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
Highlights
Myelomeningocele (MMC) is a birth defect in which the vertebral column is open, and this condition is further complicated with spinal cord involvement during embryonic development
CXCL12 was mainly observed in human-derived cells (Fig. 3B). These results indicated that human amniotic fluid stem cell (hAFSC) accumulate on the surface of the defective spinal cord via CXCL12 signaling, which is mainly derived from hAFSCs that were engrafted on the lesion
Chemokines secreted by inflammatory cells such as monocytes and T lymphocytes play a crucial role in the migration of mesenchymal stromal cells (MSCs) to the site of inflammation [28]. hAFSCs were found to engraft onto the surface of the defective spinal cord, at least in part, via endogenous CXCL12/CXCR4 signaling after spinal cord damage induced by retinoic acid (RA) exposure
Summary
Myelomeningocele (MMC) is a birth defect in which the vertebral column is open, and this condition is further complicated with spinal cord involvement during embryonic development. The exposed neural tissue degenerates in utero, resulting in sensorimotor dysfunction of the lower extremities, skeletal deformities, bladder and rectal disorders, and Chiari II malformations. The pathogenesis of MMC remains to be determined, the failure of neural tube closure leads to exposure of the spinal cord to the intrauterine environment (first hit) [1]. If the neural tissue is not protected during pregnancy, the exposed spinal cord may be chemically and mechanically damaged and destroyed in utero until birth (second hit) [2]. Fetal MMC results in irreversible neurological impairments after birth. The options for prenatal treatment are still limited
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