Congenital Diaphragmatic Hernia as a Potential Target for Transamniotic Stem Cell Therapy: Impact on Pulmonary Vascular Tone Homeostasis
Alexander V Chalphin, MD1; Sarah A Tracy, MD1; Stefanie P Lazow, MD1; Ina Kycia, PhD1; David Zurakowski, PhD1; Dario O Fauza, MD, PhD1 1Boston Children's Hospital, Boston, MA, USA
Background:
We sought to determine whether transamniotic stem cell therapy (TRASCET) impacts expression of mediators of pulmonary vascular tone homeostasis in an animal model of congenital diaphragmatic hernia (CDH).
Methods:
Pregnant dams (n=15) received Nitrofen on gestational day 9.5 (E9; term=22 days) to induce fetal CDH. Fetuses (n=141) were divided into three groups: untreated undergoing no further manipulations (n=34) and two groups receiving volume-matched intra-amniotic injections of either saline (n=39), or a suspension of amniotic fluid-derived mesenchymal stem cells (afMSCs; n=68) on E17. Infused afMSCs consisted of syngeneic rat cells with mesenchymal progenitor identity confirmed by flow cytometry. Animals were euthanized at term. Expression of endothelial nitric oxide synthase (ENOS); pre-proendothelin-1 (PPET1); endothelin receptor-A (ERA); endothelin receptor-B (ERB); and endothelin converting enzyme (ECE) were quantified by qRT-PCR in lungs ipsi- and contra-lateral to the hernia in each group. Relative mRNA fold expression was calculated in reference to normal fetuses (n=15). Statistical analysis was by the Mann-Whitney U-test with a conservative Bonferroni adjusted p≤0.009.
Results:
Among survivors with CDH (n=34/141), TRASCET led to significant downregulation of ENOS and ERA expressions compared to the untreated and saline groups (both p<0.001) (figure). Lung laterality to the hernia had minimal impact on these comparisons.
Conclusions:
Transamniotic stem cell therapy affects fetal pulmonary vascular tone homeostasis in experimental congenital diaphragmatic hernia. Further scrutiny into this novel strategy is warranted. 
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