Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges


Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Kochanek, K. D., Murphy, S. L., Xu, J., Arias, E. Mortality in the United States, 2016. NCHS Data Brief, no 293. [Internet]. Hyattsville, MD: 2017. Available from:

  2. 2.

    Nitkin, C. R., Bonfield, T. L. Concise Review: Mesenchymal Stem Cell Therapy for Pediatric Disease: Perspectives on Success and Potential Improvements. Stem Cells Transl Med 2016 (cited 20 Sep 2016) Available from:

  3. 3.

    Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705, (2001).

    CAS  PubMed  Google Scholar 

  4. 4.

    Friedenstein, A. J., Gorskaja, J. F. & Kulagina, N. N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp. Hematol. 4, 267–274, (1976).

    CAS  PubMed  Google Scholar 

  5. 5.

    Kern, S., Eichler, H., Stoeve, J., Klüter, H. & Bieback, K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24, 1294–1301, (2006).

    CAS  PubMed  Google Scholar 

  6. 6.

    Miao, Z. et al. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol. Int. 30, 681–687, (2006).

    CAS  PubMed  Google Scholar 

  7. 7.

    Dominici, M., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006 8:315–317.

    CAS  Google Scholar 

  8. 8.

    Wegmeyer, H. et al. Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev. 22, 2606–2618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Hoffmann, A., Floerkemeier, T., Melzer, C. & Hass, R. Comparison of in vitro-cultivation of human mesenchymal stroma/stem cells derived from bone marrow and umbilical cord. J. Tissue Eng. Regen. Med. 11, 2565–2581 (2017).

    CAS  PubMed  Google Scholar 

  10. 10.

    Bernardo, M. E., Pagliara, D. & Locatelli, F. Mesenchymal stromal cell therapy: a revolution in Regenerative Medicine? Bone Marrow Transpl. 47, 164–171 (2012).

    CAS  Google Scholar 

  11. 11.

    Cunningham, C. J., Redondo-Castro, E. & Allan, S. M. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J. Cereb. Blood Flow. Metab. 38, 1276–1292 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Grisafi, D. et al. Human amniotic fluid stem cells protect rat lungs exposed to moderate hyperoxia. Pedia. Pulmonol. 48, 1070–1080 (2013).

    Google Scholar 

  13. 13.

    McCulloh, C. J. et al. Treatment of experimental necrotizing enterocolitis with stem cell-derived exosomes. J. Pedia. Surg. 53, 1215–1220 (2018).

    Google Scholar 

  14. 14.

    Dekoninck, P. et al. The use of human amniotic fluid stem cells as an adjunct to promote pulmonary development in a rabbit model for congenital diaphragmatic hernia. Prenat. Diagn. 35, 833–840 (2015).

    CAS  PubMed  Google Scholar 

  15. 15.

    Zani, A. et al. Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut 63, 300–309 (2014).

    CAS  PubMed  Google Scholar 

  16. 16.

    Erkers, T. et al. Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with (111)indium radiolabeling. Stem Cells Dev. 24, 253–263 (2015).

    CAS  PubMed  Google Scholar 

  17. 17.

    Wehman, B. et al. Cardiac progenitor cells enhance neonatal right ventricular function after pulmonary artery banding. Ann. Thorac. Surg. 104, 2045–2053 (2017).

    PubMed  Google Scholar 

  18. 18.

    Avolio, E. et al. Expansion and characterization of neonatal cardiac pericytes provides a novel cellular option for tissue engineering in congenital heart disease. J. Am. Heart Assoc. 4, e002043 (2015).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Nakanishi, K. et al. Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats. Sci. Rep. 7, 44111 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Drobyshevsky, A. et al. Human umbilical cord blood cells ameliorate motor deficits in rabbits in a cerebral palsy model. Dev. Neurosci. 37, 349–362 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Greggio, S., De Paula, S., Azevedo, P. N., Venturin, G. T. & Dacosta, J. C. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in neonatal hypoxic-ischemic rats. Life Sci. 96, 33–39 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Brizard, C. P. et al. Safety of intracoronary human cord blood stem cells in a lamb model of infant cardiopulmonary bypass. Ann. Thorac. Surg. 100, 1021–1029 (2015).

    PubMed  Google Scholar 

  23. 23.

    Prockop, D. J., Kota, D. J., Bazhanov, N. & Reger, R. L. Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). J. Cell Mol. Med. 14, 2190–2199 (2010).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Fung, M. E. & Thébaud, B. Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr. Res. 75, 2–7 (2014).

    PubMed  Google Scholar 

  25. 25.

    Lee, J. W., Fang, X., Krasnodembskaya, A., Howard, J. P. & Matthay, M. A. Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells 29, 913–919 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Augustine, S. et al. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cells Transl. Med. 6, 2079–2093 (2017).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ortiz, L. A. et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc. Natl Acad. Sci. USA 104, 11002–11007 (2007).

    CAS  PubMed  Google Scholar 

  28. 28.

    Chaubey, S. et al. Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem Cell Res Ther. 9, 173 (2018).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Bartosh, T. J. et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc. Natl Acad. Sci. USA 107, 13724–13729 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Németh, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

    PubMed  Google Scholar 

  31. 31.

    Ono, M. et al. Mesenchymal stem cells correct inappropriate epithelial-mesenchyme relation in pulmonary fibrosis using stanniocalcin-1. Mol. Ther. 23, 549–560 (2015).

    CAS  PubMed  Google Scholar 

  32. 32.

    Li, L. L. et al. Mesenchymal stem cells overexpressing adrenomedullin improve heart function through antifibrotic action in rats experiencing heart failure. Mol. Med Rep. 17, 1437–1444 (2018).

    CAS  PubMed  Google Scholar 

  33. 33.

    Xu, Y.-X. et al. Mesenchymal stem cell therapy for diabetes through paracrine mechanisms. Med. Hypotheses 71, 390–393 (2008).

    CAS  PubMed  Google Scholar 

  34. 34.

    Chang, Y. S. et al. Critical role of vascular endothelial growth factor secreted by mesenchymal stem cells in hyperoxic lung injury. Am. J. Respir. Cell Mol. Biol. 51, 391–399 (2014).

    PubMed  Google Scholar 

  35. 35.

    Lee, J. W., Fang, X., Matthay, M. A., Serikov, V., Gupta, N. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc. Natl Acad. Sci. USA 106, 16357–16362 (2009).

    CAS  PubMed  Google Scholar 

  36. 36.

    van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).

    PubMed  Google Scholar 

  37. 37.

    Stoorvogel, W. Functional transfer of microRNA by exosomes. Blood 119, 646–648 (2012).

    CAS  PubMed  Google Scholar 

  38. 38.

    van Haaften, T. et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am. J. Respir. Crit. Care Med. 180, 1131–1142 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Aslam, M. et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am. J. Respir. Crit. Care Med. 180, 1122–1130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pierro, M. 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 68, 475–484 (2013).

    PubMed  Google Scholar 

  41. 41.

    Waszak, P. et al. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev. 21, 2789–2797 (2012).

    CAS  PubMed  Google Scholar 

  42. 42.

    Vizoso, F. J., Eiro, N., Cid, S., Schneider, J., Perez-Fernandez, R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int. J. Mol. Sci. 18, 1852 (2017). Available from:

    PubMed Central  Google Scholar 

  43. 43.

    Park, S.-J. et al. Tumorigenicity evaluation of umbilical cord blood-derived mesenchymal stem cells. Toxicol. Res. 32, 251–258 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Barkholt, L. et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies - Bridging scientific observations and regulatory viewpoints. Cytotherapy 15, 753–759 (2013).

    PubMed  Google Scholar 

  45. 45.

    Hamidian, Jahromi, S., Estrada, C., Li, Y., Cheng, E., Davies, J. E. Human umbilical cord perivascular cells and human bone marrow mesenchymal stromal cells transplanted intramuscularly respond to a distant source of inflammation. Stem Cells Dev. 2018;27:scd.2017.0248. Available from:

    CAS  PubMed  Google Scholar 

  46. 46.

    Luan, Y. et al. Bone marrow-derived mesenchymal stem cells protect against lung injury in a mouse model of bronchopulmonary dysplasia. Mol. Med. Rep. 11, 1945–1950 (2015).

    CAS  PubMed  Google Scholar 

  47. 47.

    Gholamrezanezhad, A. et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl. Med. Biol. 38, 961–967 (2011).

    CAS  PubMed  Google Scholar 

  48. 48.

    Zhang, X. et al. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy. J. Neurosci. Res 92, 35–45 (2014).

    PubMed  Google Scholar 

  49. 49.

    Tanaka, E. et al. Dose-dependent effect of intravenous administration of human umbilical cord-derived mesenchymal stem cells in neonatal stroke mice. Front Neurol. 9, 133 (2018).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Donega, V. et al. Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse. Pediatr. Res. 78, 520–526 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Donega, V. et al. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp. Neurol. 261, 53–64 (2014).

    CAS  PubMed  Google Scholar 

  52. 52.

    Park, D. et al. Transplantation of human adipose tissue-derived mesenchymal stem cells restores the neurobehavioral disorders of rats with neonatal hypoxic-ischemic encephalopathy. Cell Med. 5, 17–28 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Chou, H. C., Li, Y. T. & Chen, C. M. Human mesenchymal stem cells attenuate experimental bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Am. J. Transl. Res. 8, 342–353 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Ding, H. et al. Transplantation of placenta-derived mesenchymal stem cells reduces hypoxic-ischemic brain damage in rats by ameliorating the inflammatory response. Cell Mol. Immunol. 14, 693–701 (2017).

    CAS  PubMed  Google Scholar 

  55. 55.

    Sammour, I. et al. The effect of gender on mesenchymal stem cell (MSC) efficacy in neonatal hyperoxia-induced lung injury. PLoS ONE 11, e0164269 (2016).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Willis, G. R. et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am. J. Respir. Crit. Care Med. 197, 104–116 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Woik, N. & Kroll, J. Regulation of lung development and regeneration by the vascular system. Cell Mol. Life Sci. 72, 2709–2718 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Montemurro, T. et al. Angiogenic and anti-inflammatory properties of mesenchymal stem cells from cord blood: soluble factors and extracellular vesicles for cell regeneration. Eur. J. Cell Biol. 95, 228–238 (2016).

    CAS  PubMed  Google Scholar 

  59. 59.

    Wen, Y.-C. et al. EphA2-positive human umbilical cord-derived mesenchymal stem cells exert anti-fibrosis and immunomodulatory activities via secretion of prostaglandin E2. Taiwan J. Obstet. Gynecol. 57, 722–725 (2018).

    PubMed  Google Scholar 

  60. 60.

    Luan, Y. et al. Mesenchymal stem cells in combination with erythropoietin repair hyperoxia-induced alveoli dysplasia injury in neonatal mice via inhibition of TGF-β1 signaling. Oncotarget 7, 47082–47094 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Hou, C. et al. Human umbilical cord-derived mesenchymal stem cells protect from hyperoxic lung injury by ameliorating aberrant elastin remodeling in the lung of O2-exposed newborn rat. Biochem. Biophys. Res. Commun. 495, 1972–1979 (2018).

    CAS  PubMed  Google Scholar 

  62. 62.

    Liu, L. et al. Intranasal versus intraperitoneal delivery of human umbilical cord tissue–derived cultured mesenchymal stromal cells in a murine model of neonatal lung injury. Am. J. Pathol. 184, 3344–3358 (2014).

    CAS  PubMed  Google Scholar 

  63. 63.

    Zhang, Z.-H. et al. Protective effects of BMSCs in combination with erythropoietin in bronchopulmonary dysplasia-induced lung injury. Mol. Med Rep. 14, 1302–1308 (2016).

    CAS  PubMed  Google Scholar 

  64. 64.

    Wehman, B. et al. Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload. Am. J. Physiol. - Hear Circ. Physiol. 310, H1816–H1826 (2016).

    Google Scholar 

  65. 65.

    Dumpa, V. & Bhandari, V. Surfactant, steroids and non-invasive ventilation in the prevention of BPD. Semin Perinatol. 42, 444–452 (2018).

    PubMed  Google Scholar 

  66. 66.

    Menden, H. L. et al. Nicotinamide adenine dinucleotide phosphate oxidase 2 regulates LPS-induced inflammation and alveolar remodeling in the developing lung. Am. J. Respir. Cell Mol. Biol. 55, 767–778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Morty, R. E. Recent advances in the pathogenesis of BPD. Semin Perinatol. 42, 404–412 (2018).

    PubMed  Google Scholar 

  68. 68.

    Bhandari, A. & Bhandari, V. Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants. Front Biosci. 8, e370–e380 (2003).

    CAS  PubMed  Google Scholar 

  69. 69.

    Baker, C. D. & Alvira, C. M. Disrupted lung development and bronchopulmonary dysplasia. Curr. Opin. Pediatr. 26, 306–314 (2014).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Álvarez-Fuente, M. et al. Preventing bronchopulmonary dysplasia: new tools for an old challenge. Pediatr. Res 85, 432–441 (2019).

    PubMed  Google Scholar 

  71. 71.

    Jobe, A. H. & Bancalari, E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med 163, 1723–1729 (2001).

    CAS  PubMed  Google Scholar 

  72. 72.

    Caplan, A. I. Mesenchymal stem cells: time to change the name! Stem Cells Transl. Med. 6, 1445–1451 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Fischbach, M. A., Bluestone, J. A., Lim, W. A. Cell-based therapeutics: the next pillar of medicine. Sci. Transl. Med. 2013

  74. 74.

    Pierro, M., Thébaud, B. & Soll, R. Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 11, (CD011932 (2017).

    Google Scholar 

  75. 75.

    Chang, Y. S. et al. Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury. PLoS ONE 8, e52419 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Porzionato, 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. Cell Mol. Physiol. 316, L6–L19 (2019).

    CAS  Google Scholar 

  77. 77.

    Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 8, e1000412 (2010).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Chang, Y. S. et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J. Pediatr. 164, 966–972.e6 (2014).

    PubMed  Google Scholar 

  79. 79.

    Ahn, S. Y., Chang, Y. S., Kim, J. H., Sung, S. I. & Park, W. S. Two-year follow-up outcomes of premature infants enrolled in the phase I trial of mesenchymal stem cells transplantation for bronchopulmonary dysplasia. J. Pediatr. 185, 49–54.e2 (2017).

    PubMed  Google Scholar 

  80. 80.

    Douglas-Escobar, M. & Weiss, M. D. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 169, 397–403 (2015).

    PubMed  Google Scholar 

  81. 81.

    Gu, Y. et al. Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFκB pathway in rats with hypoxic-ischemic brain damage. Mol. Brain 8, 65 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Park, W. S. et al. Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. PLoS ONE 10, e0120893 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Mueller, M. et al. Wharton’s jelly mesenchymal stem cells protect the immature brain in rats and modulate cell fate. Stem Cells Dev. 26, 239–248 (2017).

    CAS  PubMed  Google Scholar 

  84. 84.

    Donega, V. et al. Intranasal administration of human MSC for ischemic brain injury in the mouse: In vitro and in vivo neuroregenerative functions. PLoS ONE 9, e112339 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Grandvuillemin, I. et al. Long-term recovery after endothelial colony-forming cells or human umbilical cord blood cells administration in a rat model of neonatal hypoxic-ischemic encephalopathy. Stem Cells Transl. Med. 6, 1987–1996 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Li, J. et al. Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells. Exp. Neurol. 283, 179–187 (2016).

    PubMed  Google Scholar 

  87. 87.

    Braccioli, L., Heijnen, C. J., Coffer, P. J. & Nijboer, C. H. Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice. Pediatr. Res. 81, 127–135 (2017).

    PubMed  Google Scholar 

  88. 88.

    Cotten, C. M. et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J. Pediatr. 164, 973–979.e1 (2014).

    PubMed  Google Scholar 

  89. 89.

    Novak, I. et al. Concise review: stem cell interventions for people with cerebral palsy: systematic review with meta-analysis. Stem Cells Transl. Med. 5, 1014–1025 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Wang, X. et al. Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study. Cytotherapy 15, 1549–1562 (2013).

    PubMed  Google Scholar 

  91. 91.

    Finch-Edmondson, M., Morgan, C., Hunt, R. W. & Novak, I. Emergent prophylactic, reparative and restorative brain interventions for infants born preterm with cerebral palsy. Front Physiol. 10, 15 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ahn, S. Y. et al. Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage. Stroke 44, 497–504 (2013).

    CAS  PubMed  Google Scholar 

  93. 93.

    Zhu, L. H. et al. 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 1563, 13–21 (2014).

    CAS  PubMed  Google Scholar 

  94. 94.

    Ahn, S. Y. et al. Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats. Cell Transpl. 26, 145–156 (2017).

    Google Scholar 

  95. 95.

    Morioka, C. et al. Neuroprotective effects of human umbilical cord-derived mesenchymal stem cells on periventricular leukomalacia-like brain injury in neonatal rats. Inflamm. Regen. 37, 1 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Feng, M. et al. Safety of Allogeneic Umbilical Cord Blood Stem Cells Therapy in Patients with Severe Cerebral Palsy: A Retrospective Study. Stem Cells Int 2015, 325652 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Liu, X. et al. Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy. J. Transl. Med 15, 48 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kang, M. et al. Involvement of Immune Responses in the Efficacy of Cord Blood Cell Therapy for Cerebral Palsy. Stem Cells Dev. 24, 1658–1671 (2015). Available from:

    CAS  PubMed  Google Scholar 

  99. 99.

    Romanov, Y. A. et al. Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. Cytotherapy 17, 969–978 (2015).

    PubMed  Google Scholar 

  100. 100.

    Huang, L. et al. A Randomized, placebo-controlled trial of human umbilical cord blood mesenchymal stem cell infusion for children with cerebral palsy. Cell Transpl. 27, 325–334 (2018).

    Google Scholar 

  101. 101.

    Wang, X. 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 17, 224–231 (2015).

    PubMed  Google Scholar 

  102. 102.

    Neu, J. & Walker, W. A. Necrotizing Enterocolitis. N. Engl. J. Med. 364, 255–264 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Herrmann, K. & Carroll, K. An exclusively human milk diet reduces necrotizing enterocolitis. Breast. Med. 9, 184–190 (2014).

    Google Scholar 

  104. 104.

    Warner, B. B. et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet 387, 1928–1936 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Cuna, A., George, L. & Sampath, V. Genetic predisposition to necrotizing enterocolitis in premature infants: Current knowledge, challenges, and future directions. Semin Fetal Neonatal Med. 23, 387–393 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Sampath, V. et al. SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 135, e1530–e1534 (2015).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Hackam, D. J. & Sodhi, C. P. Toll-like receptor-mediated intestinal inflammatory imbalance in the pathogenesis of necrotizing enterocolitis. Cell Mol. Gastroenterol. Hepatol. 6, 229–238.e1 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Galindo, L. T. et al. Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol. Res Int. 2011, 564089 (2011).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Rowart, P. et al. Mesenchymal stromal cell therapy in ischemia/reperfusion injury. J. Immunol. Res. 2015, 1–8 (2015).

    Google Scholar 

  110. 110.

    Diaco, N., Diamandis, Z. & Borlongan, C. Amniotic fluid-derived stem cells as an effective cell source for transplantation therapy in stroke. Brain Circ. 1, 119 (2015).

    Google Scholar 

  111. 111.

    McCulloh, C. J., Olson, J. K., Zhou, Y., Wang, Y. & Besner, G. E. Stem cells and necrotizing enterocolitis: a direct comparison of the efficacy of multiple types of stem cells. J. Pediatr. Surg. 52, 999–1005 (2017).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    McCulloh, C. J. et al. Evaluating the efficacy of different types of stem cells in preserving gut barrier function in necrotizing enterocolitis. J. Surg. Res. 214, 278–285 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Ghionzoli, M. et al. Amniotic fluid stem cell migration after intraperitoneal injection in pup rats: implication for therapy. Pediatr. Surg. Int. 26, 79–84 (2010).

    PubMed  Google Scholar 

  114. 114.

    Zani, A. et al. Amniotic fluid stem cells prevent development of ascites in a neonatal rat model of necrotizing enterocolitis. Eur. J. Pedia. Surg. 24, 057–060 (2013).

    Google Scholar 

  115. 115.

    Drucker, N. A. et al. Stem cell therapy in necrotizing enterocolitis: current state and future directions. Semin Pediatr. Surg. 27, 57–64 (2018).

    PubMed  Google Scholar 

  116. 116.

    Li, B. et al. Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS ONE 14, e0211431 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Liu, X. et al. Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero. Nat. Commun. 6, 8825 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Zhang, Z. et al. Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair. J Am Heart Assoc. 5, e002856 (2016).

  119. 119.

    Tarui, S. et al. Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients with Single-Ventricle Physiology (TICAP) trial. J. Thorac. Cardiovasc Surg. 150, 1198–1207 (2015).

    PubMed  Google Scholar 

  120. 120.

    Kaushal, S. et al. Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome. Am. Heart J. 192, 48–56 (2017).

    PubMed  Google Scholar 

  121. 121.

    Yuniartha, R. et al. Therapeutic potential of mesenchymal stem cell transplantation in a nitrofen-induced congenital diaphragmatic hernia rat model. Pedia. Surg. Int. 30, 907–914 (2014).

    Google Scholar 

  122. 122.

    Wang, J.-D. et al. Human bone marrow mesenchymal stem cells for retinal vascular injury. Acta Ophthalmol. 95, e453–e461 (2017).

    CAS  PubMed  Google Scholar 

  123. 123.

    Wei, Z. Z. et al. Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats. Cell Transpl. 24, 391–402 (2015).

    Google Scholar 

  124. 124.

    van Velthoven, C. T. et al. Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J. Neurosci. Res. 95, 1225–1236 (2017).

    PubMed  Google Scholar 

  125. 125.

    Van Velthoven, C. T. J. et al. Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke. Stroke 44, 1426–1432 (2013).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Jeong, C. H. et al. Mesenchymal stem cells expressing brain-derived neurotrophic factor enhance endogenous neurogenesis in an ischemic stroke model. Biomed. Res. Int. 2014, 1–10 (2014).

    CAS  Google Scholar 

  127. 127.

    Zhu, Y. et al. Human umbilical cord mesenchymal stromal cells improve survival and bacterial clearance in neonatal sepsis in rats. Stem Cells Dev. 26, 1054–1064 (2017).

    CAS  PubMed  Google Scholar 

  128. 128.

    Hamidian, Jahromi, S., Li, Y., Davies, J. E. Effect of tumor necrosis factor alpha dose and exposure time on tumor necrosis factor induced gene-6 activation by neonatal and adult mesenchymal stromal cells. Stem Cells Dev. 27, 44–54 (2018). Available from:

  129. 129.

    Panfoli, I. et al. Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants. FASEB J. 30, 1416–1424 (2016).

    CAS  PubMed  Google Scholar 

  130. 130.

    Montanucci, P. et al. Functional profiles of human umbilical cord-derived adult mesenchymal stem cells in obese/diabetic versus healthy women. Curr. Diabetes Rev. 12, 1–12 (2016).

    Google Scholar 

  131. 131.

    Turner, L. US stem cell clinics, patient safety, and the FDA. Trends Mol. Med. 21, 271–273 (2015).

    PubMed  Google Scholar 

  132. 132.

    Hodges, R. J., Bardien, N. & Wallace, E. Acceptability of stem cell therapy by pregnant women. Birth 39, 91–97 (2012).

    PubMed  Google Scholar 

  133. 133.

    Park, W. S., Ahn, S. Y., Sung, S. I., Ahn, J.-Y. & Chang, Y. S. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr. Res. 83, 214–222 (2018).

    CAS  PubMed  Google Scholar 

  134. 134.

    Honn, K. V., Singley, J. A. & Chavin, W. Fetal bovine serum: a multivariate standard. Exp. Biol. Med. 149, 344–347 (1975).

    CAS  Google Scholar 

  135. 135.

    Oikonomopoulos, A. et al. Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media. Sci Rep. 2015;5:16570.

  136. 136.

    Swamynathan, P. et al. Are serum-free and xeno-free culture conditions ideal for large scale clinical grade expansion of Wharton’s jelly derived mesenchymal stem cells? A comparative study. Stem Cell Res. Ther. 5, 88 (2014).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Boregowda, S. V., Phinney, D. G. Quantifiable Metrics for Predicting MSC Therapeutic Efficacy. J Stem Cell Res Ther. 6, pii: 365 (2016). Available from:

  138. 138.

    Volarevic, V. et al. Ethical and safety issues of stem cell-based therapy. Int J. Med. Sci. 15, 36–45 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Borghesi, A. et al. Genomic alterations in human umbilical cord-derived mesenchymal stromal cells call for stringent quality control before any possible therapeutic approach. Cytotherapy 15, 1362–1373 (2013).

    CAS  PubMed  Google Scholar 

  140. 140.

    Ferreira, J. R. et al. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Front Immunol. 9, 2837 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Kilpinen, L. et al. Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell vesicles 2013;2. Available from:

  142. 142.

    Hoch, A. I. & Leach, J. K. Concise review: optimizing expansion of bone marrow mesenchymal stem/stromal cells for clinical applications. Stem Cells Transl. Med. 3, 643–652 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Krzyżaniak, N., Pawłowska, I. & Bajorek, B. Review of drug utilization patterns in NICUs worldwide. J. Clin. Pharm. Ther. 41, (612–620 (2016).

    Google Scholar 

  144. 144.

    Herz, J. et al. Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury. Brain Behav. Immun. 70, 118–130 (2018).

    CAS  PubMed  Google Scholar 

  145. 145.

    Perlee D., et al. Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group, placebo controlled trial. Stem Cells 2018.

    CAS  PubMed  Google Scholar 

  146. 146.

    Ahn, S. Y. et al. Optimal route for mesenchymal stem cells transplantation after severe intraventricular hemorrhage in newborn rats. PLoS ONE 10, 1–14 (2015).

    CAS  Google Scholar 

  147. 147.

    Cameron, S. H. et al. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia. Mol. Cell Neurosci. 68, 56–72 (2015).

    CAS  PubMed  Google Scholar 

  148. 148.

    Park, W. S. et al. Optimal timing of mesenchymal stem cell therapy for neonatal intraventricular hemorrhage. Cell Transpl. 25, 1131–1144 (2016).

    Google Scholar 

  149. 149.

    Araújo, A. B. et al. Isolation of human mesenchymal stem cells from amnion, chorion, placental decidua and umbilical cord: comparison of four enzymatic protocols. Biotechnol. Lett. 40, 989–998 (2018).

    PubMed  Google Scholar 

Download references


This study was supported by the National Institutes of Health (R01 HL128374 [VS]; R01 DK117296-01 [VS]; R01 GM113236 [GB]; R01 HL141345 [JR]), Canadian Institutes of Health Research (BT), Ontario Institute for Regenerative Medicine (BT), Canadian Stem Cell Network (BT), and Children’s Mercy Research Institute (VS, CN).

Author information




All authors made substantial contributions to conception and design, drafting the article, revising it critically for important intellectual content, and gave final approval of the version to be published.

Corresponding author

Correspondence to Venkatesh Sampath.

Ethics declarations

Competing interests

GB is a scientific founder and stock option holder in Scioto Biosciences. CN, RJ, BT, and VS have no financial or other conflicts.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nitkin, C.R., Rajasingh, J., Pisano, C. et al. Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. Pediatr Res 87, 265–276 (2020).

Download citation

Further reading