Transamniotic mesenchymal stem cell therapy for neural tube defects preserves neural function through lesion-specific engraftment and regeneration

Abstract

Neural tube defects (NTDs) lead to prenatal mortality and lifelong morbidity. Currently, surgical closure of NTD lesions results in limited functional recovery. We previously suggested that nerve regeneration was critical for NTD therapy. Here, we report that transamniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for NTDs during early development may achieve beneficial functional recovery. In our ex vivo rat embryonic NTD model, BMSCs injected into the amniotic cavity spontaneously migrated into the defective neural tissue. Hepatocyte growth factor and its receptor c-MET were found to play critical roles in this NTD lesion-specific migration. Using the in vivo rat fetal NTD model, we further discovered that the engrafted BMSCs specifically differentiated into the cell types of the defective tissue, including skin and different types of neurons in situ. BMSC treatment triggered skin repair in fetuses, leading to a 29.9 ± 5.6% reduction in the skin lesion area. The electrophysiological functional recovery assay revealed a decreased latency and increased motor-evoked potential amplitude in the BMSC-treated fetuses. Based on these positive outcomes, ease of operation, and reduced trauma to the mother and fetus, we propose that transamniotic BMSC administration could be a new effective therapy for NTDs.

Preclinical stem cell therapy in fetuses with myelomeningocele: A systematic review and meta‐analysis

“…The characteristics of the included studies, such as type and source of stem cells, animal models and available outcomes, are shown in Table 1 30–55 . Most studies used MSCs (77%, 20/26), with the placenta, amniotic fluid and bone marrow as the source of cells.…”

“…(C) Meta‐analysis of defect coverage in the retinoic acid‐induced fetal rat MMC model. Intra‐amniotic injection of allogenic amniotic fluid‐derived mesenchymal stem cells at E17 significantly increased the likelihood of total defect coverage compared to saline injection 37–39,41 . (D) Meta‐analysis of spinal cord function in the surgical fetal ovine model of MMC determined by sheep locomotor rating scale, after fetal surgery in conjunction with the application of human placental‐derived mesenchymal stem cells compared to fetal surgery alone 48–50,52,53 …”

“…In small animal models, injection of adult rat BM‐MSCs at E16 into the spinal cord of retinoic acid generated fetal rats with MMC, was associated with a reduction in spinal cord cell death assessed by TUNEL analysis at E20 (death cells; 4.8 ± 0.3% vs. 8.9 ± 0.6%, p < 0.05), 34 and an increase in the number of sensory neurons in the dorsal root ganglion (33.4 ± 1.9% vs. 25.3 ± 1.6%, p < 0.01) 35 . The intervention also improved corticospinal tract communication to the anterior tibialis muscle, demonstrated by a rise in motor evoked potentials (0.26 ± 0.02 mV vs. 0.18 ± 0.02 mV, p < 0.05) and a shorter latency period (22.8 ± 0.3 ms vs. 25.4 ± 0.8 ms, p < 0.05) 38 …”

“…Risk of bias of the included studies is shown in Figure 2 Li, 2014 (34) Adult Wistar rat Ma, 2015 (35) Adult Wistar rat Li, 2016 (36) Adult Wistar rat Wei, 2020a (37) Adult Wistar rat Wei, 2020b (38) Adult Wistar rat Dionigi, 2015a (39) Normal Lewis rat fetus Dionigi, 2015b (40) Normal Lewis rat fetus Feng, 2016 (41) Normal Lewis rat fetus Turner, 2013 (48) Lewis rat fetuses with NTDs…”

“…Twenty-one studies reported data on animal survival after in utero stem cell application, [30][31][32][36][37][38][39][41][42][43][44][45][46][47][48][49][50][51]54 13 (62%) of them presented data on survival rates in both control and treatment groups. Overall, there was no significant effect of stem cell application on animal survival rates (Table 2).…”