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Amniotic fluid and breast milk: a rationale for breast milk stem cell therapy in neonatal diseases

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Abstract

Amniotic fluid and breast milk play important roles in structural development throughout fetal growth and infancy. Given their significance in physical maturation, many studies have investigated the therapeutic and protective roles of amniotic fluid and breast milk in neonatal diseases. Of particular interest to researchers are stem cells found in the two fluids. These stem cells have been investigated due to their ability to self-replicate, differentiate, reduce tissue damage, and their expression of pluripotent markers. While amniotic fluid stem cells have received some attention regarding their ability to treat neonatal diseases, breast milk stem cells have not been investigated to the same extent given the recency of their discovery. The purpose of this review is to compare the functions of amniotic fluid, breast milk, and their stem cells to provide a rationale for the use of breast milk stem cells as a therapy for neonatal diseases. Breast milk stem cells present as an important tool for treating neonatal diseases given their ability to reduce inflammation and tissue damage, as well as their multilineage differentiation potential, easy accessibility, and ability to be used in disease modelling.

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Abbreviations

NEC:

Necrotizing enterocolitis

AFSC:

Amniotic fluid stem cell

BMSC:

Breast milk stem cell

OCT-4:

Octamer-binding transcription factor 4

NANOG:

Nanog homeobox

SOX2:

Sex determining region Y-box 2

TSG-6:

Tumor necrosis factor-induced protein 6

CDH:

Congenital diaphragmatic hernia

ESC:

Embryonic stem cell

References

  1. Wagner CL, Taylor SN, Johnson D (2008) Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin Rev Allergy Immunol 34:191–204. https://doi.org/10.1007/s12016-007-8032-3

    Article  PubMed  Google Scholar 

  2. Dasgupta S, Jain SK (2017) Protective effects of amniotic fluid in the setting of necrotizing enterocolitis. Pediatr Res 82:584–595. https://doi.org/10.1038/pr.2017.144

    Article  PubMed  Google Scholar 

  3. Hirai C, Ichiba H, Saito M, Shintaku H, Yamano T, Kusuda S (2002) Trophic effect of multiple growth factors in amniotic fluid or human milk on cultured human fetal small intestinal cells. J Pediatr Gastroenterol Nutr 34:524–528. https://doi.org/10.1097/00005176-200205000-00010

    Article  PubMed  Google Scholar 

  4. Kitterman JA (1988) Physiological factors in fetal lung growth. Can J Physiol Pharmacol 66:1122–1128. https://doi.org/10.1139/y88-184

    Article  CAS  PubMed  Google Scholar 

  5. Martin CR, Ling PR, Blackburn GL (2016) Review of infant feeding: key features of breast milk and infant formula. Nutrients 8:279. https://doi.org/10.3390/nu8050279

    Article  CAS  PubMed Central  Google Scholar 

  6. Kotecha S (2000) Lung growth: Implications for the newborn infant. Arch Dis Child Fetal Neonatal Ed 82:F69–F74. https://doi.org/10.1136/fn.82.1.f69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Waidyatillake NT, Allen KJ, Lodge CJ et al (2013) The impact of breastfeeding on lung development and function: a systematic review. Expert Rev Clin Immunol 9:1253–1265. https://doi.org/10.1586/1744666X.2013.851005

    Article  CAS  PubMed  Google Scholar 

  8. Hassiotou F, Beltran A, Chetwynd E et al (2012) Breastmilk is a novel source of stem cells with multilineage differentiation potential. Stem Cells 30:2164–2174. https://doi.org/10.1002/stem.1188

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cregan MD, Fan Y, Appelbee A et al (2007) Identification of nestin-positive putative mammary stem cells in human breastmilk. Cell Tissue Res 329:129–136. https://doi.org/10.1007/s00441-007-0390-x

    Article  PubMed  Google Scholar 

  10. De Coppi P, Bartsch G, Siddiqui MM et al (2007) Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 25:100–106. https://doi.org/10.1038/nbt1274

    Article  CAS  PubMed  Google Scholar 

  11. Drucker NA, McCulloh CJ, Li B, Pierro A, Besner GE, Markel TA (2018) Stem cell therapy in necrotizing enterocolitis: Current state and future directions. Semin Pediatr Surg 27:57–64. https://doi.org/10.1053/j.sempedsurg.2017.11.011

    Article  PubMed  Google Scholar 

  12. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111. https://doi.org/10.1038/35102167

    Article  CAS  PubMed  Google Scholar 

  13. Chang YS, Ahn SY, Sung S, Park WS (2017) Stem cell therapy for neonatal disorders: prospects and challenges. Yonsei Med J 58:266–271. https://doi.org/10.3349/ymj.2017.58.2.266

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hall NJ, Eaton S, Pierro A (2013) Royal Australasia of surgeons guest lecture Necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg 48:2359–2367. https://doi.org/10.1016/j.jpedsurg.2013.08.006

    Article  PubMed  Google Scholar 

  15. Ikehara S (2013) Grand challenges in stem cell treatments. Front Cell Dev Biol 1:2. https://doi.org/10.3389/fcell.2013.00002

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kunisaki SM, Armant M, Kao GS, Stevenson K, Kim H, Fauza DO (2007) Tissue engineering from human mesenchymal amniocytes: a prelude to clinical trials. J Pediatr Surg 42:974–980. https://doi.org/10.1016/j.jpedsurg.2007.01.031

    Article  PubMed  Google Scholar 

  17. Kunisaki SM (2018) Amniotic fluid stem cells for the treatment of surgical disorders in the fetus and neonate. Stem Cells Transl Med 7:767–773. https://doi.org/10.1002/sctm.18-0018

    Article  PubMed  PubMed Central  Google Scholar 

  18. Prusa AR, Marton E, Rosner M, Bernaschek G, Hengstschläger M (2003) Oct-4-expressing cells in human amniotic fluid: a new source for stem cell research? Hum Reprod 18:1489–1493. https://doi.org/10.1093/humrep/deg279

    Article  PubMed  Google Scholar 

  19. Cananzi M, De Coppi P (2012) CD117+ amniotic fluid stem cells: state of the art and future perspectives. Organogenesis 8:77–88. https://doi.org/10.4161/org.22426

    Article  PubMed  PubMed Central  Google Scholar 

  20. Moschidou D, Mukherjee S, Blundell MP et al (2012) Valproic acid confers functional pluripotency to human amniotic fluid stem cells in a transgene-free approach. Mol Ther 20:1953–1967. https://doi.org/10.1038/mt.2012.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zani A, Cananzi M, Fascetti-Leon F et al (2014) 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. https://doi.org/10.1136/gutjnl-2012-303735

    Article  CAS  PubMed  Google Scholar 

  22. Zani A, Cananzi M, Lauriti G et al (2014) Amniotic fluid stem cells prevent development of ascites in a neonatal rat model of necrotizing enterocolitis. Eur J Pediatr Surg 24:57–60. https://doi.org/10.1055/s-0033-1350059

    Article  PubMed  Google Scholar 

  23. McCulloh CJ, Olson JK, Wang Y, Vu J, Gartner S, Besner GE (2017) Evaluating the efficacy of different types of stem cells in preserving gut barrier function in necrotizing enterocolitis. J Surg Res 214:278–285. https://doi.org/10.1016/j.jss.2017.03.026

    Article  PubMed  PubMed Central  Google Scholar 

  24. Koike Y, Li B, Lee C et al (2020) The intestinal injury caused by ischemia-reperfusion is attenuated by amniotic fluid stem cells via the release of tumor necrosis factor-stimulated gene 6 protein. FASEB J 34:6824–6836. https://doi.org/10.1096/fj.201902892RR

    Article  CAS  PubMed  Google Scholar 

  25. Feng C, Graham CD, Connors JP et al (2016) Transamniotic stem cell therapy (TRASCET) mitigates bowel damage in a model of gastroschisis. J Pediatr Surg 51:56–61. https://doi.org/10.1016/j.jpedsurg.2015.10.011

    Article  PubMed  Google Scholar 

  26. Michael Z, Spyropoulos F, Ghanta S, Christou H (2018) Bronchopulmonary dysplasia: an update of current pharmacologic therapies and new approaches. Clin Med Insights Pediatr 12:1179556518817322. https://doi.org/10.1177/1179556518817322

    Article  PubMed  PubMed Central  Google Scholar 

  27. Grisafi D, Pozzobon M, Dedja A et al (2013) Human amniotic fluid stem cells protect rat lungs exposed to moderate hyperoxia. Pediatr Pulmonol 48:1070–1080. https://doi.org/10.1002/ppul.22791

    Article  PubMed  Google Scholar 

  28. Pederiva F, Ghionzoli M, Pierro A, De Coppi P, Tovar JA (2013) Amniotic fluid stem cells rescue both in vitro and in vivo growth, innervation, and motility in nitrofen-exposed hypoplastic rat lungs through paracrine effects. Cell Transplant 22:1683–1694. https://doi.org/10.3727/096368912X657756

    Article  CAS  PubMed  Google Scholar 

  29. Di Bernardo J, Maiden MM, Hershenson MB, Kunisaki SM (2014) Amniotic fluid derived mesenchymal stromal cells augment fetal lung growth in a nitrofen explant model. J Pediatr Surg 49:859–865. https://doi.org/10.1016/j.jpedsurg.2014.01.013

    Article  PubMed  Google Scholar 

  30. Adzick NS, Thom EA, Spong CY et al (2011) A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 364:993–1004. https://doi.org/10.1056/NEJMoa1014379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dionigi B, Ahmed A, Iii JB, Connors JP, Zurakowski D, Fauza DO (2015) Partial or complete coverage of experimental spina bifida by simple intra-amniotic injection of concentrated amniotic mesenchymal stem cells. J Pediatr Surg 50:69–73. https://doi.org/10.1016/j.jpedsurg.2014.10.004

    Article  PubMed  Google Scholar 

  32. Ochiai D, Masuda H, Abe Y et al (2018) Human amniotic fluid stem cells: Therapeutic potential for perinatal patients with intractable neurological disease. Keio J Med 67:57–66. https://doi.org/10.2302/kjm.2017-0019-IR

    Article  CAS  PubMed  Google Scholar 

  33. Otani T, Ochiai D, Masuda H et al (2019) The neurorestorative effect of human amniotic fluid stem cells on the chronic phase of neonatal hypoxic–ischemic encephalopathy in mice. Pediatr Res 85:97–104. https://doi.org/10.1038/s41390-018-0131-8

    Article  CAS  PubMed  Google Scholar 

  34. Nitkin CR, Rajasingh J, Pisano C, Besner GE, Thébaud B, Sampath V (2020) Stem cell therapy for preventing neonatal diseases in the 21st century: current understanding and challenges. Pediatr Res 87:265–276. https://doi.org/10.1038/s41390-019-0425-5

    Article  PubMed  Google Scholar 

  35. Edgar JR (2016) Q&A: what are exosomes, exactly? BMC Biol 14:46. https://doi.org/10.1186/s12915-016-0268-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McCulloh CJ, Olson JK, Wang Y et al (2018) Treatment of experimental necrotizing enterocolitis with stem cell-derived exosomes. J Pediatr Surg 53:1215–1220. https://doi.org/10.1016/j.jpedsurg.2018.02.086

    Article  PubMed  PubMed Central  Google Scholar 

  37. Antounians L, Tzanetakis A, Pellerito O et al (2019) The regenerative potential of amniotic fluid stem cell extracellular vesicles: lessons learned by comparing different isolation techniques. Sci Rep 9:1837. https://doi.org/10.1038/s41598-018-38320-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hassiotou F, Heath B, Ocal O et al (2014) Breastmilk stem cell transfer from mother to neonatal organs (216.4). FASEB J 28:1S

    Article  Google Scholar 

  39. Aydın MŞ, Yiğit EN, Vatandaşlar E, Erdoğan E, Öztürk G (2018) Transfer and integration of breast milk stem cells to the brain of suckling pups. Sci Rep 8:14289. https://doi.org/10.1038/s41598-018-32715-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hassiotou F, Hartmann PE (2014) At the dawn of a new discovery: the potential of breast milk stem cells. Adv Nutr 5:770–778. https://doi.org/10.3945/an.114.006924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lensch MW, Schlaeger TM, Zon LI, Daley GQ (2007) Teratoma formation assays with human embryonic stem cells: a rationale for one type of human-animal chimera. Cell Stem Cell 1:253–258. https://doi.org/10.1016/j.stem.2007.07.019

    Article  CAS  PubMed  Google Scholar 

  42. Ghosh Z, Huang M, Hu S, Wilson KD, Dey D, Wu JC (2011) Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res 71:5030–5039. https://doi.org/10.1158/0008-5472.CAN-10-4402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Borhani-Haghighi M, Navid S, Mohamadi Y (2020) The therapeutic potential of conditioned medium from human breast milk stem cells in treating spinal cord injury. Asian Spine J 14:131–138. https://doi.org/10.31616/asj.2019.0026

    Article  PubMed  Google Scholar 

  44. Keller T, Körber F, Oberthuer A et al (2019) Intranasal breast milk for premature infants with severe intraventricular hemorrhage—an observation. Eur J Pediatr 178:199–206. https://doi.org/10.1007/s00431-018-3279-7

    Article  CAS  PubMed  Google Scholar 

  45. Kaingade PM, Somasundaram I, Nikam AB, Sarang SA, Patel JS (2016) Assessment of growth factors secreted by human breastmilk mesenchymal stem cells. Breastfeed Med 11:26–31. https://doi.org/10.1089/bfm.2015.0124

    Article  PubMed  Google Scholar 

  46. Karatepe HO, Kilincaslan H, Berber M et al (2014) The effect of vascular endothelial growth factor overexpression in experimental necrotizing enterocolitis. Pediatr Surg Int 30:327–332. https://doi.org/10.1007/s00383-013-3460-z

    Article  PubMed  Google Scholar 

  47. Good M, Siggers RH, Sodhi CP et al (2012) Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci USA 109:11330–11335. https://doi.org/10.1073/pnas.1200856109

    Article  PubMed  PubMed Central  Google Scholar 

  48. Good M, Sodhi CP, Egan CE et al (2015) Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor. Mucosal Immunol 8:1166–1179. https://doi.org/10.1038/mi.2015.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dailey T, Metcalf C, Mosley Y et al (2013) An update on translating stem cell therapy for stroke from bench to bedside. J Clin Med 2:220–241. https://doi.org/10.3390/jcm2040220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Loukogeorgakis SP, De Coppi P (2016) Stem cells from amniotic fluid—potential for regenerative medicine. Best Pract Res Clin Obstet Gynaecol 31:45–57. https://doi.org/10.1016/j.bpobgyn.2015.08.009

    Article  PubMed  Google Scholar 

  51. Carnevale G, Riccio M, Pisciotta A et al (2013) In vitro differentiation into insulin-producing β-cells of stem cells isolated from human amniotic fluid and dental pulp. Dig Liver Dis 45:669–676. https://doi.org/10.1016/j.dld.2013.02.007

    Article  CAS  PubMed  Google Scholar 

  52. Pacheco CMR, Ferreira PE, Saçaki CS et al (2019) In vitro differentiation capacity of human breastmilk stem cells: a systematic review. World J Stem Cells 11:1005–1019. https://doi.org/10.4252/wjsc.v11.i11.1005

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hosseini SM, Talaei-Khozani T, Sani M, Owrangi B (2014) Differentiation of human breast-milk stem cells to neural stem cells and neurons. Neurol Res Int 2014:807896. https://doi.org/10.1155/2014/807896

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sani M, Ebrahimi S, Aleahmad F et al (2017) Differentiation potential of breast milk-derived mesenchymal stem cells into hepatocyte-like cells. Tissue Eng Regen Med 14:587–593. https://doi.org/10.1007/s13770-017-0066-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Goudarzi N, Shabani R, Ebrahimi M et al (2020) Comparative phenotypic characterization of human colostrum and breast milk-derived stem cells. Hum Cell 33:308–317. https://doi.org/10.1007/s13577-019-00320-x

    Article  CAS  PubMed  Google Scholar 

  56. Tang C, Zhou Q, Lu C, Xiong M, Lee S (2019) Comparison and culturing different types of cells from fresh breast milk with different culture medium. Pediatr Med 2:5. https://doi.org/10.21037/pm.2019.02.02

    Article  Google Scholar 

  57. Kaingade P, Somasundaram I, Sharma A, Patel D, Marappagounder D (2017) Cellular components, including stem-like cells, of preterm mother’s mature milk as compared with those in her colostrum: a pilot study. Breastfeed Med 12:446–449. https://doi.org/10.1089/bfm.2017.0063

    Article  PubMed  Google Scholar 

  58. Briere CE, Jensen T, McGrath JM, Young EE, Finck C (2017) Stem-like cell characteristics from breast milk of mothers with preterm infants as compared to mothers with term infants. Breastfeed Med 12:174–179. https://doi.org/10.1089/bfm.2017.0002

    Article  PubMed  Google Scholar 

  59. Goldenberg RL, Rouse DJ (1998) Prevention of premature birth. N Engl J Med 339:313–320. https://doi.org/10.1056/NEJM199807303390506

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Agostino Pierro was supported by the Canadian Institutes of Health Research (CIHR) Foundation Grant 353857 and the Robert M. Filler Chair of Surgery, The Hospital for Sick Children.

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  1. Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada

    Rachel Filler, Bo Li, Sinobol Chusilp & Agostino Pierro

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  1. Rachel Filler
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  2. Bo Li
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RF: conceptualization, writing—original draft; BL: writing-original draft; SC: writing-original draft; AP: supervision, writing—review and editing.

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Correspondence to Agostino Pierro.

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Filler, R., Li, B., Chusilp, S. et al. Amniotic fluid and breast milk: a rationale for breast milk stem cell therapy in neonatal diseases. Pediatr Surg Int 36, 999–1007 (2020). https://doi.org/10.1007/s00383-020-04710-3

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