Kunpalin, Y;
Subramaniam, S;
Perin, S;
Gerli, MFM;
Bosteels, J;
Ourselin, S;
Deprest, J;
... David, AL; + view all
(2021)
Preclinical Stem Cell Therapy in Fetuses with Myelomeningocele: A Systematic Review and Meta-Analysis.
Obstetrical and Gynecological Survey
, 76
(7)
pp. 389-390.
10.1097/OGX.0000000000000946.
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Abstract
Myelomeningocele (MMC) is a congenital malformation of the central nervous system that is caused by an incomplete closure of the neural tube during the third to fourth week of embryonic development. An MMC can be seen in some cases by prenatal ultrasound in the first trimester, although most cases are diagnosed during the second trimester. The best treatment available is fetal surgery, but it has many shortcomings. This study reviews the potential for stem cell therapy in fetuses with an MMC through a systematic review of the application of stem cells in preclinical animal models. An electronic literature search was conducted in MEDLINE (PubMed), Embase, Web of Science, Scopus, and the Cochrane Library. Inclusion criteria were MMC animals receiving an in vivo, in utero application of stem cells including embryonic stem cells, pluripotent stem cells, neuronal stem cells, neural crest stem cells (NCSCs), and mesenchymal stem cells (MSCs). A meta-analysis was conducted if the studies were in line with the type of animal model, stem cells, and outcome measurements. After an electronic and manual search of the literature, 648 records were found (86 from MEDLINE [PubMed], 217 from Embase, 132 from Web of Science, 210 from Scopus, and 0 from the Cochrane Library). After duplicates were removed, 304 records were excluded due to them being irrelevant. As a result, 54 records were reviewed, and ultimately 26 studies were included in the qualitative synthesis. Most of the studies included had a high risk of bias owing to selective outcome reporting (23.1%, 6/26), inadequate description of sequence generation (19.2%, 5/26), allocation concealment (19.2%, 5/26), and caregiver/researcher blinding (19.2%, 5/26). The majority of studies used MSCs (77%, 20/26), and 46% (12/26) had xenogenic stem cell transplantation with human cells (embryonic stem cells, NCSCs, bone marrow, amniotic fluid, or placental). Most of the animal models were rat strains (58%, 15/26), and all had MMC created using retinoic acid (40 or 60 mg/kg). There were 7 studies (27%) in ovine, all of which used surgical creation of MMC between 75 and 112 days GA. In 3 studies (11%), chicken embryo was assessed with MMC created surgically. Last, 1 study (4%) was performed in the rabbit with MMC created surgically as well. A total of 21 studies included data on the survival of the animal after in utero stem cell application. Of these 21 studies, 13 (62%) reported data on survival rates in control and treatment groups. There was no significant effect of stem cell application on animal survival rates; after meta-analysis of 4 studies, in both the rat and sheep MMC model, stem cell application did not affect survival when comparing to controls (relative risk [RR], 1.03; 95% CI, 0.92–1.16; RR, 0.94; 95% CI, 0.78–1.13). In 13 studies, investigators also reported outcomes of the MMC repair and coverage of the lesion. Overall, stem cell injection was associated with a higher likelihood of complete defect coverage when comparing to control saline injection (RR, 16.35; 95% CI, 3.2–81.79). One study reported that intra-amniotic injection of human AF-MSCs in the retinoic acid–induced fetal rat MMC model at E17 reduced the area of the MMC defect compared with saline injection in human xenogenic transplantation. Eleven studies reported the effect of stem cells on spinal cord histopathology and/or function with using mostly MSCs. In addition, including P-MSCs at the time of MMC fetal closure increased motor function of the lower limbs when demonstrated that direct injection of mouse-derived NCSCs into the spinal cord of fetal lambs with a surgically created MMC at 125 days gestation did not improve motor function after birth (2/6%, 33% vs 2/8%, 25%, P = 0.73). Overall, this study found that there may be benefits of stem cell use on animal survival, MMC defect coverage, and spinal cord function. These finds are reassuring for human clinical translation, although more studies are needed to research neurological functional outcomes after birth and the reaction of the fetal immune system to allogeneic stem cell transplantation.
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