Transamniotic Stem Cell Therapy Impacts Cardiac Remodeling in the Nitrofen Model of Congenital Diaphragmatic Hernia
Daniel F Labuz, Stefanie P Lazow, Ina Kycia, David Zurakowski, Dario O Fauza
Department of Surgery, Boston Children's Hospital, Boston, MA
Background: Congenital diaphragmatic hernia (CDH) is associated with neonatal pulmonary hypertension and cardiac dysfunction. Transamniotic stem cell therapy (TRASCET) can impact fetal pulmonary vascular development in the Nitrofen model of CDH. We sought to determine whether TRASCET also impacts cardiac remodeling mediators in that model.
Methods: Pregnant dams (n=27) received Nitrofen on gestational day 9.5 (E9; term=22 days) to induce fetal CDH. Fetuses (n=352) were divided into three groups: untreated undergoing no further manipulations (n=110) and two groups receiving volume-matched intra-amniotic injections of either saline (n=75), or a suspension of amniotic fluid-derived mesenchymal stem cells (afMSCs; n=167) on E17. Infused afMSCs consisted of syngeneic rat cells with mesenchymal progenitor identity confirmed by flow cytometry. Animals were euthanized at term. Expression of preproendothelin-1 (PPET-1), endothelin receptor A (EdnRA), collagen-1 (Col1), elastin, Ras-related C3 botulinum toxin substrate (Rac1), and connexin-43 (Cnx43) were quantified by qRT-PCR in all hearts. Relative mRNA fold expression was calculated in reference to normal fetuses (n=23). Statistical analysis was by the Mann-Whitney U-test with a conservative Bonferroni adjusted p?0.01.
Results: Compared to both the untreated and saline groups, TRASCET led to significant downregulation of PPET-1 and significant upregulation of Rac1 and Cnx43 expressions (all p<0.001) in the 60 survivors with CDH (figure).
Conclusion: Transamniotic stem cell therapy impacts cardiac remodeling in experimental congenital diaphragmatic hernia. Further scrutiny into this novel strategy is warranted.
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