Abstract
ObjectiveWe performed a systematic review to summarize the efficacy and safety of in utero stem cells application in preclinical models with myelomeningocele (MMC).MethodsThe study was registered with PROSPERO (CRD42019160399). We searched MEDLINE, Embase, Web of Science, Scopus and CENTRAL for publications articles on stem cell therapy in animal fetuses with MMC until May 2020. Publication quality was assessed by the SYRCLE's tool. Meta‐analyses were pooled if studies were done in the same animal model providing similar type of stem cell used and outcome measurements. Narrative synthesis was performed for studies that could not be pooled.ResultsNineteen and seven studies were included in narrative and quantitative syntheses, respectively. Most used mesenchymal stem cells (MSCs) and primarily involved ovine and rodent models. Both intra‐amniotic injection of allogeneic amniotic fluid (AF)‐MSCs in rat MMC model and the application of human placental (P)‐MSCs to the spinal cord during fetal surgery in MMC ovine model did not compromise fetal survival rates at term (rat model, relative risk [RR] 1.03, 95% CI 0.92–1.16; ovine model, RR 0.94, 95% CI 0.78–1.13). A single intra‐amniotic injection of allogeneic AF‐MSCs into rat MMC model was associated with a higher rate of complete defect coverage compared to saline injection (RR 16.35, 95% CI 3.27–81.79). The incorporation of human P‐MSCs as a therapeutic adjunct to fetal surgery in the ovine MMC model significantly improved sheep locomotor rating scale after birth (mean difference 5.18, 95% CI 3.36–6.99).ConclusionsStem cell application during prenatal period in preclinical animal models is safe and effective.
Highlights
Myelomeningocele (MMC) is a severe congenital malformation of the central nervous system resulting from an incomplete closure of the neural tube during the third–fourth week of embryonic development.1 The prevalence of MMC varies greatly among geographical areas ranging from 0.3 to 59.0 cases per 10,000 births.2 MMC is characterised by the protrusion of the neural placode and its meninges through a malformed vertebral arch and skin defect
The results showed that in the rat MMC model, when compared to saline injection, intra‐ amniotic injection of allogeneic amniotic fluid (AF)‐mesenchymal stem cells (MSC) at E17 of gestation, did not affect animal survival (RR 1.03, 95% CI 0.92–1.16; Figure 3A)
Safety data represented by animal survival rates were reassuring; both for intra‐amniotic injection of allogeneic amniotic fluid‐derived mesenchymal stem cells (AF‐MSCs) in the fetal rat model and the application of placental MSCs (P‐MSCs) to the spinal cord during fetal surgical MMC closure in the MMC lamb model did not compromise fetal survival at term
Summary
Myelomeningocele (MMC) is a severe congenital malformation of the central nervous system resulting from an incomplete closure of the neural tube during the third–fourth week of embryonic development. The prevalence of MMC varies greatly among geographical areas ranging from 0.3 to 59.0 cases per 10,000 births. MMC is characterised by the protrusion of the neural placode and its meninges through a malformed vertebral arch and skin defect. The condition can be detected by prenatal ultrasound scan as early as the first trimester; the majority of cases are diagnosed during the second trimester (anomaly) ultrasound scan.. The rationale for fetal repair before birth is that MMC is a ‘progressive’ condition with cumulative spinal cord functional loss throughout gestation, as demonstrated in clinical and animal studies.. Fetal surgery can arrest this deterioration and improve the patients' ability to walk unaided at 30‐month old.. The benefit of the surgery to bladder function is still under review.. The benefit of the surgery to bladder function is still under review.12–16 Despite these improvements, there are several shortcomings of fetal surgery. Fetal surgery is usually performed in the late second trimester, between 23 and 26 weeks' gestation, to reduce the risk of chorioamniotic membrane separation and associated preterm birth.. When considering patient outcomes at 30‐month‐old age; for example, approximately half of the fetal treated patients have to rely on clean intermittent catheterization to pass urine and more than half cannot walk without the aid of orthosis.
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