126–38.
43. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12:383–96.
44. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13:392–402.
45. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE. 2008;3, e1886.
46. Cho DI, Kim MR, Jeong HY, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med. 2014;46, e70.
47. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111:1327–33.
48. Chen P, Huang Y, Womer KL. Effects of mesenchymal stromal cells on human myeloid dendritic cell differentiation and maturation in a humanized mouse model. J Immunol Methods. 2015.
49. Khan I, Zhang L, Mohammed M, et al. Effects of Wharton’s jelly-derived mesenchymal stem cells on neonatal neutrophils. J Inflamm Res. 2014;8:1–8.
50. Kramer BW, Jobe AH, Ikegami M. Monocyte function in preterm, term, and adult sheep. Pediatr Res. 2003;54:52–7.
51. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–50.
52. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105:2821–7.
53. Wang D, Huang S, Yuan X, et al. The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus. Cell Mol Immunol. 2015 [Epub ahead of print].
54. Darlington PJ, Boivin MN, Renoux C, et al. Reciprocal Th1 and Th17 regulation by mesenchymal stem cells: implication for multiple sclerosis. Ann Neurol. 2010;68:540–5.
55. Bai L, Lennon DDP, Eaton V, et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia. 2009;57:1192–203.
56. Mareschi K, Castiglia S, Sanavio F, et al. Immunoregulatory effects on T lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta. Exp Hematol. 2015; S0301-472X(15)00731-6.
57. Liu Q, Zheng H, Chen X, et al. Human mesenchymal stromal cells enhance the immunomodulatory function of CD8(+)CD28(-) regulatory T cells. Cell Mol Immunol. 2015;12:708–18. This study highlights the importance of Treg enhancement on MSC-mediated immune regulation.
58. Budoni M, Fierabracci A, Luciano R, Petrini S, Di Ciommo V, Muraca M. The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transplant. 2013;22:369–79.
59. Li W, Ren G, Huang Y, et al. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ. 2012;19:1505–13. This study helps in understanding the factors that determine the preferential switch towards either anti-inflammatory or pro-inflammatory competence of MSCs.
60. Ren G, Su J, Zhang L, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells. 2009;27:1954–62.
61. Duijvestein M, Wildenberg ME, Welling MM, et al. Pretreatment with interferon-gamma enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells. 2001;29:1549–58.
62. Polchert D, Sobinsky J, Douglas G, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol. 2008;38:1745–55.
63. Chen Y, Gan W, Li J, et al. The interaction between mesenchymal stem cells and steroids during inflammation. Cell Death Dis. 2014;5:e1009. This study shows that by attenuating inflammation, steroids hamper the anti-inflammatory role of MSCs.
64. Sudres M, Norol F, Trenado A, et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol. 2006;176:7761–7.
65. Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation. 2006;81:1589–95.
66. Ren G, Zhao X, Zhang L, et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol. 2010;184:2321–8.
67. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–43.
68. Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007;109:228–34.
69. English K, Ryan JM, Tobin L, et al. Cell contact, prostaglandin E(2) and transforming growth factor beta-1 play non-redundant roles in human mesenchymal stem cell induction of CD4 + CD25 (High) fork head box P3+ regulatory T cells. Clin Exp Immunol. 2009;156:149–6.
70. Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4 + CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;26:212–22.
71. Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells. 2007;25:2025–32.
72. Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp Hematol. 2009;37:604–15.
73. Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery - a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31:543–51.
74. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94:3791–9.
75. György B, Szabó TG, Pásztói M, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011;68:2667–88.
76. Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev. 2015;11:150–60. This systematic review shows that MSC-derived microvesicles improved organ function following injury in several experimental settings.
77. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett. 2012;147:47–54.
78. Favaro E, Carapanetto A, Lamorte S, et al. Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1diabetes. Diabetologia. 2014;57:1664–73.
79. Cruz FF, Borg ZD, Goodwin M, et al. Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates Aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent. Mice Stem Cells Transl Med. 2015;4:1302–16.
80. Lee C, Mitsialis SA, Aslam M, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.
81. Kordelas L, Rebmann V, Ludwig AK, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–3. The administration of MSC exosomes to a patient affected by refractory GvHD was safe over several months and able to reduce the symptoms of rejection.
82. Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int J Dev Neurosci. 2011;29:423–40.
83. Jellema RK, Wolfs TG, Lima Passos V, et al. Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia. PLoS One. 2013;8, e73031.
84. Zhu LH, Bai X, Zhang N, Wang SY, Li W, Jiang L. Improvement of human umbilical cord mesenchymal stem cell transplantation on glial cell and behavioral function in a neonatal model of periventricular white matter damage. Brain Res. 2014;1563:13–21.
85. Donega V, Nijboer CH, van Tilborg G, Dijkhuizen RM, Kavelaars A, Heijnen CJ. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp Neurol. 2014;261:53–64.
86. 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;180:1122–30.
87. Volpe JJ. Neonatal encephalopathy: an inadequate term for hypoxic-ischemic encephalopathy. Ann Neurol. 2012;72:156–66.
88. Garfinkle J, Wintermark P, Shevell MI, Platt RW, Oskoui M. Canadian cerebral palsy registry. Cerebral palsy after neonatal encephalopathy: how much is preventable? J Pediatr. 2015;167:58–63.e1.
89. Chor V, Charpentier TL, Lebon S, et al. Characterization of phenotype markers and neuronotoxic potential of polarized primary microglia in vitro. Brain Behav Immun. 2013;32:70–85.
90. Aly H, Khashaba MT, El-Ayouty M, El-Sayed O, Hasanein BM. IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev. 2006;28:178–82.
91. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010;24:387–93.
92. Zhang X, Zhang Q, Li W, Nie D, Chen W, Xu C. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy. J Neurosci Res. 2014;92:35–45.
93. Li M, Yu A, Zhang F, et al. Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells. J Transl Med. 2012;10:100.
94. Wang X, Hu H, Hua R, Yang J, et al. Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: pilot study on the correlation of efficacy and hereditary factors. Cytotherapy. 2015;17:224–31.
95. Wang L, Ji H, Zhou J, et al. Therapeutic potential of umbilical cord mesenchymal stromal cells transplantation for cerebral palsy: a case report. Case Rep Transplant. 2013;2013:146347.
96. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:1723–9.
97. Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA. 2015;314:1039–51.
98. Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology. 2009;95:353–61.
99. 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;68:475–84.
100. 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;20:1843–54.
101. Chang YS, Oh W, Choi SJ, et al. Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant. 2009;18:869–86.
102. Chang YS, Ahn SY, Yoo HS, et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr. 2014;164:966–72. This is first phase 1 trial in neonates proving that the treatment may be feasible and apparently safe.
103. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364:255e264.
104. Yu Y, Klemann C, Feng X, et al. Increased inflammatory reaction to intestinal ischemia-reperfusion in neonatal versus adult mice. Eur J Pediatr Surg. 2015;25:46–50.
105. Bhatia AM, Stoll BJ, Cismowski MJ, Hamrick SE. Cytokine levels in the preterm infant with neonatal intestinal injury. Am J Perinatol. 2014;31:489–96.
106. Tayman C, Uckan D, Kilic E, et al. Mesenchymal stem cell therapy in necrotizing enterocolitis: a rat study. Pediatr Res. 2011;70:489–94.
107. Yang J, Watkins D, Chen CL, Bhushan B, Zhou Y, Besner GE. Heparin-binding epidermal growth factor-like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. J Am Coll Surg. 2012;215:534–45.