O1093: Fetal Cardiac and Pulmonary Protection by Transamniotic Stem Cell Therapy (TRASCET) in a Model of Intrauterine Growth Restriction (IUGR)

Background: Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) has been shown to reverse core effects of intrauterine growth restriction (IUGR), apparently by attenuating placental inflammation. Fetal cardiopulmonary complications are among the most harmful manifestations of IUGR, including pulmonary fibrosis and undue heart strain, both associated with the underlying placental insufficiency. We sought to determine whether MSC-based TRASCET could also mitigate fetal cardiopulmonary effects of IUGR.

Methods: After IACUC approval, pregnant Sprague-Dawley dams (n=12) were exposed to alternating 12-hour hypoxia (10.5% O2) cycles from gestational day 15 (E15) until term (E21). Their fetuses (n=155) were divided into 4 groups. One group remained untreated (n=42), while three groups received volume-matched intra-amniotic injections of either saline (sham; n=34), or a suspension of amniotic fluid-derived MSCs, either in their native state (TRASCET; n=36) or “primed” by exposure to interferon-gamma (IFN-γ) and interleukin-1beta (IL-1β) prior to administration in vivo (TRASCET-primed; n=43). Donor MSCs consisted of syngeneic Lewis rat cells phenotyped by flow cytometry. Normal fetuses served as additional controls (n=30). Multiple morphometric and biochemical analyses were performed at term, including ELISA in fetal hearts and lungs for select developmental and inflammatory markers previously shown to be affected by IUGR in this model. Statistical comparisons were by Wilcox-rank sum test and Fisher's exact test.

Results: Overall survival from hypoxia was 75% (117/155). Placental efficiency (PE; fetal to placental weight ratio) was significantly lower than normal in untreated, sham, and TRASCET-primed groups (p < 0.001-0.004), but normalized in TRASCET (p=0.915). Both TRASCET groups had significantly improved PE compared to both sham and untreated groups (p < 0.001-0.012). Fetal heart to body weight ratio was increased in both the sham and untreated groups (p < 0.001 for both) but normalized in the TRASCET and TRASCET-primed groups (p=0.275, 0.069 respectively). Cardiac b-type natriuretic peptide (BNP) levels were increased in all hypoxia groups compared to normal (p < 0.001) but significantly decreased from sham and untreated in both TRASCET groups (p < 0.0001-0.005). Heart tumor necrosis factor-alpha (TNF-α) levels were significantly elevated in sham and TRASCET groups (p=0.009, 0.002) but normalized in the untreated and TRASCET-primed groups (p=0.256, 0.456). Lung transforming growth factor-beta (TGF-β) levels were significantly increased in both sham and untreated groups (p < 0.001, 0.003) but normalized in both TRASCET groups (p=0.567. 0.303). Similarly, lung endothelin-1 (ET-1) levels were elevated in sham and untreated groups (p < 0.001 for both) but normalized in both TRASCET groups (p=0.367, 0.928).

Conclusion: Transamniotic stem cell therapy with mesenchymal stem cells decreases markers of fetal cardiac strain, insufficiency, and inflammation in the rodent model of intrauterine growth restriction. This therapeutic strategy also decreases markers of pulmonary fibrosis and hypertension in this model. Further investigation into the functional and long term impact of these findings is warranted.