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

Xiaowei Wei,Hui Gu,Dan Liu,Weilin Wang,Vincent Chi Hang Lui,Peixin Yang,Yuzuo Bai,Wenting Luo,Wei Ma,Zhengwei Yuan

doi:10.1038/s41419-020-2734-3

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.

Highlights

Neural tube defects (NTDs) resulting from incomplete closure of the neural tube are the second most common congenital anomalies that currently have limited therapeutic benefits[1]
As deficiencies resulting from NTDs are found in the neural tissue, skin, muscle, and skeleton, Bone marrow-derived mesenchymal stem cell (BMSC) with multi-lineage differentiation potential could facilitate the repair of multiple tissue damages resulting from NTDs
To observe the potential effects of BMSCs on embryonic development, sterile phosphate buffered saline (PBS) or BMSCs were transamniotically delivered to E10 embryos (n = 12/group)

Summary

Introduction

Neural tube defects (NTDs) resulting from incomplete closure of the neural tube are the second most common congenital anomalies that currently have limited therapeutic benefits[1]. Foetoscopic, or mini-hysterotomy interventions have been performed to cover the neural tube lesion and prevent further neurodegeneration[3,4,5,6,7]. As deficiencies resulting from NTDs are found in the neural tissue, skin, muscle, and skeleton, BMSCs with multi-lineage differentiation potential could facilitate the repair of multiple tissue damages resulting from NTDs. our previous studies have shown that BMSCs directly injected into the fetal spinal column differentiated into nerve and muscle cells, secreted growth factors, and reduced neural apoptosis[20,21,22,23,24]. Prenatal cell transplantation surgery is typically performed during late pregnancy, when the pathology is already evident and the neural damage caused by NTDs may be irreversible[25]

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Results

Conclusion