In Utero Amniotic Fluid Stem Cell Therapy Protects Against Myelomeningocele via Spinal Cord Coverage and Hepatocyte Growth Factor Secretion

Abstract

Despite the poor prognosis associated with myelomeningocele (MMC), the options for prenatal treatments are still limited. Recently, fetal cellular therapy has become a new option for treating birth defects, although the therapeutic effects and mechanisms associated with such treatments remain unclear. The use of human amniotic fluid stem cells (hAFSCs) is ideal with respect to immunoreactivity and cell propagation. The prenatal diagnosis of MMC during early stages of pregnancy could allow for the ex vivo proliferation and modulation of autologous hAFSCs for use in utero stem cell therapy. Therefore, we investigated the therapeutic effects and mechanisms of hAFSCs‐based treatment for fetal MMC. hAFSCs were isolated as CD117‐positive cells from the amniotic fluid of 15‐ to 17‐week pregnant women who underwent amniocentesis for prenatal diagnosis and consented to this study. Rat dams were exposed to retinoic acid to induce fetal MMC and were subsequently injected with hAFSCs in each amniotic cavity. We measured the exposed area of the spinal cord and hepatocyte growth factor (HGF) levels at the lesion. The exposed spinal area of the hAFSC‐treated group was significantly smaller than that of the control group. Immunohistochemical analysis demonstrated a reduction in neuronal damage such as neurodegeneration and astrogliosis in the hAFSC‐treated group. Additionally, in lesions of the hAFSC‐treated group, HGF expression was upregulated and HGF‐positive hAFSCs were identified, suggesting that these cells migrated to the lesion and secreted HGF to suppress neuronal damage and induce neurogenesis. Therefore, in utero hAFSC therapy could become a novel strategy for fetal MMC. Stem Cells Translational Medicine 2019;8:1170–1179

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

“…4d ), and changes in TBX1 and ITGA1 protein levels were not significant. c-MET is the primary receptor of HGF, and HGF/c-MET signaling is involved in cell chemotactic migration and neuroprotection 17 , 37 . Thus, we determined HGF protein levels in both cultured BMSCs and developmental neural tubes.…”

“…These studies demonstrated that after transamniotic injection, afMSC and pMSCs robustly migrated into the fetal bone marrow, placenta, umbilical cord, and spinal cord lesion 30 , 31 , 35 – 37 . Moreover, transplanted MSCs induced varying degrees of coverage of the defects through a membrane that appeared to be rudimentary skin based on histological analysis 32 , 37 . In turn, the coverage attenuated the Chiari-II malformation in rat fetuses with spina bifida 33 .…”

“…As the embryo/fetus is surrounded by amniotic fluid, the defective neural tube is directly exposed to the injected BMSCs and, therefore, is a prime target for repair. Research has shown that transamniotic injection of stem cells, including neural stem cells (NSCs) and amniotic fluid-derived and placenta-derived MSCs (afMSC and pMSCs), is a promising treatment in animal models of congenital diseases 29 – 37 . These studies demonstrated that after transamniotic injection, afMSC and pMSCs robustly migrated into the fetal bone marrow, placenta, umbilical cord, and spinal cord lesion 30 , 31 , 35 – 37 .…”

“…Research has shown that transamniotic injection of stem cells, including neural stem cells (NSCs) and amniotic fluid-derived and placenta-derived MSCs (afMSC and pMSCs), is a promising treatment in animal models of congenital diseases 29 – 37 . These studies demonstrated that after transamniotic injection, afMSC and pMSCs robustly migrated into the fetal bone marrow, placenta, umbilical cord, and spinal cord lesion 30 , 31 , 35 – 37 . Moreover, transplanted MSCs induced varying degrees of coverage of the defects through a membrane that appeared to be rudimentary skin based on histological analysis 32 , 37 .…”

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“…Furthermore, AFSCs can also be used in prenatal therapeutic approaches through in utero transplantation (IUT); a strategy aimed at treating conditions such as congenital hematological diseases, spina bifida, and other neural tube defects. In our first Featured Article this month published in Stem Cells Translational Medicine , Abe et al establish the potential of human (h)AFSCs for the treatment of fetal myelomeningocele by demonstrating how administration via IUT reduced neural damage and promoted neural regeneration . In a Related Article published in Stem Cells , Loukogeorgakis et al demonstrated how IUT of in vitro‐expanded mouse AFSCs resulted in stable multilineage long‐term hematopoietic engraftment and, therefore, may represent an appealing approach to the treatment of inherited disorders of hematopoiesis .…”