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Intra-Amniotic Delivery of CRMP4 siRNA Improves Mesenchymal Stem Cell Therapy in a Rat Spina Bifida Model.

ABSTRACT: Neural tube defects (NTDs) result in prenatal mortality and lifelong morbidity, and available treatments have limited efficacy. We previously suggested that prenatal bone marrow-derived mesenchymal stem cell (BMSC) transplantation could treat neuron deficiency in NTD rats; however, BMSC-based therapy is limited by the low survival rate of BMSCs when used to treat severe NTDs. Herein, a new therapy using combined BMSC transplantation and small interfering RNA of collapsin response mediator protein 4 (CRMP4 siRNA), which was identified as a novel potential target for the NTD treatment, is proposed. The intra-amniotic CRMP4 siRNA, BMSC, and CRMP4 siRNA + BMSC injections repaired skin lesions, improved motor neural function, reduced neuronal apoptosis, and promoted expression of neural differentiation-related molecules and neurotrophic factors in the spinal cord of spina bifida rat fetuses. Therapeutic effects in the CRMP4 siRNA + BMSC injection group were superior to those of the CRMP4 siRNA only or BMSC only injection groups. CRMP4 siRNA + BMSC injection resulted in a 45.38% reduction in the skin lesion area and significantly shorter latency and higher amplitude of motor-evoked potentials (MEPs) in spina bifida fetuses. Our results suggest that intrauterine Ad-CRMP4 siRNA delivery with BMSCs is an innovative platform for developing fetal therapeutics to safely and efficaciously treat NTDs.

SUBMITTER: Wei X

PROVIDER: S-EPMC7177192 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Intra-Amniotic Delivery of CRMP4 siRNA Improves Mesenchymal Stem Cell Therapy in a Rat Spina Bifida Model.

Wei Xiaowei X Cao Songying S Ma Wei W Zhang Chaonan C Gu Hui H Liu Dan D Luo Wenting W Bai Yuzuo Y Wang Weilin W Yuan Zhengwei Z

Molecular therapy. Nucleic acids 20200319

Neural tube defects (NTDs) result in prenatal mortality and lifelong morbidity, and available treatments have limited efficacy. We previously suggested that prenatal bone marrow-derived mesenchymal stem cell (BMSC) transplantation could treat neuron deficiency in NTD rats; however, BMSC-based therapy is limited by the low survival rate of BMSCs when used to treat severe NTDs. Herein, a new therapy using combined BMSC transplantation and small interfering RNA of collapsin response mediator protei ...[more]

PMID: 32330869

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Project description:BackgroundSpina bifida aperta (SBA) is a relatively common clinical type of neural tube defect. Although prenatal fetal surgery has been proven to be an effective treatment for SBA, the recovery of neurological function remains unsatisfactory due to neuron deficiencies. Our previous results demonstrated that intra-amniotic transplanted bone marrow mesenchymal stem cells (BMSCs) could preserve neural function through lesion-specific engraftment and regeneration. To further optimize the role of BMSCs and improve the environment of defective spinal cords so as to make it more conducive to nerve repair, the intra-amniotic transplanted BMSCs were modified with brain-derived neurotrophic factor (BDNF-BMSCs), and the therapeutic potential of BDNF-BMSCs was verified in this study.MethodsBMSCs were modified by adenovirus encoding a green fluorescent protein and brain-derived neurotrophic factor (Ad-GFP-BDNF) in vitro and then transplanted into the amniotic cavity of rat fetuses with spina bifida aperta which were induced by all-trans-retinoic acid on embryonic day 15. Immunofluorescence, western blot and real-time quantitative PCR were used to detect the expression of different neuron markers and apoptosis-related genes in the defective spinal cords. Lesion areas of the rat fetuses with spina bifida aperta were measured on embryonic day 20. The microenvironment changes after intra-amniotic BDNF-BMSCs transplantation were investigated by a protein array with 90 cytokines.ResultsWe found that BDNF-BMSCs sustained the characteristic of directional migration, engrafted at the SBA lesion area, increased the expression of BDNF in the defective spinal cords, alleviated the apoptosis of spinal cord cells, differentiated into neurons and skin-like cells, reduced the area of skin lesions, and improved the amniotic fluid microenvironment. Moreover, the BDNF-modified BMSCs showed a better effect than pure BMSCs on the inhibition of apoptosis and promotion of neural differentiation.ConclusionThese findings collectively indicate that intra-amniotic transplanted BDNF-BMSCs have an advantage of promoting the recovery of defective neural tissue of SBA fetuses.

Dataset Information

Intra-Amniotic Delivery of CRMP4 siRNA Improves Mesenchymal Stem Cell Therapy in a Rat Spina Bifida Model.

Publications

Intra-Amniotic Delivery of CRMP4 siRNA Improves Mesenchymal Stem Cell Therapy in a Rat Spina Bifida Model.

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