Abstract
Transamniotic stem cell therapy, or TRASCET, is an emerging therapeutic concept for the management of congenital anomalies based on the augmentation of the biological role of select populations of stem cells that already occur in the amniotic fluid, for targeted therapeutic benefit. Amniotic fluid-derived mesenchymal stem cells (afMSCs) have a central role in the enhanced ability of the fetus to repair tissue damage. This germane recent finding constitutes the biological foundation for the use of afMSCs in TRASCET. It has been shown experimentally that simple intra-amniotic delivery of afMSCs in large numbers can either elicit the repair, or significantly mitigate the effects associated with major congenital anomalies by boosting the activity that these cells normally have. For example, TRASCET can induce partial or complete coverage of experimental spina bifida by promoting the local formation of host-derived skin, thus protecting the spinal cord from further damage. In another example, it can significantly alleviate the bowel damage associated with gastroschisis, one of the most common major abdominal wall defects. Other applications involving different congenital anomalies and/or other stem cells present in the amniotic fluid in diseased pregnancies are currently under investigation in this freshly evolving facet of fetal stem cell therapy.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Klein JD, Turner CG, Steigman SA et al, Amniotic mesenchymal stem cells enhance normal fetal wound healing. Stem Cells Dev 2011; 20: 969–76.
Gurtner GC, Werner S, Barrandon Y, Longaker MT . Wound repair and regeneration. Nature 2008; 453: 314–21.
Tammi R, Pasonen-Seppanen S, Kolehmainen E, Tammi M . Hyaluronan synthase induction and hyaluronan accumulation in mouse epidermis following skin injury. J Invest Dermatol 2005; 124: 898–905.
David-Raoudi M, Tranchepain F, Deschrevel B et al, Differential effects of hyaluronan and its fragments on fibroblasts: relation to wound healing. Wound Rep Regen 2008; 16: 274–87.
Wu Y, Wang J, Scott PG, Tredget EE . Bone marrow-derived stem cells in wound healing: a review. Wound Rep Regen 2007; 15 (Suppl 1): S18–26.
Kwong FN, Harris MB . Recent developments in the biology of fracture repair. J Am Acad Orthop Surg 2008; 16: 619–25.
Fu X, Li H . Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions. Cell Tissue Res 2009; 335: 317–21.
Kaviani A, Perry TE, Dzakovic A, Jennings RW, Ziegler MM, Fauza DO . The amniotic fluid as a source of cells for fetal tissue engineering. J Pediatr Surg 2001; 36: 1662–5.
Fuchs JR, Kaviani A, Oh JT et al, Diaphragmatic reconstruction with autologous tendon engineered from mesenchymal amniocytes. J Pediatr Surg 2004; 39: 834–8discussion-8.
Fauza DO, Bani M. Fetal Stem Cells in Regenerative Medicine: Principles and Translational Strategies. New York, NY, USA: Springer Science, 2016.
Turner CG, Klein JD, Wang J et al, The amniotic fluid as a source of neural stem cells in the setting of experimental neural tube defects. Stem Cells Dev 2013; 22: 548–53.
Gosden CM, Brock DJ . Morphology of rapidly adhering amniotic-fluid cells as an aid to the diagnosis of neural-tube defects. Lancet 1977; 1: 919–22.
Aula P, von Koskull H, Teramo K et al, Glial origin of rapidly adhering amniotic fluid cells. Br Med J 1980; 281: 1456–7.
Greenebaum E, Mansukhani MM, Heller DS, Timor-Tristsch I . Open neural tube defects: immunocytochemical demonstration of neuroepithelial cells in amniotic fluid. Diagn Cytopathol 1997; 16: 143–4.
Mendonca ED, Gutierrez CM, Peres LC . Brain tissue fragments in the amniotic fluid of rats with neural tube defect. Pathology 2005; 37: 152–6.
Chang YJ, Su HL, Hsu LF et al, Isolation of human neural stem cells from the amniotic fluid with diagnosed neural tube defects. Stem Cells Dev 2015; 24: 1740–50.
Pennington EC, Gray FL, Ahmed A, Zurakowski D, Fauza DO . Targeted quantitative amniotic cell profiling: a potential diagnostic tool in the prenatal management of neural tube defects. J Pediatr Surg 2013; 48: 1205–10.
Pennington EC, Rialon KL, Dionigi B, Ahmed A, Zurakowski D, Fauza DO . The impact of gestational age on targeted amniotic cell profiling in experimental neural tube defects. Fetal Diagn Ther 2015; 37: 65–9.
Hong HS, Lee J, Lee E et al, A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 2009; 15: 425–35.
Graham CD, Shieh HF, Brazzo JA 3rd, Zurakowski D, Fauza DO . Donor mesenchymal stem cells home to maternal wounds after transamniotic stem cell therapy (TRASCET) in a rodent model. J Pediatr Surg 2017; 52: 1006–9.
Shieh HF, Ahmed A, Tracy SA, Zurakowski D, Fauza DO . Fetal bone marrow homing of donor mesenchymal stem cells after transamniotic stem cell therapy (TRASCET). J Pediatr Surg2017 (in press).
Mendes SC, Robin C, Dzierzak E . Mesenchymal progenitor cells localize within hematopoietic sites throughout ontogeny. Development 2005; 132: 1127–36.
Boelig MM, Flake AW. In utero stem cell transplantation. In: Fauza DO, Bani M, eds. Fetal Stem Cells in Regenerative Medicine: Principles and Translational Strategies. New York, NY, USA: Springer/Humana Press, 2016:317-37.
Derderian SC, Jeanty C, MacKenzie TC Fet-maternal cell trafficking and labor. In: Fauza DO, Bani M, eds. Fetal Stem Cells in Regenerative Medicine: Principles and Translational Strategies. New York, NY, USA: Springer/Humana Press, 2016:33-45.
Christensen JL, Wright DE, Wagers AJ, Weissman IL . Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biol 2004; 2: E75.
Medvinsky A, Dzierzak E . Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 1996; 86: 897–906.
Mikkola HK, Gekas C, Orkin SH, Dieterlen-Lievre F . Placenta as a site for hematopoietic stem cell development. Exp Hematol 2005; 33: 1048–54.
Vrecenak JD, Flake AW . In utero hematopoietic cell transplantation—progress and the potential for clinical application. Cytotherapy 2013; 15: 525–35.
Egbe A, Lee S, Ho D, Uppu S, Srivastava S . Racial/ethnic differences in the birth prevalence of congenital anomalies in the United States. J Perinat Med 2015; 43: 111–7.
Mohamed MA, Aly H . Birth region, race and sex may affect the prevalence of congenital diaphragmatic hernia, abdominal wall and neural tube defects among US newborns. J Perinatol 2012; 32: 861–8.
Parker SE, Mai CT, Canfield MA et al, Updated national birth prevalence estimates for selected birth defects in the United States, 2004-2006. Birth Defects Res A Clin Mol Teratol 2010; 88: 1008–16.
Cragan JD, Gilboa SM . Including prenatal diagnoses in birth defects monitoring: experience of the metropolitan atlanta congenital defects program. Birth Defects Res A Clin Mol Teratol 2009; 85: 20–9.
Main DM, Mennuti MT . Neural tube defects: issues in prenatal diagnosis and counselling. Obstetr Gynecol 1986; 67: 1–16.
Botto LD, Moore CA, Khoury MJ, Erickson JD . Neural-tube defects. N Engl J Med 1999; 341: 1509–19.
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–137.
Czeizel AE, Dudas I . Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–5.
Boulet SL, Yang Q, Mai C et al, Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Res A Clin Mol Teratol 2008; 82: 527–32.
Patten BM . Embryological stages in the establishing of myeloschisis with spina bifida. Am J Anat 1953; 93: 365–95.
Osaka K, Tanimura T, Hirayama A, Matsumoto S . Myelomeningocele before birth. J Neurosurg 1978; 49: 711–24.
Hutchins GM, Meuli M, Meuli-Simmen C, Jordan MA, Heffez DS, Blakemore KJ . Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr Pathol Lab Med 1996; 16: 701–12.
Meuli M, Meuli-Simmen C, Hutchins GM, Seller MJ, Harrison MR, Adzick NS . The spinal cord lesion in human fetuses with myelomeningocele: implications for fetal surgery. J Pediatr Surg 1997; 32: 448–52.
Korenromp MJ, van Gool JD, Bruinese HW, Kriek R . Early fetal leg movements in myelomeningocele. Lancet 1986; 1: 917–8.
Sival DA, Begeer JH, Staal-Schreinemachers AL, Vos-Niel JM, Beekhuis JR, Prechtl HF . Perinatal motor behaviour and neurological outcome in spina bifida aperta. Early Hum Dev 1997; 50: 27–37.
Luthy DA, Wardinsky T, Shurtleff DB et al, Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991; 324: 662–6.
Shurtleff DB, Luthy DA, Nyberg DA, Benedetti TJ, Mack LA . Meningomyelocele: management in utero and post natum. Ciba Found Symp 1994; 181: 270–80.
Meuli M, Meuli-Simmen C, Yingling CD et al, Creation of myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep. J Pediatr Surg 1995; 30: 1028–32discussion 32-3.
Meuli M, Meuli-Simmen C, Hutchins GM et al, In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat Med 1995; 1: 342–7.
Meuli M, Meuli-Simmen C, Yingling CD et al, In utero repair of experimental myelomeningocele saves neurological function at birth. J Pediatr Surg 1996; 31: 397–402.
Adzick NS, Thom EA, Spong CY et al, A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011; 364: 993–1004.
Dionigi B, Ahmed A, Brazzo J 3rd, Connors JP, Zurakowski D, Fauza DO . Partial or complete coverage of experimental spina bifida by simple intra-amniotic injection of concentrated amniotic mesenchymal stem cells. J Pediatr Surg 2015; 50: 69–73.
Dionigi B, Brazzo JA 3rd, Ahmed A et al, Trans-amniotic stem cell therapy (TRASCET) minimizes Chiari-II malformation in experimental spina bifida. J Pediatr Surg 2015; 50: 1037–41.
Feng C, D Graham C, Connors JP, Brazzo 3rd J, Zurakowski D, Fauza DO . A comparison between placental and amniotic mesenchymal stem cells for transamniotic stem cell therapy (TRASCET) in experimental spina bifida. J Pediatr Surg 2016; 51: 1010–3.
Danzer E, Schwarz U, Wehrli S, Radu A, Adzick NS, Flake AW . Retinoic acid induced myelomeningocele in fetal rats: characterization by histopathological analysis and magnetic resonance imaging. Exp Neurol 2005; 194: 467–75.
Fauza DO . Amniotic fluid and placental stem cells. Best Pract Res Clin Obstet Gynaecol 2004; 18: 877–91.
Klein JD, Fauza DO . Amniotic and placental mesenchymal stem cell isolation and culture. Methods Mol Biol 2011; 698: 75–88.
Kunisaki SM, Fuchs JR, Steigman SA, Fauza DO . A comparative analysis of cartilage engineered from different perinatal mesenchymal progenitor cells. Tissue Eng 2007; 13: 2633–44.
Lee DH, Kim EY, Park S et al, Reclosure of surgically induced spinal open neural tube defects by the intraamniotic injection of human embryonic stem cells in chick embryos 24 hours after lesion induction. J Neurosurg 2006; 105: 127–33.
Lee DH, Park S, Kim EY et al, Enhancement of re-closure capacity by the intra-amniotic injection of human embryonic stem cells in surgically induced spinal open neural tube defects in chick embryos. Neurosci Lett 2004; 364: 98–100.
Lee DH, Phi JH, Kim SK, Cho BK, Kim SU, Wang KC . Enhanced reclosure of surgically induced spinal open neural tube defects in chick embryos by injecting human bone marrow stem cells into the amniotic cavity. Neurosurgery 2010; 67: 129–35.
Turner CG, Pennington EC, Gray FL, Ahmed A, Teng YD, Fauza DO . Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida. Fetal Diagn Ther 2013; 34: 38–43.
Langer JC, Longaker MT, Crombleholme TM et al, Etiology of intestinal damage in gastroschisis. I: Effects of amniotic fluid exposure and bowel constriction in a fetal lamb model. J Pediatr Surg 1989; 24: 992–7.
Logghe HL, Mason GC, Thornton JG, Stringer MD . A randomized controlled trial of elective preterm delivery of fetuses with gastroschisis. J Pediatr Surg 2005; 40: 1726–31.
Luton D, de Lagausie P, Guibourdenche J et al, Effect of amnioinfusion on the outcome of prenatally diagnosed gastroschisis. Fetal Diagn Ther 1999; 14: 152–5.
Bittencourt DG, Barreto MW, Franca WM, Goncalves A, Pereira LA, Sbragia L . Impact of corticosteroid on intestinal injury in a gastroschisis rat model: morphometric analysis. J Pediatr Surg 2006; 41: 547–53.
Goncalves FL, Bueno MP, Schmidt AF, Figueira RL, Sbragia L . Treatment of bowel in experimental gastroschisis with a nitric oxide donor. Am J Obstet Gynecol 2015; 212 (383): e1–7.
Hakguder G, Ates O, Olguner M et al, Induction of fetal diuresis with intraamniotic furosemide increases the clearance of intraamniotic substances: an alternative therapy aimed at reducing intraamniotic meconium concentration. J Pediatr Surg 2002; 37: 1337–42.
Till H, Muensterer O, Mueller M et al, Intrauterine repair of gastroschisis in fetal rabbits. Fetal Diagn Ther 2003; 18: 297–300.
Yu J, Gonzalez-Reyes S, Diez-Pardo JA, Tovar JA . Effects of prenatal dexamethasone on the intestine of rats with gastroschisis. J Pediatr Surg 2003; 38: 1032–5.
Feng C, Graham CD, Connors JP et al, Transamniotic stem cell therapy (TRASCET) mitigates bowel damage in a model of gastroschisis. J Pediatr Surg 2016; 51: 56–61.
Feng C, Graham CD, Shieh HF et al, Transamniotic stem cell therapy (TRASCET) in a leporine model of gastroschisis. J Pediatr Surg 2017; 52: 30–4.
Kunisaki SM, Armant M, Kao GS, Stevenson K, Kim H, Fauza DO . Tissue engineering from human mesenchymal amniocytes: a prelude to clinical trials. J Pediatr Surg 2007; 42: 974–979.
Steigman SA, Armant M, Bayer-Zwirello L et al, Preclinical regulatory validation of a 3-stage amniotic mesenchymal stem cell manufacturing protocol. J Pediatr Surg 2008; 43: 1164–9.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no conflict of interest.
Additional information
Statement of Financial Support
The work summarized in this review was funded by the Kevin and Kate McCarey Fund for Surgical Research at Boston Children’s Hospital.
Rights and permissions
About this article
Cite this article
Fauza, D. Transamniotic stem cell therapy: a novel strategy for the prenatal management of congenital anomalies. Pediatr Res 83, 241–248 (2018). https://doi.org/10.1038/pr.2017.228
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/pr.2017.228
This article is cited by
-
TRASCET—Transamniotic Stem Cell Therapy
Current Stem Cell Reports (2024)
-
ZukĂĽnftige intrauterine Therapien
Der Gynäkologe (2020)
-
A Retrospective Analysis of Safety and Efficacy of Wharton’s Jelly Stem Cell Administration in Children with Spina Bifida
Stem Cell Reviews and Reports (2019)
-
Hope vs. caution: ethical and regulatory considerations for neonatal stem cell therapies
Pediatric Research (2018)


