Transamniotic stem cell therapy (TRASCET) for intrauterine growth restriction (IUGR): A comparison between placental and amniotic fluid donor mesenchymal stem cells


      • TRASCET improves fetal outcomes in experimental IUGR.
      • TRACET with amniotic fluid-derived MSCs is superior to placental-derived MSCs in the rat model of IUGR.
      • Amniotic fluid-derived MSCs apparently modulate placental inflammation more than their placental-derived counterparts.
      • Reduction of placental inflammation with TRASCET leads to improved fetal outcomes in an IUGR model.



      Transamniotic stem cell therapy (TRASCET) with donor mesenchymal stem cells (MSCs) has been shown experimentally to reverse central effects of intrauterine growth restriction (IUGR). We sought to compare amniotic-fluid and placenta-derived MSCs (afMSCs and pMSCs, respectively) as TRASCET donor cells in a murine IUGR model.


      Pregnant Sprague-Dawley dams (n=8) were exposed to alternating 12-hour hypoxia (10.5% O2) cycles, starting on gestational day 15 (E15; term=E21-22). On E17, fetuses (n=100) were divided into four groups. An untreated group had no further manipulations (n=24). Three groups received volume-matched intra-amniotic injections of either saline (sham; n=27), or suspensions of afMSCs (n=24), or pMSCs (n=25). Normal fetuses served as controls (n=21). All infused MSCs consisted of syngeneic Lewis rat cells phenotyped by flow cytometry and GFP-labeled. At term, fetal and placental morphometrics were calculated, and placental TNF-α levels were determined by ELISA. Statistical comparisons were by Fischer's T-test or Wilcoxon rank sum test (p≤0.05).


      Overall survival of the hypoxic groups was 83% (83/100). Compared to normal, maternal-adjusted fetal weights were significantly decreased in all hypoxia groups (pairwise p<0.001), however only the afMSC group showed higher adjusted-fetal weights than sham (p<0.001). Placental efficiency was decreased in untreated, sham, and pMSC groups (p<0.001-0.056) but normalized in the afMSC group (p=0.205). Maternal-adjusted placental weights were lower than normal in all hypoxia groups (p<0.001-0.045), except for the pMSC group (p=0.387).


      Amniotic fluid-derived mesenchymal stem cells are superior to their placenta-derived counterparts in transamniotic stem cell therapy for intrauterine growth restriction in a rat model.

      Level of Evidence

      Basic/Translational science.


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        • Biron-Shental T
        • Sadeh-Mestechkin D
        • Amiel A.
        Telomere homeostasis in IUGR placentas - A review.
        Placenta. 2016; 39: 21-23
        • Malhotra A
        • Allison BJ
        • Castillo-Melendez M
        • et al.
        Neonatal morbidities of fetal growth restriction: pathophysiology and impact.
        Front Endocrinol (Lausanne). 2019; 10: 55
        • Elfarra J
        • Amaral LM
        • McCalmon M
        • et al.
        Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure.
        Clin Sci (Lond). 2017; 131: 2753-2762
        • Travis OK
        • Baik C
        • Tardo GA
        • et al.
        Adoptive transfer of placental ischemia-stimulated natural killer cells causes a preeclampsia-like phenotype in pregnant rats.
        Am J Reprod Immunol. 2021; 85: e13386
        • Tracy SA
        • Chalphin AV
        • Kycia I
        • et al.
        Hematogenous donor cell routing pathway after transamniotic stem cell therapy.
        Stem Cells Dev. 2020; 29: 755-760
        • Labuz DF
        • Whitlock AE
        • Kycia I
        • et al.
        Intrauterine growth restriction (IUGR) as a potential target for transamniotic stem cell therapy.
        J Pediatr Surg. 2022; (in press)
        • Spaggiari GM
        • Capobianco A
        • Abdelrazik H
        • et al.
        Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2.
        Blood. 2008; 111: 1327-1333
        • Haigh T
        • Chen C
        • Jones CJ
        • et al.
        Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage.
        Placenta. 1999; 20: 615-625
        • Fauza D.
        Amniotic fluid and placental stem cells.
        Best Pract Res Clin Obstet Gynaecol. 2004; 18: 877-891
        • Soares MJ
        • Chakraborty D
        • Kubota K
        • et al.
        Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy.
        Int J Dev Biol. 2014; 58: 247-259
        • Chakraborty D
        • Rumi MA
        • Konno T
        • et al.
        Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions.
        Proc Natl Acad Sci U S A. 2011; 108: 16295-16300
        • Klein JD
        • Fauza DO.
        Amniotic and placental mesenchymal stem cell isolation and culture.
        Methods Mol Biol. 2011; 698: 75-88
        • Van Geijn HP
        • Kaylor Jr., WM
        • Nicola KR
        • et al.
        Induction of severe intrauterine growth retardation in the Sprague-Dawley rat.
        Am J Obstet Gynecol. 1980; 137: 43-47
        • Chai N
        • Zhang H
        • Li L
        • et al.
        Spermidine prevents heart injury in neonatal rats exposed to intrauterine hypoxia by inhibiting oxidative stress and mitochondrial fragmentation.
        Oxid Med Cell Longev. 2019; 20195406468
        • Sharma D
        • Shastri S
        • Sharma P.
        Intrauterine growth restriction: antenatal and postnatal aspects.
        Clin Med Insights Pediatr. 2016; 10: 67-83
        • Wixey JA
        • Lee KM
        • Miller SM
        • et al.
        Neuropathology in intrauterine growth restricted newborn piglets is associated with glial activation and proinflammatory status in the brain.
        J Neuroinflammation. 2019; 16: 5
        • Williamson M
        • de Winter P
        • Masters JR.
        Plexin-B1 signalling promotes androgen receptor translocation to the nucleus.
        Oncogene. 2016; 35: 1066-1072
        • 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: 141-150